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
Claims 1-5 are rejected.
Claims 6-16 are withdrawn.
No claims are allowed.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. KR10-2024-0038101, filed on 25-Nov-2024.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-5 in the reply filed on 08-Jul-2026 is acknowledged.
Claim Objections
Claim 1 objected to because of the following informalities:
Independent claims should start with an “A”. Appropriate correction is required.
Claim 3, 8, and 13 objected to because of the following informalities: The drawing for Chemical Formula 1 has annotations that are unclear due to poor image quality. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
1. Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Na et al. (α-Tocopherol-loaded reactive oxygen species-scavenging ferrocene nanocapsules with high antioxidant efficacy for wound healing, Published: 22-Jan-2021) (hereinafter Na).
With regards to claim 1, Na discloses “a highly versatile ferrocene functional polymer was synthesized by one-pot radical polymerization, for formulating self-assembled ferrocene nanocapsules (FNCs), which could function as smart carriers of an antioxidant, α-tocopherol (TP)” (Page 1, Abstract) and “FNCs were prepared by the self-assembly of an amphiphilic FFP composed of hydrophilic PEGMA, the MA segment, and the hydrophobic FMMA segment” (i.e. a ferrocene particle comprising a polymer containing ferrocene) (Page 3, 2.2. Synthesis of ferrocene functional polymer (FFP) and ferrocene nanocapsules (FNCs)).
Lastly, Na discloses the preparation of the oxygen scavenging drug loaded into the ferrocene particle: “0.5, 1, 1.5, and 2.5 mg of TP were mixed with 5 mg of FFP in 1 mL of THF separately and then reacted with each other under rotary shaking at room temperature (25 ◦C) for 2 h. Second, TP@FNCs were prepared as described previously in Section 2.2 Finally, unloaded TP was purified by ultrafiltration using Amicon Ultra-15 centrifugal filters (MWCO 100 kDa) at 2,000 rpm for 5 min” (Page 3, 2.5. Preparation of TP-loaded FNCs (TP@FNCs) and antioxidant activity by DPPH assays) and demonstrates the resultant scavenging activity: “the antioxidant activity of TP@FNCs was compared with that of bare FNCs and TP (Fig. 9). We used the DPPH radical scavenging assay to estimate the antioxidant capacity of the samples… Consequently, the percentage of scavenged DPPH radicals can be monitored by ultraviolet–visible measurements at 517 nm. Bare TP, which is insoluble in aqueous solution, was less effective at scavenging DPPH radicals than the positive control, AA. Interestingly, FNCs by themselves showed increasing antioxidant activity, from approximately 10% to 40%, with increasing concentrations. Because of the radical scavenging ability of Fc, owing to its unique electron-abundant structure and redox activity, the use of FNCs containing a Fc moiety is an efficient strategy to increase antioxidant activity” (Page 7, 3.7. DPPH antioxidant capacity of TP@FNCs).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
1. Claim(s) 1-2 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Na et al. (α-Tocopherol-loaded reactive oxygen species-scavenging ferrocene nanocapsules with high antioxidant efficacy for wound healing, Published: 22-Jan-2021) (hereinafter Na) as applied to claim 1 above, and further in view of Woo et al. (Functional ferrocene polymer multilayer coatings for implantable medical devices: Biocompatible, antifouling, and ROS-sensitive controlled release of therapeutic drugs, Published: 28-Feb-2021) (hereinafter Woo).
With regard to claim 2, Na teaches the reactive oxygen species (ROS) responsive drug delivery particles composition comprising of a ferrocene particle and a reactive oxygen species-scavenging drug loaded in the ferrocene particle as applied to claim 1 discussed supra.
Na further teaches that the FFP was synthesized with “FMMA (2 mmol), MA (10 mmol), PEGMA (0.5 mmol), and radical initiator AIBN (0.12 mmol) were mixed and dissolved in 10 mL of anhydrous THF” (Page 3, 2.2. Synthesis of ferrocene functional polymer (FFP) and ferrocene nanocapsules (FNCs)) (i.e. ferrocenylmethyl methacrylate, polyethylene glycol methacrylate, and methacrylic acid) and the ratio between FMMA, PEGMA, and MA is 2:0.5:10 = 1:0.25:5.
However, Na does not teach that the ratio between FMMA, PEGMA, and MA is between 1:1:1 to 1:5:10. For this reason, Woo is added.
Woo teaches a FMMA-r-PEGMA-r-MA polymer composition “C series Fc polymer: poly(FMMA-r-PEGMA-r-MA)… FMMA (0.4 mmol, 0.114 g), PEGMA (3 mmol, 1.425 g), and MA (3 mmol, 0.258 g) for the Fc polymer named Poly C1” and further teaching “the initial feed ratios of the C series of the functional Fc polymers (FMMA:PEGMA:MA) were 0.4:3:3 for Poly C1, 0.4:3:5 for Poly C2, and 0.4:3:7 for Poly C3” (Page 243, 2.2. Synthesis of functional Fc polymers). This results in a FMMA, PEGMA, and MA ratio of 0.4:3:3 = 1:7.5:7.5 for Poly C1, 0.4:3:5 = 1:7.5:12.5 for Poly C2, and 0.4:3:7 = 1:7.5:17.5 for Poly C3.
