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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Jul. 8, 2026. Claims 1, 6-7, 15-20, 22 and 25-28 are pending and currently examined.
Claim Rejections - 35 USC § 103
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 of this title, 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.
(Previous Rejection – Withdrawn) Claims 1, 6-7, 15-20, 22 and 25-28 were rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Biotechnol Lett (2015) 37:773–777), D’Souza (US 2017/0157036 A1, published on Jun. 8, 2017), and CN105597092A (published on May 25, 2016).
This rejection is withdrawn in view of the amendment filed on Jul. 8, 2026.
(New Rejection – Necessitated by Amendment) Claims 1, 6-7, 15-20, 22 and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Biotechnol Lett (2015) 37:773–777), D’Souza (US 2017/0157036 A1, published on Jun. 8, 2017), and CN105597092A (published on May 25, 2016), of record in the previous Office action, in view of Yuri M Vasiliev (Expert Review of Vaccines, 2015, 14:1, 37-53) and Mehrabi et al. (Artificial Cells, Nanomedicine, and Biotechnology, 2018, 46:sup1, 230-240).
Base claims 1 and 27 are amended to specify that the chitosan adjuvant comprises an acid-soluble chitosan having a viscosity in the range of about 1cP to about 100 [[200]] cP when measured with a viscosimeter at 20°C at a standard concentration and a deacetylation of [[85%]]90%-99%.
Ma teaches that mucosal immunity may provide a defense against human papillomavirus (HPV) but there are no FDA-approved adjuvants capable of stimulating immune responses within mucosal tissues. After mice were immunized intranasally three times with HPV16 L1 virus-like particles plus with JY adjuvant, which is composed of interleukin-2 and chitosan, sera IgG antibody titer, sera neutralizing antibody titer, sIgA concentration in respiratory tract washes, sIgA concentration in vaginal washes and the number of spot-forming cells (SFC) in splenic lymphocytes were 320 ± 15, 40 ± 2, 27 ± 1.3, 27 ± 1.7 lg/ml and 176.7 ± 6 SFC/106, respectively; In the group without JY adjuvant, the outcomes were 80 ± 9.4, null, 22 ± 1, 20 ± 2.4 lg/ml and 91 ± 5.2 SFC/106, respectively. Therefore, JY adjuvant may be an effective mucosal adjuvant for HPV vaccine in mice. See Abstract.
Ma teaches that a viscous solution of chitosan, is non-toxic, non-irritable, non-antigenic, bioadhesive and biodegradable. Chitosan has specific effects on mucosal epithelia such as relaxation of tight junctions, reduction of mucociliary clearance rates and facilitation of higher drug and carrier bioavailability (Iiium et al. 2001). The mucoadhesive effect may aid contact and uptake of antigen by NALT and M cell lineage in the NALT. Chitosan has immune stimulating activities, such as increasing accumulation and activation of macrophage and polymorphonuclear cell, promoting resistance to infections by microorganisms, and inducing cytokines (Van der Lubben et al. 2001). Therefore, chitosan is able to enhance significantly the immune response of nasally administered vaccine (Nagamoto et al. 2004). See page 776, left column, para 2. Ma teaches that the chitosan used in the study is of medium molecular weight with 85% deacylated. See page 774, left column, para 2.
D’Souza teaches in Example 4 a transdermal particle-based microneedle against human papilloma virus (HPV). More than 40 various HPV serotypes cause 90% genital warts such as HPV6, 11, 31, 33,45, 52 and 58. Two HPV serotypes (16 and 18) are responsible for approximately 70% of cervical cancers and precancerous cervical lesions. Two commercial vaccines (Gardasil® from Merk, and Cervarix® from GlaxoSmithKline) are widely available in North America and Europe. Both vaccines consist of HPV16 and HPV18 to prevent cervical cancers. Additionally, Gardasil® contained 9 different HPV serotypes (HPV 6, 11, 16, 28, 31, 33, 45, 52, and 58) which enhance the protection from cancers (cervical, vulvar, vaginal and anal) and genital warts (Centers for Disease Control and Prevention, 2015). See [0286]-[0288].
