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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Jan. 28, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Jan. 28, 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.
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). All of these prior art references are of record in the previous Office actions.
Base claim 1 is directed to pharmaceutical composition comprising: virus-like particles (VLPs) comprising HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58,
between 1 mg and 12 mg of an acid soluble chitosan; and
a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is made by mixing an HPV vaccine and a chitosan adjuvant; wherein the HPV vaccine comprises HPV VLPs,
wherein the chitosan adjuvant comprises an acid-soluble chitosan having a viscosity in the range of about 1cP to about 200 cP when measured with a viscosimeter at 20°C at a standard concentration and a deacetylation of 85%-99%.
Base claim 19 is directed to a pharmaceutical composition comprising virus-like particles (VLPs) comprising HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58; and
between 1 mg and 12 mg of an acid soluble chitosan,
wherein the HPV VLPs comprise recombinant HPV L1 or recombinant HPV L1 + L2 protein,
wherein the HPV VLPs of each of the at least one HPV types are present in a concentration of about 10 mg to about 300 mg per 0.5 mL of the pharmaceutical composition, and
wherein the total VLP concentration is between 10 mg and 2000 mg per 0.5 mL of the pharmaceutical composition.
Base claim 27 is directed to single-dose intramuscular vaccine composition comprising:
between 1 mg and 12 mg of an acid soluble chitosan,
virus-like particles (VLPs) comprising HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58, and
a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is made by mixing an HPV vaccine and a chitosan adjuvant;
wherein the HPV vaccine comprises HPV VLPs, wherein the chitosan adjuvant comprises an acid-soluble chitosan having a viscosity in the range of about 1cP to about 200 cP when measured with a viscosimeter at 20°C at a standard concentration and a deacetylation of 85%-99%;
wherein the single-dose intramuscular vaccine composition provides an elevated or comparable anti-HPV immune response relative to multiple doses of the same composition formulated without a chitosan adjuvant.
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.
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.
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 Jan. 28, 2026 have been fully considered and addressed as follows.
Applicant argues that the instant application discloses a formulation capable of increasing HPV antibody titer to a 9 valent HPV vaccine (see Examples 5-6). Applicant argues that the combination of the cited (references) fails to teach or suggest ways of creating a formulation that increases HPV antibody titers relative to a 9-valent HPV vaccine, and that, accordingly, a person of skill would not be motivated to create a composition/vaccine that has higher immunogenicity that a 9-valent vaccine with HPV types 6, 11, 16, 18, 31, 33, 45 and 58, much less to create one with the additional amount and viscosity requirement.
Applicant’s arguments are not persuasive. Ma, D’Souza and CN105597092A teach the practice of combining vaccines comprising HPV VLPs with chitosan as adjuvant to enhance immunogenicity of the vaccine antigens. D’Souza further teaches a multivalent vaccine (e.g., Gardasil® 9) comprising VLPs of the 9 HPV types as claimed. One of skill in the art would have been motivated to combine the multivalent vaccine with chitosan as adjuvant to obtain a chitosan-adjuvanted multivalent vaccine. As to the claimed ranges of chitosan amount and viscosity, one of skill in the art would have been able to obtain them via routine experimental optimization unless there is evidence that the claimed ranges are critical.
Conclusion
No claims are allowed.
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