DETAILED ACTION
Applicant's amendment and response filed on 11/17/25, previously non-entered, has been entered. Claims 2-6, 8, 18, and 21 are now canceled. Claims 1, 7, 9-17, 19-20, and 22 are pending in this application. Of these, claims 13-17, and 19-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/1/23. Claims 1, 7, 9-17, and 22 are currently under examination. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 112
The rejection of claims 1, 4, 6-12 and 22 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn over canceled claims 4, 6, and 8, and further withdrawn over the pending claims in view of applicant’s amendments to the claims.
The rejection of claims 1, 4, 6-12 and 22 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, is withdrawn over canceled claims 4, 6, and 8, and maintained over claims 1, 7, 9-12, and 22. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the claims now recite subcutaneous administration of two doses of a composition comprising PEGylated gold nanoparticles where the PEGylated nanoparticles comprise PEG chains with a molecular weight of 20 kDa, and where the composition comprises PEGylated nanoparticle in an amount effective to induce production of anti-PEG IgG antibodies to a target concentration of between about 44ng/ml and about 65 ng/ml in the blood. According to applicant, these conditions generated at least 40 ng/ml of anti-PEG IgG antibodies in the blood as shown in Figures 2 and 3B and that it would not require undue experimentation to find the dose necessary to increase the concentration of the anti-PEG IgG antibodies to the claimed range.
In response, it is first noted that as written, the method does not actually identify the final concentration of anti-PEG IgG antibodies in the blood of the animal that has received two doses of the PEGylated gold nanoparticles. Instead, claim 1 recites that the composition comprising the PEGylated gold nanoparticles comprises PEGylated gold nanoparticles in an amount effective to induce production of anti-PEG IgG antibodies to a concentration between about 44ng/ml and about 65 ng/ml in the blood. As written, each dose of the composition has this functional property. However, as discussed in detail in the prior office action, the working examples disclose the administration of a single PEGylated nanoparticle, PEGylated gold nanoparticles (PEG-AuNP), to a mouse via subcutaneous injection, where the PEGylated gold nanoparticles are administered at a dose of 9.48 mol of PEG per kg. The results show that one dose of PEG-AuNP failed to generate at last 44 ng/ml of anti-PEG IgG antibodies in the blood regardless of whether the PEG present in the PEG-AuNP was 2K, 5K, 10K or 20K -see Figure 1. As discussed above, as worded, the claims recite that the composition of each dose is capable of generating this concentration range of anti-PEG IgG in the blood. Figure 1 shows that the capacity of one dose of PEG-AuNP 20K is clearly incapable of producing about 44 ng/ml of anti-PEG IgG antibodies in the blood. The working examples further show that while a booster subcutaneous administration of the same PEG-AuNP at the same dosage 14 days later than the first dose did increase the concentration of anti-PEG IgG generated, none of the groups appeared to achieve an anti-PEG IgG concentration in the blood of between 44-65 ng/ml. The majority of the groups exhibited substantially less IgG production than 40 ng/ml- see Figure 2. Based on Figure 2, only the boosted group which utilized 20K PEG-AuNP appeared to show a concentration approaching 44 ng/ml; however, the error bars for this group were substantial which brings into question the predictability of achieving anti-PEG IgG concentration between 44-65 ng/ml. Figure 3B seems to be a different representation of the same data represented in Figure 2, and based on the shading, does not appear to show the production of 44 ng/ml or more of anti-PEG IgG in the blood. It is also noted that Figure 3B has no error bars or any other indication of error or statistical significance. In addition, these results were all obtained in mice. There are no working examples showing that anti-PEG IgG can be produced in other types of animals such as insects, amphibians, birds, fish, and other mammals to the concentration recited in the instant claims. Thus, the limited working examples failed to demonstrate that a single subcutaneous injection of 2K, 5K, 10K, or 20K PEG-AuNP is capable of generating the target concentration of anti-PEG IgG recited in the claims. The working examples further demonstrate that a booster subcutaneous administration at 14 days also failed to generate at least 44 ng/ml of anti-PEG IgG. Thus, the working examples as a whole fail to provide evidence that a single subcutaneous injection, or two subcutaneous injections of PEGylated AuNPs as claimed can produce at least 44-65 ng/ml of anti-PEG IgG in blood of a mouse or any other animal.
