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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Dec. 1, 2025 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Dec. 1, 2025. Claims 1, 10-23 and 29-31 are pending. Claims 1 and 10-22 are withdrawn. Claims 23 and 29-31 are currently examined.
The current rejection is shifted to the non-elected species of mRNA encoding an interferon based on the amendment filed on Dec. 1, 2025.
Effective Filing Date
The instant application is a 371 of PCT/US2021/054622, filed on Oct. 12, 2021, and is a CIP of 17/068,087 filed on Oct. 12, 2020 (now US Patent 11813329), which is in turn a CIP of 15/442,281 filed on Feb. 24, 2017 (now US Patent 10799574), which is in turn a CIP of 14/921,648 filed on Oct. 23, 2015 (now US PAT 10238729). However, none of the prior applications provide sufficient written description support for the instant claims which specify a second active ingredient which is an immune-based therapeutic selected from N-acetyl cysteine or mRNA encoding a cytokine. Accordingly, the effective filing date of the instant application is considered as Oct. 12, 2021, the PCT filing date.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 29 is rejected 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.
Claim 29 recites “The composition of claim 27 wherein the interferon is IFN-a.” Since claim 27 is canceled, it is not clear what the metes and bounds of claim 29 are.
To facilitate examination, claim 29 is interpreted as if it depended from claim 23.
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, 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 23, 27-28 and 30-31 were rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Clin Pharmacol Ther. 2007 Feb; 81(2): 259-64) in view of Portielje et al. (Cancer Immunol Immunother (2003) 52: 133–144), and further in view of Lai et al. (Journal for ImmunoTherapy of Cancer (2018) 6:125).
This rejection is withdrawn in view of the amendment filed on Dec. 1, 2025.
(New Rejection – Necessitated by Amendment) Claims 23 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Clin Pharmacol Ther. 2007 Feb; 81(2): 259-64) in view of Arico et al. (JOURNAL OF INTERFERON & CYTOKINE RESEARCH, 2012, 32(6): 235-247), and further in view of Hotz et al. (Sci. Transl. Med. 13, eabc7804 (2021), 8 September 2021).
Base claim 23, as amended, is directed to a pharmaceutical composition comprising: Human Papilloma Virus (HPV) vaccine comprising at least one purified viral L1 protein or fragment thereof; a second active pharmaceutical ingredient which is an mRNA encoding interferon or granulocyte-macrophage colony-stimulating factor; and a pharmaceutically-acceptable carrier.
Shi teaches that GARDASIL (Merck, Whitehouse Station, NJ) is a noninfectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid proteins of human papillomavirus (HPV) types 6, 11, 16, and 18. GARDASIL is the first vaccine approved for use in women aged 9–26 years for the prevention of cervical cancer and genital warts, as well as vulvar and vaginal precancerous lesions. See Abstract. Shi teaches that an extensive bench top formulation research and process development was carried out to obtain a vaccine dosage form with enhanced stability and potency to support sample handling, bioprocess development, and clinical supply preparations. This was achieved by novel formulation design with the introduction of stabilizing non-ionic surfactants and adjusting salt concentration (Figure 1). See para bridging the left and right columns of page 262.
Accordingly, Shi teaches an HPV vaccine composition comprising highly purified L1 (major capsid) proteins from HPV type 6, 11, 16 and 18, and a pharmaceutically-acceptable carrier. However, Shi is silent on mRNA encoding an interferon or granulocyte-macrophage colony-stimulating factor as a second active pharmaceutical ingredient which is an immune-based therapeutic.
Arico reviews studies on interferon-a as antiviral and antitumor vaccine adjuvants. Arico teaches that recent studies conducted on both mouse and human models suggest that IFN-a act as effective immune adjuvants for inducing antiviral and antitumor immunity and that the effects of IFN on the differentiation and activation of dendritic cells (DC) play an important role in the induction of protective responses. In spite of the long record of IFN-a clinical use, a few clinical trials have attempted to evaluate the efficacy of these cytokines used as vaccine adjuvants. Recently, studies on the IFN-a signature in cells from patients treated with IFN-a under different modalities and various clinical settings have provided important insights for understanding the in vivo mechanisms of the IFN immune adjuvant activity in humans and may contribute to the identification of molecular markers with a clinical response. These studies further support the interest of evaluating the clinical efficacy of IFN-a when used as a vaccine adjuvant and also suggest that the DC generated in vitro from monocytes in the presence of this cytokine can exhibit a special advantage for the development of effective therapeutic vaccination strategies in cancer patients. See Abstract.
Accordingly, teachings of Arico indicate that interferon-a has potential adjuvant activities and is promising in modulating cancer vaccinations. However, Arico is silent on an mRNA encoding interferon-a.
Hotz teaches that the authors investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-a (IFN-a), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-a induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and
uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway. See Abstract.
Accordingly, teachings of Hotz indicate that interferon-a can be delivered to a subject in need thereof via administration of an encoding mRNA.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Shi, Arico and Hotz to arrive at the invention as claimed. One would have been motivated to do so to combine the vaccine adjuvant and/or immune modulatory effect of interferon-a disclosed in Arico and Hotz with the HPV vaccines disclosed in Shi. There is a reasonable expectation of success that administrations of the vaccines of Shi and interferon-a of Arico and Hotz can be combined and effect of the combination evaluated based on the teachings of the prior art references.
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