D’Souza teaches formulation of characterization of HPV VLP microparticles. It teaches that the HPV VLP was incorporated into an enteric-coated polymer matrix in this formulation. This matrix consisted of cellulose acetate phthalate (CPD) hydroxypropylmethylcellulose acetate succinate (HPMCAS), ethylcellulose (EC), trehalose and glycol chitosan polymers. First, CPD dispersion (30% w/v) was diluted in deionized water with a concentration of five mg/ml under stirring. CPD and HPMCAS were dissolved separately using 1 N sodium hydroxide to make final solutions at pH of 6.0 and 8.0, respectively. The mixture of CPD, HPMCAS, and EC was obtained as mentioned above, and the final solution pH was adjusted to be 7.0. Glycol chitosan was then added along with HPV 16 VLP and trehalose. In addition, Tween- 20 was added to enhance the smooth surface of the microparticles (MPs). The solution was stirred at 50 rpm during the spraying process using a Buchi B290 spray dryer to maintain its homogeneity. Microparticulate adjuvants were formulated using the same procedure as the vaccine microparticles. See [0300]-[0301].
CN105597092A teaches an invention relating to a vaccine spraying agent for preventing and treating HPV infection. The vaccine spraying agent comprises the following components: HPV-16L1 virion, HPV-18L1 virion, and interleukin 15 interferon. Compared with the HPV spray vaccine in the prior art, the spraying agent composition can be used for obtaining a higher antibody level of IgG and sIgA. According to cellular immunity detection, a higher IFN-gamma level is detected. See Abstract in the Google translate of the Chinese publication.
Claim 1 of CN105597092A is directed to a prophylactic HPV spray vaccine composition comprising per ml volume:
effective amount of inactivated virions, wherein the inactivated virions are HPV16 L1 virus-like particles and/or HPV18 L1 virus-like particles;
5-50 ten thousand units of human interleukin 15;
1-10 mg of chitosan; and
a phosphate buffer adjusted to pH 4.0 to 6.0.
Accordingly, Ma, D’Souza, and CN105597092A each individually teaches a pharmaceutical composition comprising a virus-like particle of HPV L1 or HPV L1+L2, a chitosan, and a pharmaceutically acceptable carrier. D’Souza further teaches that Gardasil® contained 9 different HPV serotypes (HPV 6, 11, 16, 28, 31, 33, 45, 52, and 58) which enhance the protection from cancers (cervical, vulvar, vaginal and anal) and genital warts, indicating that HPV antigens of various relevant serotypes have been included in a vaccine composition. However, while Ma teaches that chitosan is viscous and that the chitosan used in the study is 85% deacylated, D’Souza and CN105597092A are silent on the structural characteristics of chitosan used in the studies. It is noted here that the chitosan products used in the three references are included in vaccines as adjuvant and have intrinsic viscosity and deacetylation degree.
Vasiliev reviews about chitosan-based vaccine adjuvants. It teaches that a number of preclinical and clinical studies with chitosan-adjuvanted antigen- and DNA-based vaccines have been carried out. Various chitosans and their modifications, in different forms (solutions, powders, gels and particles), have been evaluated with various antigens administered via different routes. Chitosan is a generic name for a wide array of glucosamine-based substances derived from biological sources, and standardization is necessary. However, in most of the studies published to date, molecular weight, viscosity, deacetylation degree and/or purity level (especially endotoxins) are not provided for the initial chitosan substance and/or final formulation and the preparation procedure is not detailed. Evaluation of adjuvant properties is challenging, given that the only available data are insufficient to demonstrate immunogenicity for chitosans with characteristics within certain intervals to elucidate mechanisms of action or to exclude impurities as the active substance. These and other issues of chitosan-based vaccine adjuvants are summarized and a step-by-step evaluation approach for chitosan-based vaccine adjuvants is outlined. See Abstract.
Vasiliev teaches that biological origin of chitosan results in varying activity, and therefore standardization is necessary. The principal characteristics of chitosan include molecular weight (Mw, Mn and Mv – average weight, average number and average viscosity molecular weight [mass], respectively), viscosity and deacetylation degree (DAD). Purity is also very important because contaminants could modulate adjuvant activity or even be the active substance. See page 37, right column, para 1. Vasiliev teaches that chitosan products with various deacetylation degrees (DAD) have been used in studies, with DAD values of 85%, 92%, >95%, 98% etc. See page 38. Vasiliev further teaches that chitosan gel had a differentiating effect on TLR ligands in porcine and human DC. The influence on DC endocytosis of the TLR ligands was apparently a major contributory element. The authors note that interplay of delivery vehicles and immune stimulators should be predefined to ensure appropriate immune activation and efficacious combinations, and that low viscosity, 95% DAD chitosan (Primex, Iceland) was dissolved at pH <4. See page 45, left column, para 2.
Accordingly, teachings of Vasiliev indicate that chitosan products with various different deacetylation degrees (DAD) can be used in vaccine preparations, including ones with DAD in the claimed range of 90-99%, and that each chitosan product has an intrinsic viscosity.
