DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 9, 2026 has been entered.
Claim Amendments
3. The amendment filed July 9, 2026 has been entered. Claims 1 and 4 have been amended. Claims 5-14 and 18 are withdrawn from consideration. Claims 1-2, 4 and 20-22 with the election drawn to HPV are under consideration in this Office Action.
Priority
4. The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 61924108, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In this case, the amended claims require that the PDL-1 antibody is selected from the group consisting of: MPDL3280A (atezolizumab or Tecentriq®), MDX1105-01 (BMS-936559), and MEDI4736 (durvalumab or Imfinzi®). These antibodies are now recited in amended claim 2. The specific antibodies are not recited in the provisional application 61,924,108. Therefore, priority cannot be granted to 61,924,108 for instant claim 2. At best, priority can be granted to International Patent Application No. PCT/US15/10305, filed on January 1, 2015 for claim 2.
Withdrawal of Rejections
5. Claims 1-2, 4 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Fotin-Mleczek et al., in view of Weiner et al., is withdrawn in view of Applicants amendments and arguments.
New Grounds of Rejection Necessitated By Applicants Amendments
Claim Rejections - 35 USC § 103
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.
6. Claims 1-2, 4 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Fotin-Mleczek et al., (WO 2014127917 published Aug. 28, 2014 priority to Feb. 22, 2013) in view of Yan et al., (Vaccine. 19 September 2008. Vol. 26, Issue 40: pages 5210-5215).
The claims are drawn to an immunogenic composition for enhancing a T cell response against an antigen in a subject in need thereof, comprising: a) programmed death-ligand 1 (PD-L1) antibody, or combination thereof, b) a DNA molecule comprising a DNA sequence encoding a synthetic consensus antigen capable of generating an immune response in the subject, or an immunogenic fragment or variant thereof wherein the synthetic consensus antigen is HPV, wherein the HPV synthetic consensus antigen is a synthetic consensus antigen from HPV subtypes selected from the group consisting of HPV6, HPV11, HPV18, HPV31, HPV33, HPV52 and HPV58 and a combination thereof.
The claims are also drawn to a method for increasing an immune response in a subject in need thereof as compared to the level of an immune response that is induced in a subject administered a vaccine not including PDL1 antibody, the method comprising administering an immunostimulatory amount of the composition of claim 1 to the subject.
Fotin-Mleczek et al., teach vaccine/inhibitor combinations to treat cancers and tumors including cervical cancers and/or carcinoma, head and neck cancers and anal cancers [para 0278] which are HPV associated cancers. A vaccine is typically understood to be a prophylactic or therapeutic material providing at least one antigen, preferably an immunogen. The antigen or immunogen stimulates the body's adaptive immune system to provide an adaptive immune response [para 46]. Genetic vaccination may typically be understood to be vaccination by administration of a nucleic acid molecule encoding an antigen or an immunogen or fragments thereof. The nucleic acid molecule may be administered to a subject's body or to isolated cells of a subject. Upon transfection of certain cells of the body or upon transfection of the isolated cells, the antigen or immunogen may be expressed by those cells and subsequently presented to the immune system, eliciting an adaptive, i.e. antigen-specific immune response [para 50]. Finally, a method of treating a subject comprising administering to the subject an effective amount of: (i) an immunogenic composition comprising at least one RNA encoding at least one antigen; and (ii) a PD-1 pathway inhibitor [See claim 1]. Thus, Fotin-Mleczek et al., clearly teach an immunogenic composition.
Also included herein are RNA/DNA hybrids which means that the at least one RNA molecule of the RNA vaccine consists partially of ribonucleotides and partially of deoxyribonucleotides [para 48]. Fotin-Mleczek et al., teach the term nucleic acid means any DNA- or RNA-molecule and is used synonymous with polynucleotide. Furthermore, modifications or derivatives of the nucleic acid as defined herein are explicitly included in the general term “nucleic acid” [para 52]. For preparation of a nucleic acid molecule, especially if the nucleic acid is in the form of an RNA or mRNA, a corresponding DNA molecule may e.g. be transcribed. This DNA matrix preferably comprises a suitable promoter [para 91]. Example 1 Step 1 teach the preparation of DNA and mRMA constructs where the DNA sequence coding for the above mentioned mRNA was prepared [para 419-421]. The respective DNA plasmid was prepared [para 422]. The at least one RNA of the RNA vaccine encoding at least one antigen in the inventive vaccine/inhibitor combination, may be prepared using any method known in the art, including synthetic methods [para 330].