Woo further teaches that “[t]he amounts of the hydrophobic Fc, hydrophilic PEG, and COOH (or NH 2 ) residues in the functional Fc polymers could be controlled by simply changing the initial molar ratios of FMMA, PEGMA, and MA (or DMAEMA) to obtain optimized C or N series Fc polymers” (Page 245, 3.1. Synthesis and characterization of functional Fc polymers), and “The main requisite for multilayer film deposition via electrostatic interaction is the availability of charged species with sufficient charge density…our group synthesized a series of polymers with positive and negative charges by simply adjusting the ratios of the polymer composition without relying on pH dependence or salt addition, and through this, we attempted to obtain an optimized polymer for LbL film formation by controlling the ionic strength in the same pH environment” (Page 246, 3.2. Optimization of LbL films through a combination of Fc polymers), demonstrating that the FMMA, PEGMA, and MA ratio is a result-effective variable to be tuned to influence the polymer’s hydrophilic versus hydrophobic balance and charge density.
Neither Na nor Woo teaches a molar ratio falling within the instant claimed range of 1:1:1 to 1:5:10. However, a person having ordinary skill in the art would have had specific reasons to select a ratio within this range when combining the teachings of Na and Woo:
Woo’s disclosed ratios of 1:7.5:7.5 to 1:7.5:17.5 reflects compositions optimized for a different purpose, such that sufficient PEGMA and MA content is present to achieve necessary charge density and biocompatibility for LbL film formation. Woo demonstrates that Poly C1 “provided the thinnest film (15 ± 2 nm)” and Poly C2 provided “[t]he thickest film (130 ± 17 nm) (Page 246, Optimization of LbL films through a combination of Fc polymers). Concluding that “Poly N1 and Poly C1, which are polymers with relatively weak ionic strength, have weak electrostatic attraction compared to the other polymers” (Page 246, Optimization of LbL films through a combination of Fc polymers) and the bonding of the “film is not firm and only a small amount accumulates so that the stacked film is thin. In addition, this weak bond is likely to degrade during the washing process of the film. Furthermore, high charge density… is also believed to cause inefficient film formation… Optimal LbL multilayer film formation conditions occur with (Poly N2/C2) n when using various combinations of C and N series Fc polymers. Furthermore, the functional Fc polymers were optimized for multilayer thin film formation by simply controlling the monomer composition ratio of the polymer without requiring pH changes or salt addition” (Page 247, Optimization of LbL films through a combination of Fc polymers). Thus, this establishes that the FMMA:PEGMA:MA ratio is understood by a skilled artisan to have a functional optimum lying in between low and high PEGMA/MA content, rather than the extremes.
A person having ordinary skill in the art seeking to combine Na’s ROS scavenging ferrocene particle with Woo’s teaching that increased PEGMA/MA content improves biocompatibility and particle charge density would have been motivated to increase Na’s minimal PEGMA content above 0.25, since Woo teaches that greater PEGMA/MA is beneficial for those properties. The instant claimed range of 1:1:1 to 1:5:10 represents the intermediate compromise between competing design pressures disclosed in Na and Woo, and a skilled artisan would have arrived at the ratio within this range through routine experimentation with a reasonable expectation of success.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Na’s ferrocene polymers comprising FMMA, PEGMA, and MA in a molar ratio of 1:0.25:5 loaded with the reactive oxygen species scavenging drug α-tocopherol, by adjusting the FMMA, PEGMA, and MA molar ratio to fall within the instant claimed range of 1:1:1 to 1:5:10 as evidenced by Woo’s teachings of varying FMMA, PEGMA, and MA molar ratio to optimize for polymer performance and physical characteristics, and would have amounted to routine experimentation with a reasonable expectation of success.
With regard to claim 5, the particle of claim 1 is structurally indistinguishable from the particle of the instant claims, it would be expected that the prior art particle and the instantly claimed particle have the same inherent properties. The limitation of instant claim 5 is an inherent property of the prior art particle. For the foregoing reasons, Claims 1-2, and 5 are rendered obvious by the teachings of the prior art.
2. Claim(s) 1 and 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Na et al. (α-Tocopherol-loaded reactive oxygen species-scavenging ferrocene nanocapsules with high antioxidant efficacy for wound healing, Published: 22-Jan-2021) (hereinafter Na) as applied to claim 1 above, and further in view of Jones et al. (Thermoresponsive Copolymers of Methacrylic Acid and Poly(ethylene glycol) Methyl Ether Methacrylate, Published: 2005) (hereinafter Jones).
With regards to claim 3, Na discloses the structure of Chemical Formula 1 in the NMR spectra of Fig 2a:
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606
622
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Greyscale
As shown above, Na teaches three pendent groups attached to a carbon backbone.
However, Na does not teach that the PEGMA derived side chain as depicted in instant Chemical Formula 1, which requires a differently capped end group than Na’s disclosed methoxy terminated PEGMA, Na does not teach the specific homolog of the instant claim. For this reason, Jones is added.
