DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/17/2025 has been entered.
Status of Claims
3. Claims 1,5-7,9,13 and 15-16 as amended in filing dated 11/17/2025 are pending.
4. Claims 1,5-7,9,13 and 15-16 as filed on date 11/17/2025 are under examination.
Priority
5. 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. CN 201910822785.3, filed on 2 September 2019. This application is a National Phase application of PCT application no. PCT/CN2020/098205 filed on June 24, 2020, which claims the priority of the Chinese patent application filed with the Chinese Patent Office on 2 September 2, 2019, with the application number CN 201910822785.3.
Information Disclosure Statement
6. The information disclosure statements (IDSs) filed on 12/29/2021 and 11/17/2025 are acknowledged. The submission is in-compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
7. No drawing are submitted with the application.
Claim Rejections - 35 USC § 103 (Amended)
8. 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.
9. 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.
10. Claims 1, 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Castellsagué et al 2015 (published in Vaccine 33 (2015) 6892–6901) and further in view of Bryan et al 2008 WO2008112125A1 (published 18 September 2008), Giannini et al 2006 (published in Vaccine 24 (2006) pages 5937–5949), Cheng et al 2014 (Clin Vaccine Immunol. 2014 Mar;21(3):329-39), Shirota et al 2014 (Expert Rev Vaccines. 2014 Feb;13(2):299-312), Monie et al 2008 (published in Biologics: Targets & Therapy 2008:2(1) 107–113), Sangar et al 2015 (published in Indo American Journal of Pharmaceutical Research, 2015, Vol 5, Issue 06, 2015), Liu 2018 (published online: www.fiercepharma.com/vaccines/merck-quadruples-gardasil-supply-china-contract-but-still-might-not-meet-full-demand) and further in view of Su Wenquan CN109701010A (published 03 May 2019), Gong et al 2012 (published in Vaccine 30, pages 7498– 7505) and Haefliger et al 2011 (US20110110979A1, 05/12/2011).
Claims 1: A recombinant human papillomavirus (HPV) vaccine formulation composition, comprising 9 types of VLPs, each formed by the assembly of one of the 9 types of major capsid proteins: HPV 16L1, 18L1, 6L1, 11L1, 31L1, 33L1, 45L1, 52L1, and 58L1; and a pharmaceutically acceptable combined adjuvant system, wherein the pharmaceutically acceptable combined adjuvant system is a combination of an aluminum salt adjuvant and a CpG ODN adjuvant;
a content of L1 protein VLPs of each HPV type is between 2-60 µg;
contents of VLPs for HPV 16L1, 18L1, 6L1, 11L1, 31L1, 33L1, 45L1, 52L1, and 58L1 types are respectively 6-60 µg, 4-40 µg, 3-30 µg, 4-40 µg, 2-20 µg, 2-20 µg, 2-20 µg, 2-20 µg, and 2-20 µg;
a content of aluminum adjuvant is approximately 225-1000 µg; and
a content of the CpG ODN is approximately 250-1000 µg.
Claim 9: The vaccine formulation composition according to claim 1, wherein the content of the aluminum adjuvant is approximately 500 µg.
Claim 13: The vaccine formulation composition according to claim 1, wherein the contents of VLPs for HPV 16L1, 18L1, 6L1, 1L1, 31L1, 33L1, 45L1, 52L1, and 58L1 types are respectively 6-60 µg, 4-40 µg, 3-30 µg, 4-40 µg, 2-20 µg, 2-20 µg, 2-20 µg, 2-20 µg, and 2-20 µg, the content of the aluminum adjuvant is approximately 500 µg, and the content of the CpG ODN is approximately 500-1000 µg.