Fotin-Mleczek et al., teach a vaccine/inhibitor combination comprising an RNA vaccine comprising at least one RNA comprising at least one antigen and a composition comprising at least one PD-L1. The present invention furthermore relates to a pharmaceutical composition [abstract]. The use of immune checkpoint inhibitors appears to represent a promising approach for improved cancer immunotherapy. However, the combination of vaccines with a single ICI often did not lead to the hoped improvement of the immunotherapy and the combined clinical use of ICIs targeting multiple negative co-stimulatory receptors or the combination of ICIs with other treatments may induce clinical complications as e.g. induction of an autoimmune disease [para 20].
The vaccine/inhibitor combination comprising: (i) as vaccine an RNA vaccine comprising at least one RNA comprising at least one open reading frame (ORF) coding for at least one antigen, and (ii) as an inhibitor a composition comprising at least one PD-1 pathway inhibitor [para 288]. A vaccine an RNA vaccine comprising at least one RNA comprising at least one open reading frame coding for at least one antigen and as inhibitor a PD-1 pathway inhibitor, preferably directed against ligands PD-L1 [para 22]. The inhibitor may be an antagonistic antibody as defined herein, targeting any member of the PD-1 pathway, preferably directed against PD-L1. This antagonistic antibody may also be encoded by a nucleic acid. Such encoded antibodies are also called “intrabodies” as defined herein [para 271]. Preferably, such antibody binds proximal to and disruptive of the PD-1 or PD-2 binding site on the ligand [para 279]. Particularly preferred are the anti-PD-L1 antibodies MDX-1105/BMS-936559; MPDL3280A/RG7446, or MEDI4736 [para 380]. Thus teaching claim 2. An antibody may be selected from any antibody, e.g. any recombinantly produced or naturally occurring antibodies, known in the art, in particular antibodies suitable for therapeutic, diagnostic or scientific purposes, particularly directed against PD-L1 [para 273]. Therefore nucleic acids coding for an antibody, preferably as defined above, particularly an antibody directed against a member of the PD-1 pathway, e.g. PD-L1 may be used [para 287].
In the context of the present invention, tumour antigens and pathogenic antigens as defined herein are particularly preferred [para 41]. A vaccine comprising at least one open reading frame codes for at least one tumour antigen [para 301]. Particular preferred tumour antigens include HPV-E6, HPV-E7 [para 303]. Pathogenic antigens are peptide or protein antigens derived from a pathogen associated with infectious disease which are preferably selected from antigens derived from the pathogens including Human papillomavirus (HPV) [para 306]; wherein Human papillomavirus (HPV) is a particularly preferred pathogenic antigen [para 307].
This inventive immunogenic vaccine/inhibitor combination preferably allows to elicit an adaptive immune response (and optional an innate immune response) in a patient to be treated, preferably a mammal, by using as a first component an RNA vaccine, comprising at least one RNA comprising at least one open reading frame encoding at least one antigen, preferably encoding a tumour antigen or a pathogenic antigen. The inhibitor of the inventive vaccine/inhibitor combination, preferably a PD-1 pathway inhibitor may antagonize PD-1 pathway signaling by preferably inhibiting or suppressing signal transduction mediated by the PD-1 receptor. Thus, the administration of the vaccine and the inhibitor may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, as further outlined below. Such a vaccine/inhibitor combination may induce an active immune response and thereby prevents e.g., tumour growth or induces tumour regression [para 291].
An adjuvant or an adjuvant component in the broadest sense is typically a pharmacological and/or immunological agent that may modify, e.g. enhance, the effect of other agents, such as a drug or vaccine. It is to be interpreted in a broad sense and refers to a broad spectrum of substances. Typically, these substances are able to increase the immunogenicity of antigens. For example, adjuvants may be recognized by the innate immune systems and, e.g., may elicit an innate immune response. “Adjuvants” typically do not elicit an adaptive immune response. Insofar, “adjuvants” do not qualify as antigens. Their mode of action is distinct from the effects triggered by antigens resulting in an adaptive immune response [para. 39]. A vehicle is typically understood to be a material that is suitable for storing, transporting, and/or administering a compound, such as a pharmaceutically active compound. The vaccine of the inventive vaccine/inhibitor combination may comprise further components for facilitating administration and uptake of the components of the RNA vaccine. Such further components may be an appropriate carrier or vehicle, or e.g. additional adjuvants for supporting any immune response [para 0244]; thereby teaching claim 20.
