DETAILED ACTION
Status of the Claims
Claims 1-2, 4-10, 12-13, 15-17, 19 and 20 are pending in the instant application. Claim 9 has been withdrawn based upon Restriction/Election. Claims 1-2, 4-8, 10, 12-13, 15-17, 19 and 20 are being examined on the merits in the instant application.
Request for Continued Examination
A request for continued examination (RCE) 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/10/2026 has been entered.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 05/14/2021, the filing date of PCT/JP2021/018485. Applicant's claim for a priority date of, 05/15/2020 and 02/16/2021, the filing date of documents JP2020-086250 and JP2021-022612, is acknowledged, however no English translation of the foreign priority documents have been provided such that the examiner can confirm written description (112(a)) support therein. Accordingly, foreign priority to these documents cannot be afforded at this time.
Information Disclosure Statement
The information disclosure statements submitted on 02/25/2026, 04/10/2026 and 06/02/2026, were filed before the mailing date of the first office action subsequent to the above-discussed RCE. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Objections
Claims 6, 13, and 15-16 each recite “wherein administration” in line 1 of each claim which lacks a proper article such as “the administration”. Appropriate clarification is required.
Claim Rejections - 35 USC § 112(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 5, 10, 11, 16 and 20 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 pre-AIA the applicant regards as the invention.
Claim 5 recites the limitation "the gold nanoparticle" in 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation "the gold nanoparticle" in 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 recites the limitation "the gold nanoparticle" in 2. There is insufficient antecedent basis for this limitation in the claim.
Claims 16 and 20 are rejected as inheriting the above-discussed indefinite issue with claim 5 and doing nothing to clarify the claim(s).
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 5-8, 10, 13, 16-17 and 20 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Dziawer et al.1 ("Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer" 2019; MDPI; Nanomaterials, Vol, 9, No. 632 - 9040632; pp. 1-15); as evidenced by Thorek et al. (“Comparative Analysis of Nanoparticle-Antibody Conjugations: Carbodiimide versus Click Chemistry,” 2009, DECKER; Molecular Imaging, Vol 8, No 4, pp. 221–229) and/or Bolley et al. (“Carbodiimide versus Click Chemistry for Nanoparticle Surface Functionalization: A Comparative Study for the Elaboration of Multimodal Superparamagnetic Nanoparticles Targeting αvβ3 Integrins,” 2013; ACS; Langmuir, Vol. 29, pp. 14639-14647).
Applicant Claims
Applicant claims a medicine for treating a proliferative disease, comprising gold nanoparticles having a particle size of 0.5 to 110 nanometers and, wherein the surface of the gold nanoparticles is bound to At-211, and wherein the surface of the gold nanoparticles is modified with a molecule that is not bound to a targeting molecule for a specific cell. (instant claim 1). Applicant further claims the molecule that is not bound to a targeting molecule for a specific cell is selected from polyethylene glycol […] (instant claim 2).
Applicant claims a gold nanoparticle which has a particle size of 0.5 to 110 nanometers, binds to At-211 and includes a surface modification with polyethylene glycol that is not bound to a targeting molecule for a specific cell (instant claim 8).
Disclosure of the Prior Art
Dziawer et al. discloses "Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab)." [emphasis added](Abstract, lines 1-6; see whole document)(instant claim 1, gold nanoparticles having a particle size of 0.5 to 110 nanometers and bound to At-211; instant claims 2, 5-7, 10-20; “local intratumoral injection” is within the scope of “injection into a lesion”; cancer is breast cancer). The examiner notes that claims 6-7, and 13, 15-17, 19 and 20 are regarded as intended use claims where a recitation of the intended use of the claimed invention 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. In the instant case the compositions are directed at treating breast cancer, and therefore suitable for “treating a proliferative disease”.
Dziawer et al. discloses that: “Using the discovery of a strong bond formation between the gold surface and the astatine atoms, we have successfully synthesized a stable astatinated-trastuzumab bioconjugate. 211At-AuNP-trastuzumab was specifically bound, internalized, and distributed to a peri-nuclear location within HER-positive cancer cells. Trastuzumab-modified 211At-AuNPs exhibited higher cytotoxicity than non-targeted 211At-AuNPs. These results are encouraging for further development of 211At-AuNP-trastuzumab as an innovative-radiation nanomedicine for local therapy of HER2-positive cancers due to high tumor retention, internalization, and specific tumor cell binding.” (p. 11, §4-conclusions, lines 1-7)(instant claim 1, gold nanoparticles […] bound to At-211; instant claims 2 & 8, “with polyethylene glycol that is not bound to a targeting molecule for a specific cell.”).