Regarding Claims 1, 9 and 13: Castellsagué is in the art and discloses immunogenicity and safety of the 9-valent HPV vaccine in human. Castellsagué teaches instant claim 1 limitation, a recombinant human papillomavirus (HPV) vaccine formulation composition, comprising 9 types of VLPs, each formed by the assembly of one of the 9 types of major capsid proteins: HPV 6L1, 11L1, 16L1, 18L1, 31L1, 33L1, 45L1, 52L1, and 58L1 comprising an aluminum salt adjuvant (an amorphous aluminum hydroxyphosphate sulfate (AAHS) (See, Castellsagué et al 2015, page 6893, col 2, section 2.2 on vaccine dosing; page 6894, col 1 para 2, recites HPV VLPs made of L1 proteins, table 2, col1, legend (e)).
Castellsagué further teaches the instant claim 1 limitations by disclosing a 0.5 mL dose of 9 types HPV L1 VLPs vaccine contained 30 µg HPV 6, 40 µg HPV 11, 60 µg HPV 16, 40 µg HPV 18, 20 µg HPV 31, 20 µg HPV 33, 20 µg HPV 45, 20 µg HPV 52, 20 µg HPV 58 L1 VLP (See, page 6893, col 2, para 2.2 Vaccine dosing). The concentration of HPV L1 VLPs disclosed by Castellsagué is within the range of claimed concentration of HPV L1 VLPs.
Castellsagué do not disclose a pharmaceutically acceptable combined adjuvant system an aluminum salt adjuvant and a CpG ODN adjuvant for the vaccine composition comprising HPV VLPs L1 capsid derived from 9 types.
Bryan is in the HPV L1 capsid protein VLP vaccine art and teaches an octavalent HPV L1 VLP vaccine composition comprising 8 types HPV 6L1, 11L1, 16L1, 18L1, 31L1, 45L1, 52L1, and 58L1 and a combined adjuvant system ISCOMATRIX® (CSL Limited ABN, Parkville, Australia) and aluminum salt adjuvant (See, WO2008112125A1, page 18, Example 1). Although Bryan teaches HPV 33L1 VLP, Bryan do not teach the vaccine composition comprising 9 types of HPV L1 VLPs (See, WO2008112125A1, Claim 2). Bryan further teaches that aluminum adjuvants are able to induce potent antibody (Th2) responses against many antigens; but rarely stimulate cellular (Th1) immune responses (WO2008112125A1, page 2, lines 23-34) and ISCOMATRIX adjuvant of Bryan induces cellular immune response (Th1).
Bryan teaches limitations on aluminum adjuvant content by disclosing 150 μg to about 600 μg of aluminum adjuvant (See, WO2008112125A1, claim 10, (b)). Thus teaches the added limitations on aluminum adjuvant content of claim 1 and claim 9.
Gong et al 2012 is in the vaccine and adjuvant art and teaches influenza recombinant hemagglutinin protein subunit vaccine with 10 µg CpG oligodeoxynucleotides adjuvant (CpG ODN) per injection in mice and the vaccine was found to be effective in inducing protective humoral (antibody) as well as cellular immunity in mice and able to protect the immunized mice from related influenza virus challenge (See, Gong et al 2012, abstract, page 7499 col 1 on mice immunization; and figure 2, tables 1-3).
Cheng et al 2014 is in the protein-based vaccine adjuvanted with CpG ODN adjuvant and teaches robust CD8(+) T cell responses are essential for immune protection against intracellular pathogens. Topical CpG adjuvantation of a protein-based vaccine induces protective immunity to intra-cellular pathogen Listeria monocytogenes. In addition, using parenteral administration of ovalbumin (OVA) protein as a model antigen, the effect of the Toll-like receptor 9 (TLR9) agonist, CpG oligodeoxynucleotide (ODN) 1826, as an adjuvant delivered either topically, subcutaneously, or intramuscularly on antigen-specific CD8+ T cell responses in a mouse model was evaluated (See, abstract), immunization. C57BL/6 or TLR9 KO female mice 6 to 12 weeks of age, and next 250 µg or 50 µg of CpG ODN was administered topically, subcutaneously, or intramuscularly in an epifocal manner (See, Page 330, col 1 section on Immunization). Thus Cheng et al 2014 teaches use of 250 µg or 50 µg of CpG ODN as an adjuvant for a vaccine against an intra-cellular pathogen (viruses (HPV) are intracellular pathogens).
