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 .
Priority
The instant application is the national stage entry of PCT/US21/48081 filed 27 August 2021. Acknowledgement is made of the Applicant’s claim of domestic priority to provisional application 63/046,611 filed 30 June 2020.
Examiner’s Note
Applicant's amendments and arguments filed 24 August 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 24 August 2026, it is noted that claims 1 and 16 have been amended. Support can be found in the specification at [0096]. No new matter or claims have been added.
Status of the Claims
Claims 1-6, 8-16, and 18-20 are pending.
Claims 1-6, 8-16, and 18-20 are rejected.
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 1-4, 6, 8, 10-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Drescher et al. (Nanoscale, 2017, 9, 11647-11656) in view of Vo-Dinh et al. (WO 2016/209936) in view of Mortenson et al. (US 2013/0259903) as evidenced by Zhao et al. (ACS Nano 2017, 11, 8103−8113).
Drescher teaches exposing fibroblast cells with tetrachloroauric acid in the presence of a culture medium and buffer (pg 11649, ¶3). The HAuCl4 forms into small gold clusters inside the cells, which can then have beneficial properties for theranostic applications (pg 11649, ¶5). Formation in situ allows for obtaining gold nanostructures in direct proximity to their target (pg 11647, ¶4).
Drescher does not teach treating a patient with gold clusters nor does it teach administering radiation to the patient’s body. Drescher does not teach a polyethylene glycol.
Vo-Dinh teaches reducing tetrachloroauric acid with ascorbic acid and sodium citrate to obtain gold nanostars (as a chloroaurate salt) (pg 15, lns 5-12). Next, mice with sarcoma on the right leg were injected with the PEG-coated gold nanostars and observations were made as to the efficacy of the gold locating in the tumor (pg 16, lns 1-6; Fig 4a-4b). Injection can occur directly at the primary cancer site (pg 13, lns 4-7). Moreover, the subject, although exemplified in a mouse, can be human (pg 6, lns 5-8). In a separate example, mice were implanted with cancer cells in their flanks and then intravenously provided gold nanostars followed by photothermal laser therapy (i.e. radiation) (pg 16, lns 8-17; pg 3, lns 17-20). The radiation step can comprise multiple sources including X-ray radiation (pg 3, lns 17-20). After irradiation, the mice were injected with anti-PD-L1 antibody chemotherapy (pg 16, lns 18-19). In a broader teaching, the cancers that can be treated by the gold nanostars include breast, bladder, colon, rectal, endometrial, kidney, leukemia, lung, melanoma, pancreatic, prostate, and thyroid (pg 2, lns 14-17). The gold nanostars can further be included in a kit for treating cancer along with an immune checkpoint modulator (pg 2, ln 29-pg 3, ln 4).
Mortenson teaches that processing a gold nanoparticle with a PEG coating is known [0056]. Doing so provides a benefit by increasing the half-life of the nanoparticles and improving the blood-brain barrier transport thereof [0056].
Zhao evidences that pancreatic cancer is characterized by desmoplasia (abstract).
It would have been prima facie obvious to take the in-situ formation method of gold nanostructures of Drescher, from buffered chloroauric acid, which teaches the benefit of obtaining gold nanostructures in direct proximity to their target, and modify it to treat an in vivo subject as taught by Vo-Dinh. Vo-Dinh teaches a method of treating cancer in a human subject comprising administering a PEG-coated gold nanostar (as a chloroaurate salt) followed immediately by irradiation with X-rays and then further treating with additional chemotherapy such as checkpoint inhibitor therapy. The cancer can be selected from any cancer taught by Vo-Dinh including pancreatic cancer, which is known to be characterized by desmoplasia. However, by forming the nanstar in vivo, as taught by Drescher, the nanostructures will form in direct proximity to their target. Vo-Dinh teaches a PEG coating of the nanostar however does not explain its purpose. Mortenson explains that the coating is desirable due to its ability to increase blood half-life of the nanoparticles, thus providing a motivation to include the PEG-coating.