Dziawer et al. discloses that: “The synthesized AuNP-S-PEG-trastuzumab bioconjugates were labeled with 131I and 211At by adsorption radionuclides on the gold surface. The radioactivity of 211At ranged from 100 to 150 Mbq upon arrival at the laboratory.” (p. 8, 2nd paragraph, lines 1-3). And that: “The labeling yields of AuNPs and AuNP-S-trastuzumab with 211At are shown in Table 2. The AuNPs labeling efficiency with 211At was >99% and was significantly higher than that of another commonly used prosthetic group, N-succinimidyl-3-(tri-n-butylstannyl) benzoate, where the labeling efficiency ranged from 60 to 70%.” (p. 8, 3rd paragraph, lines 1-4). And further: “As presented in Table 2, 211At absorption on the gold surface in AuNP-S-PEG-trastuzumab conjugates was nearly the same as for naked AuNPs, indicating that the attachment of PEG-trastuzumab molecules to the AuNP surface changes the adsorption properties of AuNPs minimally. This is expected because, according to our calculations, half of the surface gold nanoparticles is not occupied by trastuzumab molecules and 211At can be attached there.” (Id., lines 5-10)(instant claim 1, “wherein in the surface modification comprises a molecule that is not bound to a targeting molecule for a specific cell.” particularly 211At).
MPEP §2131.01 makes clear that “Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: […] (C) Show that a characteristic not disclosed in the reference is inherent.” In the instant case the examiner relies on Thorek et al. and/or Bolley et al. to show a characteristic not disclosed in Dziawer et al. is inherent.
Particularly, Dziawer et al. discloses that: “AuNPs of 5 nm diameter (0.1 _g in 1 mL) were first coated with the PEG linker comprising the disulfide bridge with carboxyl groups at each end (HOOC-PEG-SS-PEG-COOH) in molar ratios of 100:1 of PEG to gold nanoparticles. After 24 h, a mixture of 2-fold excess molar amounts of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHS) was added to the solution of pegylated gold nanoparticles to form an amide bond with the amine group of lysine. After an additional 4 h (without purification of the excess of EDC/NHS reagents), trastuzumab (100 μg per mL of modified gold nanoparticle solution) was attached to the AuNP-PEG-NHS. The bioconjugate solution was alkalinized to pH 9.0 and the sample was stirred for 24 h at ambient temperature in an inert gas atmosphere. After this time, the product was purified in dialysis cassettes and labeled with astatine-211 according to the previous procedure.” (pp. 4-5, §2.5).
Thorek et al. teaches that: “One example of a common approach used for conjugation of antibodies to NPs involves carbodiimide cross linking. The zero-length cross-linker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) reacts with carboxylated NPs in the presence of sulfo-N-hydroxylfosuccinimide (sulfo-NHS) to form amine-reactive sulfo-NHS esters. Subsequent addition of antibodies results in coupling between the NPs and primary amines on the antibody via a stable amide bond. Unfortunately, the reaction is nonideal as it is highly inefficient and thus requires a high excess of antibody. Typically, only about 1 to 20% of the antibody used during the conjugation procedure will be coupled to the NPs.” (p. 221, col. 2, 2nd paragraph). And that: “Recently, the emergence and adoption of click chemistry have had a large impact on drug discovery and materials synthesis owing to the ability to achieve conjugation efficiencies nearing 100%.” (p. 221, col. 2, 3rd paragraph).
Bolley et al. teaches that “In addition to their chemoselective natures, click reactions were shown to be far more efficient than the carbodiimide coupling.” (abstract, lines 12-14). And that: “we evaluated the efficiency of conjugation using carbodiimide coupling and two click reactions (CuAAC and thiol-yne) (Scheme 1).” (p. 14639, last two lines through p. 14640, line and Scheme 1). Bolley et al. teaches “Coupling Efficiency Study by Carbodiimide and Click Chemistry.” (p. 14643, cols. 1-2), and concludes that: “Thiol-yne reaction clearly appears as far more efficient than carbodiimide chemistry even with microwave assistance, leading to a 50% coupling yield.” (p. 14643, col. 2, last paragraph, lines 1-3).