Shirota et al 2014 is in the vaccine (viral vaccine, VLP) and adjuvant art and teaches recent progress concerning CpG DNA and its use as a vaccine adjuvant. CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides designed to specifically agonize Toll-like receptor 9 (See, abstract). Doses of CpG ODN in the range of 0.5 - 3 mg (500 µg to 3000 µg) were generally used in vaccine adjuvant trials (See, Page 11, para 3 line 1).
Therefore, Cheng et al 2014 and Shirota et al 2014 teaches the added limitations of claims 9 and 13 on content of CpG ODN adjuvant in the range of 500 µg or 500 µg-3000 µg, respectively, in a vaccine immunogenic composition as recited supra.
Giannini teaches induction of enhanced humoral and memory B cellular immunity in monkey and mouse model by HPV16/18 L1 VLP vaccine formulated with the MPL+aluminium salt combination (AS04) adjuvant compared to aluminium salt adjuvant only (See, Giannini et al 2006, abstract; figures 1-6).
Monie 2008 teaches commercially licensed Cervarix™ - a vaccine comprising L1 VLPs that includes L1 from HPV types 16 and 18, (the two major serotypes that are involved with cervical cancer for the prevention of HPV 16, 18-associated cervical cancer) and further discloses that the vaccine formulated in the proprietary adjuvant ASO4, which consists of alum combined with a TLR4 ligand, MPL (3-O desacyl- 4'-monophosphoryl lipid A), (See, Monie et al 2008, abstract and page 108, col 2 para 2).
Thus, Bryan, Giannini and Monie teaches an importance of cellular immune response in addition to antibody response for a vaccine composition and thus importance of adjuvant combination comprising an adjuvant inducing Th1 immune response.
Bryan, Giannini, Cheng et al 2014, Shirota et al 2014 and Monie 2008 do not teach a combination adjuvant comprising an aluminum salt adjuvant and a CpG ODN adjuvant.
Su Wenquan (CN109701010A) teaches a vaccine composition comprising human papilloma virus major cat protein L1 and combination adjuvant system characterized by comprising aluminium adjuvant (aluminium hydroxide Adjuvant, Aluminium phosphate adjuvant), and double stranded polynucleotide-epsilon-polylysine (See, CN109701010A claims 1-8; pdf page 6 para 9 for HPV vaccine composition and adjuvant system). The double stranded polynucleotide-epsilon-polylysine is a TLR stimulant similar to CpG ODN that has adjuvant effect that includes aspects of enhancing humoral immunity and cellular immunity. (See, CN109701010A pdf page 4, para on “nucleic acid adjuvant).
Gong et al 2012 is in the vaccine and adjuvant art and teaches influenza recombinant hemagglutinin protein subunit vaccine with combined aluminum hydroxide (alum) and CpG oligodeoxynucleotides adjuvant (CpG ODN) and the vaccine was found to be effective in inducing protective humoral (antibody) as well as cellular immunity in mice and able to protect the immunized mice from related influenza virus challenge (See, Gong et al 2012, abstract, page 7499 col 1 on mice immunization; and figure 2, tables 1-3). Although Gong et al 2012 is directed to an influenza HA subunit antigen, the vaccine composition is formulated in the combination with aluminum hydroxide (alum) and CpG oligodeoxynucleotides adjuvant (CpG ODN) and thus teaches the inventive concept of the adjuvant in combination to induce both antibody and cellular immune response against influenza HA subunit.
The teachings of Bryan on a combined adjuvant system that comprise ISCOMATRIX® and aluminum hydroxide phosphate adjuvant or teachings of Giannini on a combined adjuvant system comprising ASO4, which consists of alum combined with a TLR4 ligand, MPL (3-O desacyl-4'-monophosphoryl lipid A) are important to understand the approach to induce both cellular and antibody immune response to an immunogen as a vaccine formulation.