Moveover, it would have been obvious to provide the gold nanostars and checkpoint inhibitor in a kit, as taught by Vo-Dinh. Although Vo-Dinh does not teach further including instructions, the reference itself can function as instructions on how to use the kit. Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (see MPEP 2112.01 (III)). The resulting method and kit render obvious instant claims 1-4, 6, 8, 10-16, and 18-20.
Claims 1-6, 8-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Drescher et al. (Nanoscale, 2017, 9, 11647-11656) in view of Vo-Dinh et al. (WO 2016/209936) in view of Mortenson et al. (US 2013/0259903) in view of Krishnan et al. (WO 2011/127061) as evidenced by Zhao et al. (ACS Nano 2017, 11, 8103−8113).
Drescher, Vo-Dinh, and Mortenson, as applied supra, are herein applied in their entirety for the teachings of a method of treating cancer by irradiating gold particles formed in situ.
Drescher does not teach wherein the cancer is head-and-neck cancer.
Krishnan teaches a method for using high-Z particles to enhance ionizing radiation to target tumor cells (abstract). Examples of a high-Z particle includes gold nanoparticles [0053]. The gold can be used in a concentration of greater than 7 mg/g of tumor [0032]. Regarding the cancer targeted, the method of Krishnan can target pancreatic, brain, lung, breast, and head-and-neck cancer, among others [0077].
It would have been prima facie obvious to carry out a method of treating cancer in a human subject comprising administering a PEG-coated gold nanostar (as a chloroaurate salt) that can be formed in situ, as taught by Drescher and Vo-Dinh, followed immediately by irradiation with X-rays and then further treating with additional chemotherapy such as checkpoint inhibitor therapy. The cancer can be selected from any cancer taught by Vo-Dinh including pancreatic cancer, which is known to be characterized by desmoplasia. Krishnan teaches that gold nanoparticles can be used in 7 mg/g of tumor to treat head-and-neck cancer as well as pancreatic, thus it would have been obvious to use said concentration and cancer target in the invention of Vo-Dinh.
Moveover, it would have been obvious to provide the gold nanostars and checkpoint inhibitor in a kit, as taught by Vo-Dinh. Although Vo-Dinh does not teach further including instructions, the reference itself can function as instructions on how to use the kit. Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (see MPEP 2112.01 (III)). The resulting method and kit render obvious instant claims 1-6, 8-16, and 18-20.
Response to Arguments
Applicant's arguments filed 24 August 2026 have been fully considered but they are not persuasive. The Applicant argues, on pages 6-7 of their remarks, that none of the prior art suggest that GNCs are formed in situ in a patient. Moreover, the Applicant argues that Drescher teaches formation of gold structures in the cancer cell as being medium dependent. The Applicant points out that under serum-containing conditions, gold species may be formed in solution before cellular uptake rather than inside the cell.
In response, while Drescher does teach that gold nanostructure formation can occur in the medium extracellularly, it also teaches that some nanostructures do form intracellularly. The prior art thus suggests that gold nanostructure formation can occur either outside or inside the cell with a portion of formation occurring inside the cell, as required in the instant claims. As such, there would have been a reasonable expectation of success of carrying out the method of Drescher as modified by the secondary references in a method of forming gold nanostructures in situ in cancer cells.
The Applicant argues, on page 7 of their remarks, that one of skill in the art would not have had a reasonable expectation that administration of a gold solution to a patient would result in GNCs forming in situ in an amount sufficient for radiation dose enhancement.
In response, as explained above, the art teaches that at least a portion of the gold nanostructures are formed within the cell. Regarding the sufficient amount, the instant claims do not define how much gold nanostructure in the cell constitutes a sufficient amount for radiation dose enhancement beyond the range provided in instant claim 9 of from 0.0001-10 mg/g. Krishnan is applied for its teaching that gold nanoparticles can be used in 7 mg/g of tumor to treat head-and-neck cancer as well as pancreatic cancer. Thus, there is motivation to modify the prior art method in order to achieve a dose of at least 7 mg/g, which addresses the instant claims.