Given that Thorek et al. and Bolley et al. each teach that carbodiimide chemical cross linking is not very efficient at chemical coupling, it is more likely than not, that not each and every PEG molecule in the compositions disclosed by Dziawer et al. are substituted with Trastuzumab targeting antibody. The instant claims require “wherein the surface of the gold nanoparticles is modified with a molecule that is not bound to a targeting molecule for a specific cell.” which includes any un-substituted PEG molecules which is clearly suggested by Thorek et al. and Bolley et al. as Carbodiimide Chemistry was known as not being very efficient. Thus, the examiner takes the position that the compositions disclosed by Dziawer et al. inherently include unsubstituted PEG molecules on the surface of their Trastuzumab-Modified Gold Nanoparticles Labeled with 211At.
Response to Arguments:
Applicant's arguments filed 04/10/2026 have been fully considered but they are not persuasive.
Applicant argues that: “Applicant has amended claim 1 to explicitly distinguish between (i) 211At bound to the surface of the gold nanoparticle and (ii) a separate surface-modifying molecule associated with the nanoparticle surface. As amended, the claim language makes clear that the surface-modifying molecule is distinct from the 211At radionuclide.” And that: “This amendment forecloses any interpretation under which 211 At itself could be considered the claimed surface modifying molecule. Dziawer discloses gold nanoparticles labeled with 211At and functionalized with trastuzumab; however, it does not disclose or suggest the amended claim structure requiring both (1) 211At bound to the nanoparticle surface and (2) a separate surface-modifying molecule as now expressly recited.” (p. 6, last two paragraphs through p. 7, line 2).
The examiner agrees with Applicant’s position, however, the examiner finds and cites evidence that not every PEG molecule would have been substituted with Trastuzumab antibody where any unsubstituted PEG would constitute “a molecule that is not bound to a targeting molecule for a specific cell.” per Applicants own disclosure (instant Specification, p. 5, paragraphs 3-4; [0012]-[0013], as published). Therefore the rejection under 35 U.S.C. 102(a)(1) is maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-8, 10, 12-13, 15-17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Dziawer et al. ("Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer" 2019; MDPI; Nanomaterials, Vol, 9, No. 632 - 9040632; pp. 1-15) in view of Bilewicz et al.2 (“Gold nanoparticle bioconjugates labelled with 211At for targeted alpha therapy,” 2017; RSC Advances, Vol. 7, pp. 41024-41032); Cai et al.3 (“Applications of gold nanoparticles in cancer nanotechnology,” 2008; Nanotechnology, Science and Applications, Vol. 1, pp. 17-32); BASILION (US 2014/0044791; published February, 2014); and Sykes et al. (“Investigating the Impact of Nanoparticle Size on Active and Passive Tumor Targeting Efficiency,” 2014; ACS; ACSNano, Vol. 8, No. 6, pp. 5696-5706); and as evidenced by Torek et al. and/or Bolley et al. (cited above).
Applicants Claims
Applicant claims a medicine for treating a proliferative disease, comprising gold nanoparticles having a particle size of 0.5 to 110 nanometers and, wherein the surface of the gold nanoparticles is bound to At-211, and wherein the surface of the gold nanoparticles is modified with a molecule that is not bound to a targeting molecule for a specific cell. (instant claim 1). Applicant further claims the molecule that is not bound to a targeting molecule for a specific cell is selected from polyethylene glycol […] (instant claim 2), having an average molecular weight of 2,000 Da to 20,000 Da (instant claim 4). Applicant further claims the particle size of the gold nanoparticles
Determination of the scope
and content of the prior art (MPEP 2141.01)
Dziawer et al. teaches "Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). " (Abstract, lines 1-6; see whole document)(instant claim 1, gold nanoparticles having a particle size of 0.5 to 110 nanometers and bound to At-211; instant claims 2, 5-7, 10-20; “local intratumoral injection” is within the scope of “injection into a lesion”; cancer is breast cancer). The examiner notes that claims 6-7, and 13-20 are regarded as intended use claims where a recitation of the intended use of the claimed invention 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.