The immunostimulatory composition may be typically understood to be a composition containing at least one component which is able to induce an immune response or from which a component which is able to induce an immune response is derivable. The unique ability of B cells to bind and internalize soluble protein antigens via their receptors may also be important to induce T cells. MHC-molecules are, typically, responsible for presentation of an antigen to T-cells. Therein, presenting the antigen on MHC molecules leads to activation of T cells which induces their proliferation and differentiation into armed effector T cells. The most important function of effector T cells is the killing of infected cells by CD8+ cytotoxic T cells and the activation of macrophages by Th1 cells which together make up cell-mediated immunity, and the activation of B cells by both Th2 and Th1 cells to produce different classes of antibody, thus driving the humoral immune response. T cells recognize an antigen by their T cell receptors which do not recognize and bind the antigen directly, but instead recognize short peptide fragments e.g. of pathogen-derived protein antigens, e.g. so-called epitopes, which are bound to MHC molecules on the surfaces of other cells [para 29]. In the context of the present invention “antigen” refers typically to a substance which may be recognized by the immune system, preferably by the adaptive immune system, and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies and/or antigen-specific T cells as part of an adaptive immune response [para 41].
Such immune response may be preferably an innate immune response or a combination of an adaptive and an innate immune response [para 173]. Such a vaccine/inhibitor combination may induce an active immune response and thereby prevents e.g. tumour growth or induces tumour regression. The inventive vaccine/inhibitor combination is thus suitable to effectively stimulate antigen-specific immune responses against cancer and pathogen infected cells [para 291]. In connection with the present invention, the Th1-cell/Th2-cell ratio of the (adaptive) immune response is preferably shifted in the direction towards the cellular response (Th1 response) and a cellular immune response is thereby induced [para. 360].
Fotin-Mleczek et al., teach ‘transfection’ refers to the introduction of nucleic acid molecules, such as DNA or RNA molecules, into cells, preferably into eukaryotic cells. In the context of the present invention, the term ‘transfection’ encompasses any method known to the skilled person for introducing nucleic acid molecules, preferably RNA molecules into cells, preferably into eukaryotic cells, such as into mammalian cells. Such methods encompass electroporation [para 119]. Thereby teaching claim 22.
Finally, Fotin-Mleczek et al., teach treatment of rectal tumours, cervical cancers, papilloma virus-induced carcinomas (e.g. cervical carcinoma=cervical cancer), carcinomas, vaginal cancer, anal carcinomas and /or vulval cancers [para. 402]. Fotin-Mleczek et al. showed the beneficial combination of a tumour vaccine based on mRNA and an antibody directed against the CTLA4 receptor which attenuates the signaling of T cells [para 19]. Fotin-Mleczek et al., surprisingly found that the combination of an RNA vaccine and a PD-1 pathway inhibitor shows an extremely advantageous inhibition of tumour growth resulting in enhanced survival which could not be expected from the prior art. Thus, the combined treatment with a vaccine, e.g. coding for a specific antigen (active vaccination) such as a tumour antigen, and with an inhibitor directed to a member of the PD-1 pathway, particularly PD-1 receptor or its ligands PD-L1 and PD-L2, could strongly decrease the harmful impact of a disease to be treated, e.g. the growth rate of a tumour. In this context, Fotin-Mleczek et al., surprisingly found that treatment with a nucleic acid vaccine comprising an RNA coding for a tumor antigen in combination with a PD-1 pathway inhibitor unexpectedly inhibited tumor growth resulting in an improved survival of tumor challenged mice in a synergistic manner as evidenced by the occurrence of 50% complete responses [para 292].
Therefore, Fotin-Mleczek et al., teach the method for increasing an immune response and an immunogenic composition comprising: a) programmed death-ligand 1 (PD-L1) antibody, or combination thereof, b) a DNA molecule comprising a DNA sequence encoding an antigen capable of generating an immune response in the subject, or an immunogenic fragment or variant thereof wherein the antigen is HPV, but does not teach the HPV is a synthetic consensus antigen selected from the instantly recited HPV subtypes.
Yan et al., teach over 40 distinct HPV types have been identified to infect the genital tract, and 15 of them have been classified as high risk in the development of cervical cancer. Among these high-risk HPV types, HPV16 is the predominant type in squamous cell carcinoma of the cervix, and HPV18 is the second most common type with prevalence ranging from 12.6% in Central/South America to 25.7% in South Asia. In addition, HPV18 has been implicated in rapidly developing and potentially more aggressive cervical carcinomas [Introduction]. Thus, development of therapeutic HPV vaccines through the induction of a strong cell-mediated response is still of great importance. E6 and E7, represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are ideal immunotherapeutic targets to induce cellular immune responses against HPV-transformed cells. Significant efforts have been made to develop HPV16 therapeutic vaccines that target either E6 or E7 proteins [Introduction]. Yan et al., studied a novel HPV18 DNA vaccine encoding an E6/E7 fusion consensus protein [Discussion]. Since E6 and E7 proteins of different types of HPV are very variable and current HPV vaccines confer only type-specific immunity, novel immunotherapies for cervical cancer must consider that there is an urgent need to develop HPV18 therapeutic vaccines. DNA vaccines have conceptional advantages over traditional vaccines such as live attenuated virus and recombinant protein-based vaccines in the context of immune therapy. DNA vaccines appear to be very well tolerated in humans. Preclinical safety studies indicate that there was little evidence of plasmid integration [Introduction].