Haefliger et al 2011 (US20110110979A1) is in the HPV vaccine art and teaches method and HPV vaccine for optimizing the specific immune responses (T cell responses) for treating a Human Papillomavirus (HPV) infection or an associated disease or lesion in a subject using the TLR 9 agonist is CpG ODN adjuvant (See, abstract, para [0004], [043], [085], claim 34, claim 43), entire prior art).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Castellsagué’s 9 different types of HPV L1 capsid protein VLPs vaccine composition with the additional prior art teachings as applied and recited supra including teachings of Su Wenquan on TLR stimulant adjuvant and Gong on combined aluminum hydroxide (alum) and CpG oligodeoxynucleotides adjuvant (CpG ODN, a TLR stimulant) and CpG ODN adjuvant quantity content 500 µg to 3000 µg taught by Cheng et al 2014 and Shirota et al 2014 to arrive at the invention of instant claims 1. One would have been motivated to do so given the teaching of Bryan that aluminum adjuvants are able to induce potent antibody (Th2) responses against many antigens; but rarely stimulate cellular (Th1) immune responses. With regards to HPV, it has been shown that HPV L1 VLP-based vaccine in which the VLPs were adsorbed to an aluminum adjuvant produced a significantly stronger immune response in rhesus macaques than the response resulting from a corresponding L1 VLP vaccine lacking aluminum and … it would be advantageous to achieve higher magnitude immune responses comprising strong humoral as well as cellular immune responses (See page 2, lines 23-37). The motivation to incorporate combination adjuvant aluminum salt and CpG ODN would be to induce both higher magnitude immune responses comprising strong humoral as well as cellular immune responses to the HPV L1 9 types of VLPs vaccine composition of claims 1, 9 and 13 to afford better protection against the HPV serotypes from which the claimed nine HPV L1 capsid protein VLPs. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Castellsagué on the amount of claimed HPV VLP antigen doses and quantity or content of the aluminum adjuvant and CpG ODN based on the additional applied prior arts to arrive at instant claims 1, 9 and 13 and to optimize the dose of the HPV L1 9 valent VLPs vaccine composition to obtain optimal immune response using the nine different types HPV L1 VLPs vaccine composition for vaccine formulation and commercial vaccine product success.
The motivation to comprise 9 types of HPV L1 VLPs would be to induce broader immune protection against important 9 HPV types. Another motivation to comprise combined adjuvant comprise 9 types of HPV L1 VLPs would be to induce enhanced and durable antibody and cellular immune response immune protection (See, Giannini et al 2006, abstract; figures 1-6). The commercial and licensed Cervarix™ HPV L1 vaccine against HPV 16 and HPV 18 comprise combined adjuvant system ASO4 (aluminum salt+MPL) and induces enhanced humoral and memory B cellular immunity as per teachings of Giannini. A vaccine with 9 different HPV type L1 VLPs comprising combined adjuvant aluminum salt and CpG ODN would be to induce both higher magnitude humoral as well as cellular immune would provide a competitive vaccine product and commercial success because a shortage of the commercial vaccine Gardasil®9 is recited for developing countries (See, Liu et al 2018 and Sangar et al et al 2015, abstract and entire research paper). Thus, the invention of claims 1, 9 and 13 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention in particular in view of the teachings of prior arts with a focus in vaccine research to comprise induction of both humoral (antibody) and cellular immune response and prior art by Gong on combined aluminum hydroxide (alum) and CpG oligodeoxynucleotides adjuvant (CpG ODN, a TLR stimulant) formulation with influenza HA subunit antigen. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1, 9 and 13. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, G).
Furthermore, as applicable to instant claim 1, according to section 2144.05 of the MPEP, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages”).