Dziawer et al. teaches that: “Using the discovery of a strong bond formation between the gold surface and the astatine atoms, we have successfully synthesized a stable astatinated-trastuzumab bioconjugate. 211At-AuNP-trastuzumab was specifically bound, internalized, and distributed to a peri-nuclear location within HER-positive cancer cells. Trastuzumab-modified 211At-AuNPs exhibited higher cytotoxicity than non-targeted 211At-AuNPs. These results are encouraging for further development of 211At-AuNP-trastuzumab as an innovative-radiation nanomedicine for local therapy of HER2-positive cancers due to high tumor retention, internalization, and specific tumor cell binding.” (p. 11, §4-conclusions, lines 1-7)(instant claim 1, gold nanoparticles […] bound to At-211; instant claims 2 & 8, “with polyethylene glycol that is not bound to a targeting molecule for a specific cell.”).
The examiner notes the showing of inherency that the carbodiimide chemistry used by Dziawer et al. does not result in 100% of the PEG molecules to be substituted with the antibody Trastuzumab, as discussed above, is incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Dziawer et al. is that Dziawer et al. does not expressly teach an average molecular weight of the polyethylene glycol (PEG) is 2,000 to 20,000 (instant claim 4).
Bilewicz et al. teaches gold nanoparticle bioconjugates labelled with 211At for targeted alpha therapy (title, see whole document), which includes “Gold nanoparticles (AuNPs) with 5 and 15 nm diameter were modified with Substance P(5-11), a peptide fragment which targets the NK1 receptors on the glioma cells, through the HS–PEG–NHS linker.” (abstract, lines 9-11). And more specifically teaches that: “The biologically active fragment of Substance P(5-11), named shortly as SP(5-11), was conjugated to the gold nanoparticles to obtain bioconjugates targeting NK1 receptors on glioma cells. […] The PEG linker (2000 kDa) comprising the disulfide bridge and the N-hydroxysuccinimide esters (NHS) at the ends was used for synthesis of the SP(5-11)–PEG–SS–PEG–SP(5-11) conjugate. The process of nanoparticles biofunctionalization is summarized in Fig. 1.” [emphasis added](p. 41026, col. 2, 2nd paragraph, Figure 1)(instant claim 4).
Additionally, Cai et al. teaches applications of gold nanoparticles in cancer nanotechnology (title, see whole document). And teaches that: “The stability of gold nanoparticle bioconjugates in high ionic strength media has been characterized as a function of the nanoparticle size, PEG length, and the monolayer composition (Liu et al 2007a). It was found that nanoparticle stability increased with increasing PEG length, decreasing nanoparticle diameter, and increasing PEG mole fraction. Importantly, gold nanoparticles modified with PEG chains of molecular weight (MW) 5000 were internalized as efficiently as analogous conjugates with PEG chains of MW 900. Based on this finding, gold nanoparticles functionalized with optimal-sized PEG chains (at least of MW 5000 to efficiently bypass the RES), with circulation half-life of at least a few hours, may be the most efficacious for cancer therapy.” (paragraph bridging pp. 26-27).
BASILION teaches targeted nanoparticle conjugates (title, see whole document), particularly “A composition for treating a disorder in a subject includes a polyethylene glycolylated (PEGylated) nanoparticle, at least one hydrophobic therapeutic agent coupled to the surface of the nanoparticle; and at least one targeting moiety coupled to polyethylene glycol of the nanoparticle for targeting the composition to a cell associated with disorder.” (abstract. BASILION teaches that “
The application further relates to a method for treating brain cancer. The method includes administering systemically to a subject with brain cancer a therapeutically effective amount of a composition comprising PEGylated gold nanoparticles […].” ([0009]).
BASILION teaches that: “The targeted nanoparticle can be coated with a plurality of polymer chains and at least some of the polymer chains are coupled to at least one cellular targeting moiety. In some embodiments, a first end of a polymer chain can be coupled and/or bound to a surface of the nanoparticle and a second opposite end that extends from the surface of the nanoparticle is coupled and/or bound to a targeting moiety. The targeting moiety can allow the targeted nanoparticle conjugates to transiently interact, couple, and/or bind to the targeted cell or tissue.” ([0050]). And that: “In one embodiment, the polymer coating can include polyethylene glycol (PEG). The PEG can be a heterobifunctional PEG, such as COOH-PEG-SH (MW3000), and/or a monofunctional PEG, such as PEG-SH (MW 5000), that can readily bind to the nanoparticle to coat the nanoparticle.” ([0055]).