Furthermore, based on the state of the prior art with regards to the generation of anti-PEG IgG in an animal using PEGylated nanoparticles, applicant’s argument that it would be routine to determine dosages other than 9.48 mol of PEG per kg which might be capable of producing the claimed amount of anti-PEG IgG antibodies in the blood is not found persuasive. At the time of filing, the prior art does teach that anti-PEG antibodies, both IgM and IgG, are responsible for the accelerated blood clearance (ABC) phenomenon observed following the administration of PEGylated nanoparticles. Several groups have reported the generation of anti-PEG IgG in response to the administration of PEGylated NPs (see Zhao et al. (2018) Biomater. Sci., Vol. 6, 200-206, in view of Suk et al. (2016) Adv. Drug Deliv. Rev., Vol. 99(Pt A), 28-51, and Abu Lila et al. (2013) J. Control. Release, Vol. 172, 38-47). Suk et al., for example, teaches that although smaller PEGylated NPs such as PEGylated gold NPs exhibit improved blood pharmokinetics (PK) compared to larger PEGylated NPs, they also induce anti-PEG antibodies in animals models, such as mice, which increase the clearance of a second dose of the PEGylated NPs, a phenomenon known as accelerated blood clearance (ABC) (Suk et al., pages 32-33). Abu Lila et al. also teaches that the administration of the PEGylated substances leads to the induction of anti-PEG antibodies in monkeys, rats, and mice (Abu Lila et al., page 40). Abu Lila et al. further teaches that anti-PEG antibody induced ABC of a second dose of PEGylated polymeric nanoparticles in rats occurs within 3 days of injection of the first dose, and further teaches the administration of a second dose of PEGylated polymeric nanoparticles at day 14 (Abu Lila et al., pages 40-41). Abu Lila et al. also teaches that both intravenous and subcutaneous injection of the PEGylated nanocarriers induces ABC (Abu Lila et al., page 42). However, neither Suk et al. nor Abu Lila et al. teach that PEGylated nanoparticles can induce the production of at least 44 ng/ml-65 ng/ml after 1 dose, or even after a second booster dose using any route of administration in any animal. Zhao et al. is the closest prior art. Zhao et al. teaches intravenous administration of PEGylated gold nanoparticles (AuNP-PEG) to mice, where the AuNP-PEG was administered twice, 5 days apart, at a dosage of 2 mg/kg and reported that 12 days after the second administration (17 days after the first administration) anti-PEG IgG antibody production was observed compared to mice administered AuNP nanoparticles without PEG (Zhao et al., pages 201-204, especially Figure 7). Zhao et al. teaches that the generation of anti-PEG antibodies, both IgM and IgG, following administration of PEGylated nanoparticles is responsible for the accelerated blood clearance (ABC) phenomenon associated with the use of PEGylated nanoparticles (Zhao et al, page 200). Zhao et al. teaches the generation of the PEGylated AuNP using 2kDa HS-PEG and HAuCL4, with no additional immunogenic material. Zhao, however, reported on the increase in total IgG following intravenous administration of PEGylated AuNP versus non-PEGylated AuNP, and did not test the specific amount of anti-PEG antibodies within the increased IgG population. Therefore, while the prior art of record establishes an expectation for the ability to generate some level of anti-PEG IgG in a mammal such as a mouse following at least 2 subcutaneous or intravenous administrations of PEGylated NPs, including PEGylated AuNPs, the prior art of record does not appear to demonstrate or suggest that the production of between 44-65 ng/ml of anti-PEG IgG antibodies in the blood or in any other tissue in any animal would have been predictable or achievable using any dosage of any PEGylated NP as claimed using any route of administration including subcutaneous administration.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 4, 8, 10-12, and 22 under 35 U.S.C. 102(a)(1) as being anticipated by Zhao et al. (2018) Biomater. Sci., Vol. 6, 200-206, is withdrawn over canceled claims 4, and 8, withdrawn over amended claims 1, and 10-11 in view of applicant’s amendments to the claims which limit the method of administration to subcutaneous administration, and maintained over claims 12 and 22. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons discussed below.
The applicant argues that claim 1 has been amended to limit the administration to subcutaneous administration and that Zhao et al. does not each subcutaneous administration. In response, while the amendments to the method of claim 1 do overcome the rejection of method claims 1, and 10-11, claims 12 and 22 are not method claims. Claims 12 and 22 are product by process claims. Applicant is reminded that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). In the instant, the product is mammal which is a research animal (claim 12) or mouse (claim 22) which produces anti-PEG antibodies. While the method of claim 1 is a method of producing antibodies using two subcutaneous doses of a PEGylated gold nanoparticles comprising PEG chains with a molecule weight of 20 kDa wherein the PEGylated gold nanoparticles are in an amount effective to induce production of anti-PEG IgG antibodies to a target concentration of between about 44 ng/ml and about 65 ng/ml in the blood of the animal, the animal recited in claims 12 and 22 is not limited to animal at any particular time after receiving the PEGylated gold nanoparticles. The animal is further not recited as having any particular amount of anti-PEG antibodies in the blood. Therefore, the claimed animal encompasses an animal at any time post immunization from several days to several months or years post-immunization with any amount of anti-PEG IgG antibodies in the blood.
Zhao et al. teaches a mouse post immunization with PEGylated gold nanoparticles whose blood comprises anti-PEG IgG antibodies (Zhao et al., pages 200-204). As such, it is maintained that Zhao et al., by teaching a mouse whose blood comprises anti-PEG IgG antibodies, anticipates the products recited in claims 12 and 22.
No claims are 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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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634