Further combining two different adjuvants (e.g. aluminum salt induces primarily Th2 response (antibody) and CpG ODN primarily induces Th1 response (cellular immune response)) for additive immune response and protective immune response effects falls under an Art Recognized Equivalence for the Same Purpose. See, MPEP 2144.06. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Also See, MPEP 716.02(a) Evidence Must Show Unexpected Results [R-07.2022]
I. GREATER THAN EXPECTED RESULTS ARE EVIDENCE OF NONOBVIOUSNESS
"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
The applicant has recited anti-HPV neutralizing antibody response titers in the specification in Table 2-6. The table 2 did not include the separate immunization groups (i) HPV 1X (without adjuvant), (ii) HPV 1X+ AP, (iii) HPV 1X + AP +CpG, to demonstrate synergistic effects of the combination adjuvant on the immune response measured by anti-HPV neutralizing antibody response titers.
In Tables 3-6 applicant further included Gardasil 9 HPV +AP adjuvant to compare with instant claimed HPV 1X + AP +CpG vaccine and the immunization groups did not include three separate immunization groups (i) HPV 1X (without adjuvant), (ii) HPV 1X+ AP or did not include three separate immunization groups (i) Gardasil HPV 1X (without adjuvant), (ii) Gardasil HPV 1X+ AP, and (iii) Gardasil HPV 1X + AP +CpG to demonstrate synergistic effects of the combination adjuvant on the immune response measured by anti-HPV neutralizing antibody response titers. Therefore, there is no evidence or record of the claimed surprising effect or synergistic effect induced by the claimed combination adjuvant AP+ CpG ODN comprised in the HPV VLP vaccine.
11. Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Castellsagué et al 2015 (published in Vaccine 33 (2015) 6892–6901), Bryan et al 2008 WO2008112125A1 (published 18 September 2008), Giannini et al 2006 (published in Vaccine 24 (2006) pages 5937–5949), Cheng et al 2014 (Clin Vaccine Immunol. 2014 Mar;21(3):329-39), Shirota et al 2014 (Expert Rev Vaccines. 2014 Feb;13(2):299-312), Monie et al 2008 (published in Biologics: Targets & Therapy 2008:2(1) 107–113), Sangar et al 2015 (published in Indo American Journal of Pharmaceutical Research, 2015, Vol 5, Issue 06, 2015), Liu 2018 (published online: www.fiercepharma.com/vaccines/merck-quadruples-gardasil-supply-china-contract-but-still-might-not-meet-full-demand), Su Wenquan CN109701010A (published 03 May 2019), Gong et al 2012 (published in Vaccine 30, pages 7498– 7505), Haefliger et al 2011 (US20110110979A1, 05/12/2011) as applied to claim 1 above and further in view of Tritama et al 2018 (published in Human Vaccines & Immunotherapeutic, 2018, VOL. 14, NO. 6, 1524–1529), Mahboubi et al 2008 (published in Iran J Immunol. Vol 5 No 3) and Dagouassat et al 2001 (published in Vaccine 19 (2001) 4143–4152).
Regarding Claim 5: The combined prior art teachings as applied to claim 1 and recited supra teaches instant claim 1 and are incorporated here in entirety.
Bryan, inter alia, further teaches the pharmaceutical composition of HPV L1 9 type VLPs wherein the aluminum adjuvant is selected from the group consisting of: aluminum phosphate (AlPO4) and aluminum hydroxide (Al (OH)3) (See, WO2008112125A1 claim 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings as applied to the invention of instant claim 1 by incorporating further additional teachings of Bryan on the HPV VLPs vaccine composition to further comprise aluminum adjuvant selected from the group consisting of: aluminum phosphate (AlPO4) and aluminum hydroxide (Al (OH)3). The motivation would be aluminum phosphate and aluminum hydroxide have different properties and thus adsorption capacities of HPV L1 VLPs would differ as taught by Tritama which is in the vaccine and the adjuvant art for “the extent of adsorption of Typhoid conjugate vaccine (TCV) in AlOH was greater than that in AlPO4. (See, Tritama et al 2018 abstract). Therefore, it is obvious that aluminum hydroxide with a better adsorption property would be preferable for HPV L1 VLPs. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claim 5. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, G.