The Applicant argues, on page 8 of their remarks, that the art does not teach if the gold precursor would survive circulation, avoid extracellular conversion, enter cancer cells, and then biomaterialize intracellularly in a sufficient amount to enhance radiation.
In response, based on Drescher the skilled artisan would know how to form gold nanostructures in situ and, based on Krishnan, would be motivated to modify the method so that the dose achieved was at least 7 mg/g. The Applicant has provided no evidence that the prior art method would not work to provide in situ-formed nanostructures in a required dose.
The Applicant argues, on page 8, that Mortenson does not disclose use of PEG with respect to a precursor-based ionic gold composition.
In response, Mortenson teaches that coating a gold nanoparticle with PEG provides a benefit by increasing the half-life of the nanoparticles and improving the blood-brain barrier transport thereof. While Mortenson does not teach this as an in situ process, it would have been obvious to the skilled artisan to modify the method of Drescher so that the PEG coating would be applied in situ.
The Applicant argues, on page 9-11 of their remarks, that the Applicant has surprisingly found that administration of preformed nanoparticles does not produce the same level of radiosensitization as GNCs formed in situ. The Applicant points to Fig. 3B and Example 2.
In response, the compounds of Fig 3B show that GNC formation from gold ions had much higher radiosensitization than prefabricated GNCs. The prior art provides motivation for including a PEG coating and teaches that it enhances blood half-life of the nanoparticles. Moreover, the prior art teaches forming gold nanostructures in situ in the targeted cell. Thus, the art renders obvious the treatment that Fig. 3b is encompassing. That being said, the examples in Fig 3B are not commensurate in scope with the claimed invention. The claims are broad to multiple options for gold atoms and only teach albumin as the coating. There is a fundamental requirement that must be met before secondary considerations can carry the day. "For objective evidence of secondary considerations to be accorded substantial weight, its proponent must establish a nexus between the evidence and the merits of the claimed invention." Wyers v. Master Lock Co., 616 F.3d 1231, 1246 [95 USPQ2d 1525] (Fed. Cir. 2010) (quotation omitted). Where the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention. Takai Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1369 [97 USPQ2d 1673] (Fed. Cir. 2011) ("If commercial success is due to an element in the prior art, no nexus exists."); Ormco Corp., 463 F.3d at 1312 ("[l]f the feature that creates the commercial success was known in the prior art, the success is not pertinent."); In re Woodruff, 919 F.2d 1575, 1578 [16 USPQ2d 1934] (Fed. Cir. 1990). Therefore, the data in the specification does not amount to unexpected results that are sufficient in overcoming the pending obviousness rejection.
The Applicant further points to prior art reference Schwartz-Duval to corroborate that PEG can enhance the behavior and effectiveness of the ionic-gold precursor system.
In response, Schwartz-Duval does not appear to be prior art nor is it incorporated into the present disclosure. The Applicant is advised to submit any additional supporting data in the form of a Declaration under 37 CFR 1.132 to be considered.
The Applicant argues, on page 12 of their remarks, that the Examiner has applied impermissible hindsight analysis.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The Applicant argues, on pages 13-14 of their remarks, that Krishnan does not address the medium-dependent scavenging and transformation problems of Drescher.
In response, Krishnan is applied for its teaching that gold nanoparticles can be used in 7 mg/g of tumor to treat head-and-neck cancer as well as pancreatic. As such, Krishnan is applied for dosage and for equivalency of the cancer targets. In addition, secondary references Vo-Dinh and Mortenson provide motivation for coating with PEG. The art teaches that doing so provides a benefit by increasing the half-life of the nanoparticles and improving the blood-brain barrier transport thereof, thus providing a motivation to include the PEG-coating on the in situ-formed particles.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW S ROSENTHAL whose telephone number is (571)272-6276. The examiner can normally be reached M-F 8-5pm EST.
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/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613
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