DETAILED ACTION
This office action is in response to the Applicant’s filing dated November 3rd, 2025.
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 .
Status of Claims
Claims 1-18 are pending in the instant application. Acknowledgement is made of Applicant’s remarks and amendments filed on November 3rd, 2025. Acknowledgement is made of the Applicant’s amendment of claims 1-2 and 16. Claims 17-18 remain withdrawn, as they are drawn to a non-elected group. Claims 1-16 read on the elected species, PPCBA-PEI-Arg, and will be examined herein.
Priority
This application is a 371 of PCT/KR2020/015459 filed on November 6th, 2020; and claims benefit of foreign priority of KR10-2019-0141988 filed on November 7th, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
New Objections and/or Rejections
Necessitated by Claim Amendment
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 1-7, 9-14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yun et al (US 2018/0243430 A1), cited in a previous Office Action; in view of Wonganan et al (Viruses, (2010), 2, 468-502); as evidenced by Abdallah et al. (Human Gene Therapy, (1996), 7(16), 1947-1954), cited for evidentiary purposes only in a previous Office Action; as evidenced by Yun et al (Biomaterials, (2015), Volume 41, 53-68), cited for evidentiary purposes only in a previous Office Action.
Regarding Claim 1, Yun teaches mPEG-piperazine-N, N’-cystaminebisacrylamide; PPCBA (page 7, paragraph [0112]), shown below:
PNG
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120
605
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Wherein an arginine-conjugated PEI polyethyleneimine is bound to the terminal end of CBA (page 10, paragraph [0145]).
Yun states, “The disclosure of the cited papers and patent literatures are incorporated herein by reference in their entirety, and thus the level of the technological field including the present application and the scope of the present application are more fully described” (page 1, paragraph [0006]). Yun does not explicitly disclose the molecular weight of PEG used for the synthesis of PPCBA, the value of “n” or PEI being branched, but does directly cite the below papers regarding PEI used and compound preparation (page 2, paragraph [00226]; page 7, paragraph [0112]).
MPEP 2131.01 states:
When the claimed composition or machine is disclosed identically by the reference, an additional reference may be relied on to show that the primary reference has an “enabled disclosure.” In re Samour, 571 F.2d 559, 197 USPQ 1 (CCPA 1978) and In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
Abdallah et al. (Human Gene Therapy. (1996), 7(16), 1947-1954), cited for evidentiary purposes only, teaches that PEI is a branched organic polymer (page 1948, left column, fourth paragraph) and can be used to introduce genes into the mature mammalian brain (page 1953, right column, third paragraph).
Yun et al. (Biomaterials, (2015) Volume 41, 53-68), cited for evidentiary purposes only, teaches that 2.0 kDa mPEG-acrylate was used for synthesis of PPCBA (page 54, right column, second paragraph). Yun further teaches the value of “n” is 6 stating, “The ratios of -OCH3 of PEG and -S-S-CH2-CH2-NH-CO- of alkyl chain were calculated by integrals of the two peaks, and value was identified as 1:6. These results suggest that the polymer is close to the expected composition, in a good agreement with MALDI-TOF data” (page 55, right column, second to last paragraph).
Yun does not teach the use of a PEG with a molecular weight of 5 kDa - 10 kDa.
Wonganan teaches that increasing PEG molecular weight increases circulation time and alters biodistribution (page 483, first paragraph and Table 4). Wonganan teaches that the protrusion of long chain PEG molecules likely minimizes cellular interactions and extending circulation half-life (page 483, last paragraph). Wonganan further teaches that conjugation with 5.0 kDa PEG “does not compromise transduction efficiency”, indicating conjugation with this molecular weight preserves the virus’ ability to deliver the genetic material and achieve functional gene expression (page 483, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art to utilize the 2.0 kDa PEG taught by Yun as a starting point for optimizing the size of PEG utilized to escape immune reaction since Yun teaches 2.0 kDa PEG used for that purpose in synthesis of PPCBA and Wonganan teaches that using a PEG with a larger molecular weight is useful for increasing circulation time and improving biodistribution and are thus result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum molecular weight PEG (i.e. 5-10 kDa) would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the polymers and the criticality of the claimed range, the determination of the optimum or workable PEG molecular weight given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding Claims 2 and 4, Yun and Wonganan render obvious the polymer compound as described in the above rejection. Yun further teaches PPCBA-PEI-Arg, as described in the above rejection, is complexed (claim 4) with a therapeutic agent, specifically a viral DNA of a tumor-selective oncolytic adenovirus RdB/Interleukin-12 (IL-12)/GMCSF, expressing IL-12 and GMCSF as adenovirus DNA (page 10, paragraph [0145]).