Regarding Claim 6: The combined prior art teachings as recited supra teaches instant claim 5, however, do not specifically teach the added limitation of instant claim 6 wherein the vaccine formulation comprises aluminum adjuvant is aluminum phosphate.
Mahboubi is in the viral vaccine and adjuvant art and teaches a Hepatitis B vaccine immune response using aluminum hydroxide or aluminum phosphate adjuvants and teaches that better adjuvanticity of aluminum phosphate may be due to less ligand exchange between phosphate group of the antigen and the hydroxyl group of aluminum phosphate (Al(OH)m(PO4)n,) in comparison to aluminum hydroxide (AlO(OH)), leading to a less stable binding of the adjuvant to antigen with higher elution rate. Different mechanisms of antigen presentation to immune competent cells and the production of different lymphokines such as interleukins and tumor necrosis factor may be some of the other factors responsible in raising antibody titer (See, Mahboubi, abstract and page 168-169 for discussion, see results figures and tables).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings as applied to the invention of instant claim 5 by incorporating teachings of Mahboubi on aluminum phosphate adjuvant to apply to the HPV L1 VLPs vaccine composition to obtain enhanced immune response. The motivation would be aluminum phosphate and aluminum hydroxide have different adsorption and immune response induction properties and incorporation of aluminum phosphate adjuvant would result in a superior HPV L1 VPLs vaccine leading to commercial success. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claim 6. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, G.
Regarding Claim 7: The combined teachings as applied supra teaches instant claim 5, however, do not specifically teach the added limitation of instant claim 7, wherein the aluminum phosphate has a PI value of 5 to 9.5.
Dagouassat is in the vaccine and aluminum salt adjuvant art and inter alia teaches a BBG2Na, a recombinant chimeric protein vaccine candidate against RSV, the BB domain has an acidic isoelectric point (pI 5.5) and the G2Na domain a highly basic one (pI 10.0). BBG2Na has a basic isoelectric point (pI 9.3) and as expected, is strongly adsorbed by aluminum phosphate (AP). Surprisingly, BBG2Na is also strongly adsorbed by aluminum hydroxide (AH), which normally binds molecules with acidic isoelectric points. This behavior was unexpected. Therefore, in the instant claim 7 invention, 9 different types of VLPs assembled from L1 major capsid proteins of HPV 16 L1, HPV 18 L1, HPV 6 L1, HPV 11 L1, HPV 31 L1, HPV 33 L1, HPV 45 L1, HPV 52 L1, and HPV 58 L1 need to be adsorbed on aluminum phosphate adjuvant. The L1 capsid proteins of different HPV serotypes would differ in PI values depending upon the amino acid sequence composition.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the prior art element (PI of specific HPV serotype L1 VLP) with the compatible a specific PI value ranging from 5 to 9.5 for the preparation of aluminum phosphate adjuvant solution to optimally adsorbs the specific HPV serotype L1 VLP with known and compatible PI value. This is similar to combining prior art elements according to known methods to yield predictable results to arrive at the invention of instant claim 7. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
12. Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Castellsagué et al 2015 (published in Vaccine 33 (2015) 6892–6901), Bryan et al 2008 WO2008112125A1 (published 18 September 2008), Giannini et al 2006 (published in Vaccine 24 (2006) pages 5937–5949), Cheng et al 2014 (Clin Vaccine Immunol. 2014 Mar;21(3):329-39), Shirota et al 2014 (Expert Rev Vaccines. 2014 Feb;13(2):299-312), Monie et al 2008 (published in Biologics: Targets & Therapy 2008:2(1) 107–113), Sangar et al 2015 (published in Indo American Journal of Pharmaceutical Research, 2015, Vol 5, Issue 06, 2015), Liu 2018 (published online: www.fiercepharma.com/vaccines/merck-quadruples-gardasil-supply-china-contract-but-still-might-not-meet-full-demand), Su Wenquan CN109701010A (published 03 May 2019), Gong et al 2012 (published in Vaccine 30, pages 7498– 7505), and Haefliger et al 2011 (US20110110979A1, 05/12/2011) as applied to claim 1 above and further in view of Sievers et al 2012 (US20120045479A1, published 23 February 2012) and Merck and Co Inc (2006).