BASILION teaches that: “The targeting moiety can be coupled to the polymer chain prior to and/ or after coupling of the polymer chain to the nanoparticle. For example, FIG. 1 is a schematic illustration of targeted nanoparticles that are prepared: (A) by coupling the targeting moiety to the polymer chain after the polymer chain is coupled to the nanoparticle; and (B) by coupling of the targeting moiety to the polymer chain prior to coupling the polymer chain to the nanoparticle.” ([0075]). The examiner notes that Figure 1 clearly depicts conjugated PEG (arrow attached) and unconjugated PEG (no arrow attached). BASILION teaches that: “The PEG ligand on the Au NPs creates excellent water miscibility, biocompatibility, and long circulation in the blood of the conjugate system. PEG also prevents protein agglomeration on the NP surface. More importantly, the PEG layer provides bifunctionality to conjugate EGF peptides, which are internalizing and norunitogenic, to recognize EGFRs on the glioma cancer cell surface.” ([0129]-[0130]). And that: “PEGylated Au NPs were synthesized and modified with a mixture of 20% heterobifunctional COOH-PEG-SH (MW 3000) and 80% monofunctional mPEG-SH (MW 5000).” ([0131]). The examiner notes that Figure 8 clearly depicts mPEG-SH (MW 5000) that is bound to gold nanoparticle core and remains unconjugated to a targeting moiety (arrow attached - COOH-PEG-SH (MW 3000)). Therefore, it would have been prima facie obvious to include “a surface modification with polyethylene glycol that is not bound to a targeting molecule for a specific cell.” (instant claim 8) because “The PEG ligand on the Au NPs creates excellent water miscibility, biocompatibility, and long circulation in the blood of the conjugate system. PEG also prevents protein agglomeration on the NP surface.”
Sykes et al. teaches passive tumor targeting (title), particularly that: “Passively targeted particles have been shown to nonspecifically enter the tumor based on their size and shape. Inert surface coatings such as poly(ethylene glycol) (PEG) enhance the passive tumor uptake of nanoparticles by preventing serum protein binding and the subsequent plasma clearance by macrophages. This lengthened circulation lifetime is hypothesized to enhance tumor delivery by maintaining a high concentration of nanoparticles in the bloodstream for tumor extravasation. Alternatively, active targeting attempts to enhance the retention and specificity of passive nanoparticle delivery systems by coating their surfaces with antibodies, peptides, and aptamers that recognize and bind to blood vessels, overexpressed cancer cell receptors, and other components of the tumor microenvironment (Figure 1).” (p. 5696, 2nd paragraph; Figure 1). And that: “Figure 1. Illustration of the proposed mechanism for passive (A) and active (B) gold nanoparticle tumor targeting exploited in this study. […] passive particles do not directly associate with cancer cells, while active particles are capable of endocytosis through surface-bound targeting ligands (green) […] (D) Model nanoparticle designs used in this study.” (p. 5697, Figure 1, caption).
Sykes et al. teaches that: “AuNPs with core diameters of 15, 30, 60, and 100nmwere prepared for passive and active targeting by surface modification with either PEG or PEG in conjunction to OPSS-modified transferrin (Figure 2)” (p. 5697, col. 2, lines 5-9). And that: “Transferrin and fluorescent PEG quantities on particle surfaces were empirically chosen to ensure optimal fluorescence. AuNPs were also tuned by mPEG blocking to ensure particle zeta-potentials were within the neutral range so as to minimize charge-specific differences in cell and tumor uptake that have been reported previously for positively and negatively charged particles. Fluorescent PEG on active and passive formulations was held constant, while transferrin density was maintained between 0.02 and 0.04 ligands/nm2 for all active AuNPs to ensure that differences in tumor targeting were related to targeting modality and size over differences in ligand density. Table 1 provides a summary of the functionalized AuNPs used in this study.” (p. 5697, col. 2, line 17 through p. 5698, col. 1, 1st paragraph).