Jones teaches copolymers of methacrylic acid and poly(ethylene glycol) methyl ether methacrylate (PEGMA) (Page 6095, Abstract), and establishes that the hydrophobic content of PEGMA is a known and predictable variable that controls the copolymer’s physical behavior: “the cloud point decreases with decreasing PEG chain length, because of the presence of a larger number of hydrophobic methyl and methacrylate groups” (Page 6095, Abstract). Thus, Jones confirms that adjusting the hydrophilic and hydrophobic balance of PEGMA side-chain, including modifications to the terminal capping group or carbon length is a known and routinely optimized parameter in a MA/PEGMA copolymer system to affect copolymer physical behaviors.
A person of ordinary skill in the art would have been motivated to modify the terminal capping group or carbon length of Na’s PEGMA derived side chain by increasing the carbon length to arrive at the structure of Chemical Formula 1 to produce a ferrocene particle with a tuned hydrophilic/hydrophobic balance in the PEGMA branch, allowing predictable adjustment of the resultant copolymer solution’s behavior. Jones established that in this MA/PEGMA copolymer system, the hydrophobic content of the PEG side chain is a known and predictable variable for tuning the copolymer’s physical properties. Further, under MPEP 2144.09 (II), “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.” Because the homolog of the instant claims differs from Na’s disclosed structure by only the addition of an extra CH2 and because Jones confirms that capping group and side chain length are routinely manipulated and predictable design parameters, a skilled artisan would have had a reasonable expectation of success in selecting the homolog reflected in Chemical Formula 1 of the instant claim to further tune the copolymer’s hydrophilic and hydrophobic balance.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the PEGMA derived side chain of Na’s ferrocene polymer by increasing its carbon chain at the terminal capping group to arrive at the structure of Chemical Formula 1.
3. Claim(s) 1 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Na et al. (α-Tocopherol-loaded reactive oxygen species-scavenging ferrocene nanocapsules with high antioxidant efficacy for wound healing, Published: 22-Jan-2021) (hereinafter Na) as applied to claim 1 above, and further in view of Ebau et al. (Centella asiatica extract-SiO2 nanocomposite: More than a drug-delivery system for skin protection from oxidative damage, Published 24-Oct-2022) (hereinafter Ebau).
Na teaches the reactive oxygen species-responsive drug delivery particles composition comprising of a ferrocene particle and a reactive oxygen species-scavenging drug loaded in the ferrocene particle as applied to claim 1 discussed supra.
Na does not teach the reactive oxygen species-scavenging drug comprises a Centella asiatica component. For this reason, Ebau is added.
Ebau discloses a Centella asiatica extract with SiO2 nanocomposite:“[d]ifferent amounts of C. asiatica glycolic extract (1.0, 3.0, 5.0, and 10.0 wt %) and fumed silica were used to prepare the nanocomposites…which showed high in-vitro ability to scavenge 2,2-diphenyl-1-picrylhydrazyl and to protect human keratinocytes” (Page 300, Abstract) and “[a]long with the advantages described before, the incorporation of natural products in the silica-based delivery system can protect the natural extract from physical and chemical degradation, therefore enhancing its bio-availability and pharmacological activity” (Page 301, Introduction).
A person having ordinary skill in the art would have been motivated to combine the teachings of Na and Ebau to arrive at a ferrocene particle loaded with ROS scavenging drug comprising a Centella asiatica component to produce a ROS responsive ferrocene drug delivery particle with an art recognized natural antioxidant such as Centella asiatica component in place of α-tocopherol suitable for scavenging ROS and protection from oxidative damage. Na teaches “Fc-containing polymer nanocapsules are potential carriers for effective ROS-mediated drug delivery (Mu et al., 2019; Zhang et al., 2018). These systems have displayed outstanding release performance in environments containing ROS. Moreover, when Fc is connected with other organic antioxidant molecules, the ferrocenyl compounds obtained are polar molecules with higher antioxidant capacities than Fc alone (Liu, 2011). Therefore, antioxidants with a ferrocenyl structure might be candidate drugs for wound treatment” (Page 2, Introduction). Ebau established that the Centella asiatica extract is a ROS scavenging and antioxidant agent, confirmed by the DPPH radical scavenging assay (Page 6, 3.2 Radical scavenging activity of samples by DPPH test). Since Na’s platform is agnostic as to the specific loaded antioxidant, and the Centella asiatica extract is a known and effective antioxidant, a skilled artisan would have had a reasonable expectation of success in loading Ebau’s Centella asiatica component in place of α-tocopherol in Na’s ferrocene particle.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Na’s ferrocene polymer particle, loaded with α-tocopherol, by substituting the loaded drug with the Centella asiatica of Ebau since Ebau establishes the Centella asiatica extract is a known ROS scavenging and antioxidant agent suitable for the purpose of protecting tissue from oxidative damage. This represents the simple substitution of one known ROS scavenging active ingredient for another in a known drug delivery platform to obtain predictable results. For the foregoing reasons, Claims 1 and 4 are rendered obvious by the teachings of the prior art.
Conclusion
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/W.L./Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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