Regarding Claim 15: A test vaccine kit, comprising the vaccine formulation composition according claim 1, wherein the kit comprises a vaccine administration device selected from a syringe device, a liquid ejection device, a powder device, and a nebulizer device.
The combined prior art teachings as applied to claim 1, recited supra, teaches instant claim 1 and the prior art teachings as applied to claim 1 supra are incorporated here in entirety, however, the prior arts applied to claim 1 do not teach a test vaccine kit.
Sievers et al 2012 (US20120045479A1) teaches the added limitation of instant claim 15, HPV L1 VLP powder vaccine administration and nebulization (a nebulizer device) (See, claims 1-21, para [015] and [028]).
Merck and Co Inc (2006) teach HPV vaccine administration by a syringe device (See, pages 1-28).
The concept of packaging components into a kit is well known and routine in the art. The references teaches that vaccine composition can be packaged into a kit comprising vials, bottles, syringes, (article of manufacture) etc. The syringe can be provided loaded with a single dose of the vaccine and carrier may be provided mixed in one or more containers (multiple doses). It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components into a kit. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed invention is obvious over combined prior art teachings as applied to claim 15 as recited supra.
13. Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Castellsagué et al 2015 (published in Vaccine 33 (2015) 6892–6901), Bryan et al 2008 WO2008112125A1 (published 18 September 2008), Giannini et al 2006 (published in Vaccine 24 (2006) pages 5937–5949), Cheng et al 2014 (Clin Vaccine Immunol. 2014 Mar;21(3):329-39), Shirota et al 2014 (Expert Rev Vaccines. 2014 Feb;13(2):299-312), Monie et al 2008 (published in Biologics: Targets & Therapy 2008:2(1) 107–113), Sangar et al 2015 (published in Indo American Journal of Pharmaceutical Research, 2015, Vol 5, Issue 06, 2015), Liu 2018 (published online: www.fiercepharma.com/vaccines/merck-quadruples-gardasil-supply-china-contract-but-still-might-not-meet-full-demand), Su Wenquan CN109701010A (published 03 May 2019), Gong et al 2012 (published in Vaccine 30, pages 7498– 7505), and Haefliger et al 2011 (US20110110979A1, 05/12/2011) as applied to claim 1 above, and further in view of Cooper et al 2005 (published in AIDS 2005, Vol 19 No 14).
Regarding Claim 16: The combined prior art teachings as applied and recited supra teaches instant claim 1; however, do not teach instant claim 16 added limitation, wherein the CpG ODN adjuvant is CpG7909.
Cooper et al 2005 is in the viral vaccine and adjuvant art and teaches that CpG 7909 adjuvant improves hepatitis B virus vaccine sero-protection in antiretroviral-treated HIV-infected adults. Cooper teaches that addition of CPG 7909 achieves rapid, higher, and sustained HBV sero-protection and increases HBV-specific T helper cell response to HBV vaccine in HIV subjects. These results confirm a potential adjuvant role for CPG 7909 in vaccine hyporesponsive populations including those living with HIV (See, abstract and entire research paper).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior arts applied to instant claim 1 based on the teachings of Cooper et al 2005 to optimize and improve the dose of the HPV VLPs, aluminum adjuvant and incorporate CPG 7909 adjuvant to obtain optimal humoral (antibody) and cellular immune response using the nine different types HPV L1 VLPs vaccine composition for vaccine formulation in HIV infected patients and to have the HPV L1 VLPs based vaccine for HIV patients that are immunosuppressed and obtain commercial success. There would have been a reasonable expectation of success based on the success of CPG 7909 adjuvanted HBV vaccine immune response in immunosuppressed HIV patients. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 16. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, G).