Sykes et al. teaches that: “The targeting property for active and passive schemes was also confirmed in vitro by cell binding analysis using inductively coupled plasma atomic emission spectroscopy. Cellular uptake of actively targeted particles was consistently higher than passive formulations but could be competitively reversed by the addition of free transferrin to cell media (Figure S4). Larger particles were also found to achieve stronger affinity to cancer cells than their smaller counterparts (Figure S5 and Table 1). The confirmed specificity of actively targeted AuNPs for transferrin receptor in the presence of serum indicated that the OPSS-PEG spacer prevented loss of targeting function by distancing transferrin from the adsorbed serum protein brush layer.” (p. 5698, 2nd paragraph). Sykes et al. concludes that: “In this study, we systematically compared the effect of nanoparticle size on active and passive tumor targeting using eight spherical AuNP formulations in tumors. Our results have helped to explain some of the countervailing observations reported by other groups by establishing the impact of AuNP size on tumor accumulation kinetics for active and passive targeting strategies. We identified that transferrin-decorated AuNPs within the 60 nm range were capable of faster and higher tumor delivery than passive formulations while PEG-coated designs infiltrated deeper into tumors, but at the expense of slower and lower total tumor delivery.” (p. 5703, §Conclusion).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a gold nanoparticle bound to At-211, as suggested by Dziawer et al. and Bilewicz et al., and to utilize an effective length of PEG for local administration (e.g. intratumoral injection), as suggested by Dziawer et al. and Bilewicz et al., and Cai et al. in order to produce the most effective cancer therapy using the same, and to included both targeted PEG ligands and unsubstituted PEG ligands for excellent water miscibility, biocompatibility, long circulation in the blood of the conjugate system, and to prevent protein agglomeration, as suggested by BASILION and Sykes et al., or alternatively to active targeting using the antibody, passive targeting using only PEG or PEG with a fluorescent label, as suggested by Sykes et al. teaching passive tumor targeting using PEG coated gold nanoparticles. Additionally, the examiner argues that there are several embodiments that render the instant limitation - “wherein the surface of the gold nanoparticles is modified with a molecule that is not bound to a targeting molecule for a specific cell.” - obvious including (1) active targeting using trastuzumab-modified gold nanoparticles of Dziawer et al. where not all of the PEG molecules are substituted with the antibody; (2) modification of Dziawer et al. composition to include fluorescent label on the PEG, as taught by Sykes et al.; (3) modification of Dziawer et al. composition to passive targeting with only PEG, as suggested by Sykes et al.; or (4) a combination of (1) to (3), by, e.g., active targeting with trastuzumab on some PEG molecules, some unsubstituted PEG molecules and some PEG molecules substituted with fluorescent molecules (see, e.g., Figure 1(D) of Sykes et al.).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill to include an appropriate PEG chain length in the compositions of Dziawer et al. and/or Bilewicz et al., and to modify the PEG with a fluorescent molecule such as suggested by Sykes et al., or passive targeting with only PEG. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 04/10/2026 have been fully considered but they are not persuasive.
Applicant argues that: “As clarified by the accompanying amendments, the claims are directed to gold nanoparticle compositions in which a radionuclide, such as At-211, is associated with the nanoparticle, and a surface-modifying molecule is present that is distinct from the radionuclide and is not bound to a targeting molecule for a specific cell. The claimed invention is therefore directed to a non-targeted surface-modified nanoparticle configuration that is structurally and functionally distinct from targeted nanoparticle systems.” And that “The amendments further clarify that radionuclide binding does not itself constitute the claimed surface modification, and that the surface-modifying molecule is not merely a linker, such as PEG, for a targeting ligand. These limitations define a composition that intentionally excludes targeting functionality.” (p. 8, item (i)).
In response the examiner argues that the claims do not exclude active targeting such as trastuzumab bonded to the surface of the gold through PEG or any other linker, as the claims only require that “the gold nanoparticles is modified with a molecule that is not bound to a targeting molecule for a specific cell.” which could be an unsubstituted PEG molecule, a PEG molecule substituted with some other molecule such as a fluorescent label. Therefore, the instant claims are not limited to “a composition that intentionally excludes targeting functionality.” as suggested by Applicant.