Regarding Claims 3, 5-7 and 9-10, Yun and Wonganan render obvious the drug delivery system as described in the above rejection. It is respectfully pointed out that a recitation of an intended use of the claimed invention, as recited in instant claim 3, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Thus, the intended use recited in instant claim 3, namely that the drug delivery system is used for intranasal administration, is not afforded patentable weight. See Pitney Bowes Inc. v. Hewlett-Packard Co., 182 F.2d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 378, 42 USPQ2d 1550, 1554 and MPEP 2112.02(II).
Yun further teaches the drug delivery system of PPCBA-PEI-Arg described above wherein the complexed therapeutic agent is a gene delivery system (addressing claim 5). Specifically, the gene delivery system is a viral DNA vector (addressing claim 6) of a recombinant tumor-selective oncolytic adenovirus (addressing claim 7); RdB/Interleukin-12 (IL-12)/GMCSF, expressing IL-12 (addressing claim 9) and GMCSF as adenovirus DNA (pages 10-11, paragraphs [0145-0149]).
Yun further teaches that the therapeutic agent can be an anti-cancer agent (claim 10), selected from cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan. nitrosourea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifon, transplatinum, 5-fluorouracil, vincristin, vinblastin, and methotrexate (page 5, paragraph [0068]).
Regarding Claims 11-14, Yun and Wonganan render obvious the drug delivery system as described in the above rejection. It is respectfully pointed out that a recitation of an intended use of the claimed invention, as recited in instant claims 11-14, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Thus, the intended use recited in instant claims 11-14, namely that the composition is used for prevention or treatment of any one of a central nervous system disease, neurodegenerative disease or a brain tumor, is not afforded patentable weight. See Pitney Bowes Inc. v. Hewlett-Packard Co., 182 F.2d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 378, 42 USPQ2d 1550, 1554 and MPEP 2112.02(II).
Regarding Claim 16, Yun and Wonganan render obvious the drug delivery system as described in the above rejection. It is respectfully pointed out that a recitation of an intended use of the claimed invention, as recited in instant claim 16, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Thus, the intended use recited in instant claim 16, namely that the composition is used for intranasal administration, is not afforded patentable weight. See Pitney Bowes Inc. v. Hewlett-Packard Co., 182 F.2d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 378, 42 USPQ2d 1550, 1554 and MPEP 2112.02(II).
Yun further teaches the PPCBA-PEI-Arg drug delivery system as described in the above rejection. Yun further teaches that the drug delivery system can be used as a pharmaceutical composition with the anti-cancer drugs listed in the above rejection (page 5, paragraph [0068]). Wonganan renders obvious the use of larger molecular weight PEG (i.e. 5 kDa) in the conjugation.
Taken together, all this would result in a compound, drug delivery system and composition of instant claims 1-7, 9-14 and 16 with a reasonable expectation of success.
Applicant argues:
The use of 5 kDa – 10 kDa PEG led to an unexpected result of superior antitumor effect and biodistribution when compared to the 2 kDa PEG of Yun.
Applicant has pointed to Experimental Example 4 of the specification (pages 25-26, paragraphs [000117-000120]) for support that 5 kDa PEG had a superior antitumor effect when compared to 2 kDa PEG as illustrated by Fig. 4; and that 5 kDa PEG showed improved biodistribution when compared to 2 kDa PEG as illustrated by the more pronounced fluorescence intensity present in brain tissue in Fig. 5. This ultimately results in a superior brain delivery effect.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Although it is noted there is a superior brain delivery effect when using a PEG of higher molecular weight (i.e. 5 kDa – 10 kDa), as discussed in the above rejection, the result is not unexpected in view of Wonganan who teaches that using a PEG with an increased molecular weight minimizes cellular interactions and extends circulation half-life (page 483, last paragraph), and alters biodistribution. Wonganan further teaches that conjugation with 5.0 kDa PEG “does not compromise transduction efficiency”, indicating conjugation with this molecular weight preserves the virus’ ability to deliver the genetic material and achieve functional gene expression (page 483, last paragraph). Applicant’s asserted improvements in antitumor efficacy and brain biodistribution are the same predictable results expected from prolonged systemic circulation and altered biodistribution associated with increased PEG molecular weight as taught by Wonganan.