Response to Arguments
14. Applicant's arguments filed on 11/17/2025 have been fully considered but they are not persuasive.
Applicant’s arguments are considered in view of the currently pending and amended claims 1,5-7,9,13 and 15-16 (filed on 11/17/2025) that are examined in this office action as recited supra.
Applicant argument: The main argument is that the pending claims are non-obvious, novel and patentable, and the distinguishing technical features of the claim inventions of claim 1 and dependent claims thereon are: (i) a content of the CpG ODN is approximately 250-1000 µg, (ii) the 9-valent VLPs and the combined adjuvant described in amended claim 1 should be treated as an integral technical solution, (iii) unexpected technical effect is first reflected in that, compared with the group containing only the aluminum adjuvant without the addition of the CpG ODN adjuvant (No. 1), the group with the aluminum adjuvant plus the CpG ODN adjuvant (No. 3) can significantly increase the neutralizing antibody titer in the serum of immunized mice.
In Response: Applicant's arguments have been fully considered but they are not persuasive because of the new search in view of the amended independent claim 1. The additional new prior arts Cheng et al 2014 (Clin Vaccine Immunol. 2014 Mar;21(3):329-39), and Shirota et al 2014 (Expert Rev Vaccines. 2014 Feb;13(2):299-312) applied to the claim 1 teaches “the content of the CpG ODN is approximately 250-1000 µg” and in combination with other prior arts applied as recited supra renders obvious the amended claim 1 and dependent claims 5-7,9,13 and 15-16 in further view of additional prior arts as recited supra.
Further combining two different adjuvants (e.g. aluminum salt induces primarily Th2 response (antibody) and CpG ODN primarily induces Th1 response (cellular immune response)) for additive immune response and protective immune response effects falls under an Art Recognized Equivalence for the Same Purpose. See, MPEP 2144.06. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Also See, MPEP 716.02(a) Evidence Must Show Unexpected Results [R-07.2022]
I. GREATER THAN EXPECTED RESULTS ARE EVIDENCE OF NONOBVIOUSNESS
"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
The applicant has recited anti-HPV neutralizing antibody response titers in the specification in Table 2-6. The table 2 did not include the separate immunization groups (i) HPV 1X (without adjuvant), (ii) HPV 1X+ AP, (iii) HPV 1X + AP +CpG, to demonstrate synergistic effects of the combination adjuvant on the immune response measured by anti-HPV neutralizing antibody response titers.
In Tables 3-6 applicant further included Gardasil 9 HPV +AP adjuvant to compare with instant claimed HPV 1X + AP +CpG vaccine and the immunization groups did not include three separate immunization groups (i) HPV 1X (without adjuvant), (ii) HPV 1X+ AP or did not include three separate immunization groups (i) Gardasil HPV 1X (without adjuvant), (ii) Gardasil HPV 1X+ AP, and (iii) Gardasil HPV 1X + AP +CpG to demonstrate synergistic effects of the combination adjuvant on the immune response measured by anti-HPV neutralizing antibody response titers. Therefore, there is no evidence or record of the claimed surprising effect or synergistic effect induced by the claimed combination adjuvant AP+ CpG ODN comprised in the HPV VLP vaccine.
Therefore, the claim rejections are maintained as recited supra.
15. Relevant Prior Arts:
Hickling et al 2003. WO2002070004A3 (12/31/2003). Papillomavirus vaccines.
Volkin et al 2001. US6251678B1 (06/26/2001). Human papillomavirus vaccine formulations.
Conclusion
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Quality Assurance Specialist, Art Unit 1600