Applicant argues that: “None of these references teaches or suggests removing targeting ligands from a targeted nanoparticle system or designing a system in which the surface-modifying molecule is intentionally not bound to a targeting moiety.” (p. 9, 2nd paragraph).
In response, as discussed above, there are many embodiments that include a surface-modifying PEG molecule that is not bound to a targeting moiety. Additionally, the examiner argues that the compositions of Dziawer et al., intentionally or not, more likely than not, include unsubstituted PEG molecules (i.e. PEG molecules that is not bound to a targeting molecule for a specific cell.
Applicant further argues that there is no motivation to combine the cited references, particularly that: “The cited art consistently teaches toward enhancing targeting, not eliminating it, and the proposed modification would run counter to the fundamental purpose of the references. The Examiner's reliance on Basilion is especially misplaced. Although Basilion may describe PEG species that are not conjugated to targeting ligands, those materials are still disclosed as part of an overall targeted nanoparticle architecture. Basilion does not suggest removing targeting functionality or provide any technical reason that would have led a skilled artisan to do so.” (p. 9, 4th paragraph).
In response the examiner argues that it would have been prima facie obvious that targeting antibodies such as trastuzumab cost money and therefore it would be prima facie obvious to exclude any targeting moiety as in “Passive Targeting” or to minimize the number of anti-body substituted PEG molecules to only the number needed to achieve the “Active Targeting” result, such as including intentionally including unsubstituted PEG molecules with antibody-targeting-PEG molecules on the surface of the gold nanoparticles. Additionally, it would have been prima facie obvious to include an imaging agent such as a fluorescent marker attached to some PEG molecules, as discussed above. Additionally, each of the cited references teach gold nanoparticles in cancer therapy such that they are all considered to be in the same field of invention, and are therefore considered analogous art to the claimed invention (MPEP §2141.01(a)(I)).
Applicant argues that: “The claim amendments materially clarify that the surface-modifying molecule is distinct from the radionuclide and is not bound to a targeting molecule. These limitations distinguish the claims from the cited references, which are directed exclusively to targeted systems.” (p. 9, last paragraph). And that: “Even if combined, the cited references would not teach or suggest the claimed nontargeted surface-modified At-211-bound gold nanoparticle compositions. Accordingly, the rejection fails to establish a prima facie case of obviousness.” (p. 10, 1st paragraph).
In response the examiner respectfully disagrees with Applicants interpretation of the claims and the prior art to which the invention pertains, which interpretation parses “targeted systems” versus “nontargeted systems”. Rather one of ordinary skill in the art would have considered the PEG coating as “Passive Targeting” and the antibody targeting as “Active Targeting”. And the instantly rejected claim clearly encompass both, for example, Au(-PEG-targeting-antibody) with PEG-unsubstituted molecules in the same Au particles, or numerous other species of “a molecule that is not bound to a targeting molecule for a specific cell.” such as a PEG-fluorescent-label and/or PEG-drug-conjugate. The examiner notes that claims must be given their broadest reasonable interpretation during examination (MPEP §2111), and the claims include the transitional phrase “comprising” (claim 1, line 1) – MPEP §2111.03 “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” Therefore, the claims are being interpreted as not excluding an active targeting such as the Trastuzumab-PEG-Au nanoparticles of Dziawer et al. so long as “the surface of the gold nanoparticles is modified with a molecule that in not bound to a targeting molecule for a specific cell.” such as an unsubstituted PEG molecule, a PEG-fluorescent label, a PEG-drug molecule bound to the gold nanoparticles, as discussed above.
Conclusion
Claims 1-2, 4-8, 10, 12-13, 15-17, 19 and 20 are pending and have been examined on the merits. Claims 5, 10, 11, 16 and 20 are rejected under 35 U.S.C. 112(b); claims 1-2, 5-8, 10, 13, 16-17 and 20 are rejected under 35 U.S.C. 102(a)(1); and claims 1-2, 4-8, 10, 12-13, 15-17, 19 and 20 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 Of record as cited by Applicants on IDS dated 01/24/2023, non-patent literature document citation no. 4.
2 Of record as cited by Applicants on IDS dated 01/24/2023, non-patent literature document citation no. 3.
3 Of record as cited by Applicants on IDS dated 01/24/2023, non-patent literature document citation no. 1.
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