Claims 8 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Yun et al (US 2018/0243430 A1), cited in a previous Office Action; in view of Wonganan et al (Viruses, (2010), 2, 468-502); further in view of Zhou et al (Biomaterials science, (2017), 5(3), 494–501), cited in a previous Office Action; further in view of Wang et al (Laser Physics Letters, (2016), 13(9), 1-8), cited in a previous Office Action for evidentiary purposes only.
Regarding claims 8 and 15, Yun and Wonganan render obvious the drug delivery system as described in the above rejection.
Yun and Wonganan do not teach a delivery system wherein a photosensitizer selected from the group consisting of porphyrins, chlorins, bacteriochlorins, phthalcyanines, naphthalocyanines, and 5-aminolevulinic acid esters; or wherein a diagnostic agent is a near-infrared fluorescent material, a radio pharmaceutical, or a contrast.
Zhou teaches a polymeric gene delivery system comprising chlorin e6 (Ce6), a widely used photosensitizing agent, conjugated to a PEG-PEI copolymer to form PEG-PEI-Ce6 nanoparticles. Zhou teaches, “Free Ce6 has very low solubility in the aqueous phase which limits its practical use as a pharmaceutical agent. In view of this, a water-soluble Ce6 was prepared by conjugating it with a cationic PEG-PEI copolymer. Owing to the existence of numerous nitrogen atoms and PEG arms, PEG-PEI-Ce6 shows polyelectrolyte characteristics with good solubility in water. Benefiting from its good solubility in water, the Singlet Oxygen Generation (SOG, an important parameter for PDT) level of PEG-PEI-Ce6 is enhanced greatly compared with free Ce6” (page 497, right column).
Furthermore, Zhou teaches the use PEG-PEI-Ce6 nanoparticles in Photo-Dynamic Therapy (PDT) stating, “PEG-PEI-Ce6 displays very low cytotoxicity in human oral squamous cell carcinoma (KB) cells treated with PEG-PEI-Ce6 without laser irradiation. The viabilities for KB cells are more than 90%, even at a high concentration. After 670nm laser irradiation, the viabilities for KB cells gradually decrease with the increase of PEG-PEI-Ce6 concentrations, demonstrating the high efficacy of PEG-PEI-Ce6 mediated PDT (Fig. 5A). As silencing of Wnt-1 expression can inhibit cell survival, a decrease of cell viabilities in accordance with PEG-PEI-Ce6 concentration is also observed for cells treated with PEG-PEI-Ce6/siWnt-1 for gene therapy alone (Fig. 5B). Importantly, compared with single PDT or gene therapy, the combination of PDT and gene therapy shows a much higher cell killing effect (Fig. 5B), indicating the synergistic anticancer effect of gene therapy combined with PDT” (page 498, right column, last paragraph; page 499, Figure 5).
Chlorin e6 is a well-known near-infrared (NIR) fluorescent material. Wang, cited for evidentiary purposes only, teaches that covalently incorporated Chlorin e6 molecules (conjugated to PEI) retained their functional properties for near-infrared (NIR) fluorescence imaging and PDT (page 1, Abstract).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
It would have been prima facie obvious to a person of ordinary skill in the art to incorporate the chlorin e6 photosensitizer taught by Zhou into the PPCBA-PEI-Arg delivery system rendered obvious by Yun and Wonganan in order to enable the added benefit of photodynamic therapy and near-infrared fluorescent imaging, while maintaining gene delivery functionality. Ce6 is a well-known chlorin class photosensitizer and near-infrared fluorescent compound, as evidenced by Wang. Zhou teaches that Ce6 retains its photodynamic activity and exhibits improved aqueous solubility when conjugated to PEI-based polymers, a platform structurally similar to Yun’s PPCBA-PEI-Arg system. Given the chemical and structural similarity between Yun and Zhou’s delivery systems, and the well-known NIR behavior of Ce6, its incorporation into Yun’s delivery system represents a predictable combination of known elements yielding expected results, enabling photodynamic therapy and NIR functionality.
Taken together, all this would result in the drug delivery system of instant claims 8 and 15 with a reasonable expectation of success.
Conclusion
Claims 1-16 are rejected.
No claim is allowed.
THIS ACTION IS MADE FINAL. 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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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691