Mehrabi teaches a vaccine composition containing recombinant hepatitis B surface antigen (rHBsAg) entrapped in chitosan and mannosylated chitosan nanoparticles, used as vaccine delivery system and adjuvant. See Abstract. Mehrabi teaches that low molecular weight chitosan (CS) was purchased from Primex, Iceland (deacetylation degree >95% and viscosity<20 cps), which was obtained from fresh North Atlantic shrimp (Pandalus Borealis) shells. See page s231, left column, para 3.
Accordingly, teachings of Mehrabi indicate that chitosan with deacetylation degree >95% and viscosity<20 cps was used in vaccine formulation. Moreover, teachings of Mehrabi suggest that chitosan with DAD >95% has a viscosity of <20 cps.
It would have been prima facie obvious for one of ordinary skill in the art at the time of invention to modify the teachings of the cited references to arrive at the invention as claimed. E.g., one of skill in the art would have found it obvious to arrive at the claimed viscosity, amount and concentration ranges through routine experimental optimization unless there is evidence that the claimed ranges are critical. See MPEP 2144.05 IIA. And, one of skill in the art would also have found it obvious to use a vaccine comprising VLPs of multiple HPV types, such as ones taught in D’Souza (e.g., Gardasil® 9) so that the resulting vaccine/chitosan formulation can cover multiple HPV types.
Regarding claim 7, which specifies an additional aluminum adjuvant, CN105597092A teaches that MPL-A is approved for human use and is incorporated in combination with aluminum hydroxide collectively referred to as ASO4 and marketed in CervarixTM, a vaccine against the human papillomavirus (HPV). See [0242].
Regarding claim 27 which specifies a single-dose intramuscular vaccine composition, the claim does not associate this limitation with any structural or functional properties. Therefore, this limitation is not considered to further limit the vaccine composition specified in claim 27 in a meaningful way.
Response to Applicant’s Arguments
Applicant’s arguments filed on Jul. 8, 2026 have been fully considered arguments regarding withdrawn rejections are moot. Applicant’s arguments relevant to the current rejection are addressed as follows.
Applicant disagrees with the examiner’s standing that it would have been prima facie obvious to “arrive at the claimed viscosity, amount and concentration ranges through routine experimental optimization.” Applicant argues that the cited art, at beast provides motivation for one skilled in the art to experiment, that the combination of the art does not even teach or suggest that use of a chitosan adjuvant much less the specific claimed concentrations, viscosity, deacetylation percentages, etc… would be effective in creating higher antibody titers when analyzed against a comparator vaccine that lacks chitosan. Applicant argues that claims 1 and 27 are amended to recite an acid-soluble chitosan having a viscosity between 1 cp and 100 cp and deacetylation percentage between 90% and 99%. Applicant argues that the combination of teachings in the cited art does not teach or suggest these ranges. Applicant argues that claims 1, 19 and 27 recite a range of between 1 mg and 12 mg of an acid soluble chitosan, and that a chitosan adjuvant including 1 mg, 4 mg or 12 mg resulted in antibody titers higher than a single-dose 9-valent HPV vaccine, as shown in examples 5-6 and figures 5-6.
Applicant’s arguments are not persuasive. As indicated in the new rejection above, Ma teaches that the chitosan used in the study has the deacetylation degree of 85%, while D’Souza and CN105597092A are silent on the structural characteristics of chitosan used in the studies. On the other hand, Vasiliev and Mehrabi teach that chitosan of various different deacetylation degrees (DAD) and viscosity can be used in the formulation of vaccine as carrier and adjuvant. Moreover, Mehrabi particularly teaches that chitosan used in the vaccine formulation has the DAD of >95% with viscosity of <20 cps. Therefore, teachings of the cited prior art indicate that it is known and the practiced in the art to use chitosan of various different structural characteristics in vaccine formulation as adjuvants which increase host immune responses to the vaccine antigen. Based on the teachings of the cited prior art, one of skill in the art would have found it obvious to arrive at the claimed viscosity, amount and concentration ranges through routine experimental optimization unless there is evidence that the claimed ranges are critical. See MPEP 2144.05 IIA.
As to Applicant’s arguments that the application provides results showing chitosan with the claimed characteristics resulted in antibody titers higher than a vaccine without chitosan, such results are expected based on the teachings of the cited references that chitosan functions as adjuvant, implying that chitosan is expected to increase host immune response to vaccine antigens compared with a vaccine without adjuvant.
Conclusion
No claims are allowed.
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 extension fee 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 NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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