Class A viruses include HPV types 16, 31, 33, 35, 52, 58 and 67, whereas class C comprise HPV types 18, 39, 45, 59 and 68. The homology of E6 and E7 proteins within each class suggest the possibility that a broad coverage may be achieved by using a HPV16 or HPV18 vaccine [Discussion]. DNA vaccines can also be used for repeat administration as the efficacy of plasmid vectors are not influenced by pre-existing neutralizing antibodies [Introduction]. Yan et al., present a novel engineered HPV18 consensus E6 and E7 fusion DNA immunogenic designed by utilizing a multi-phase strategy [Introduction]. Yan et al., generated HPV type 18 consensus E6 and E7 sequences, twelve HPV18 E6 and E7 gene sequences collected from different countries were selected from Embank to avoid sampling bias. The HPV type 18 E6 and E7 consensus nucleotide sequences were obtained after performing multiple alignments [Materials and Methods]. The fusion gene encoding modified HPV type 18 consensus E6/E7 fusion protein (18ConE6E7) was synthesized and sequence verified by GENEART [HPV18 E6 and E7 DNA immunogen]. For DNA immunizations, the mice were separated into two groups of five mice each and immunized by electroporation with pVAX (control group) and p18ConE6E7, respectively. Each mouse was immunized three times, each with DNA at biweekly intervals [Mice and immunization/electroporation]. Yan et al., teach vaccination with p18ConE6E7 generates strong E6- and E7-specific T-cell immune responses. The E6 and E7 proteins are intracellular and represent genuine tumor-specific antigens that could act as targets for destruction of tumor cells without damage of healthy host cells, thus providing a clear opportunity for cervical cancer immunotherapy. Yan et al., designed an engineered HPV18 E6 and E7 vaccine for use in the treatment of human cervical cancer. Yan et al., showed that this vaccine could elicit CTLs in a murine model [Discussion]. However, the average IFN-γ responses for the monkeys immunized with p18ConE6E7 increased significantly with the third immunization. The average number of IFN-γ producing cells in these animals increased to 669 ± 369 SFU/106 PBMCs (Fig. 5D). Hence, immunization of rhesus macaques with p18ConE6E7 could elicit clear HPV18 E6- and E7-specific cellular responses [3.4. Vaccination with p18ConE6E7 generates strong E6- and E7-specific T-cell immune responses in rhesus monkeys]. The advantages of DNA vaccination are that they can be used for repeat administration as the efficacy of plasmid vectors are not influenced by pre-existing neutralizing antibodies, which is very important in cancer therapy. The immune responses increased significantly when the immunization was conducted, suggesting that enhanced CTLs may be obtained by multiple vaccinations [Discussion]. Thus Yan et al., clearly teach a synthetic HPV18 comprising E6 and E7 domains consensus antigen just as instantly recited.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to have applied the teaching of Yan et al., to the immunogenic composition of Fotin-Mleczek et al., because Fotin-Mleczek et al., teach that PD-L1 antibodies could be combined with a HPV antigens to treat cancers, while Yan al., teach the generation of strong E6- and E7-specific T-cell immune responses. Furthermore, Yan et al., teach the engineered HPV18 consensus E6 and E7 fusion DNA immunogenic to achieve broad coverage using a HPV16 or HPV18 vaccine. Moreover, it would have been prima facie obvious at the time of applicants’ invention to have applied the teaching of Yan et al., to the immunogenic composition and method of Fotin-Mleczek et al., because Fotin-Mleczek et al., teach inhibited tumor growth resulting in an improved survival of tumor challenged mice; while Yan et al., teach E6 and E7 are ideal immunotherapeutic targets to induce cellular immune responses against HPV-transformed cells. Additionally, Yan et al., teach DNA vaccines have conceptional advantages over traditional vaccines; are very well tolerated in humans; and studies indicate that there was little evidence of plasmid integration. Finally, it would have been prima facie obvious to combine the invention of Fotin-Mleczek et al., and Yan et al., to obtain the advantageous benefits of a vaccine which encodes an immunostimulatory HPV antigen.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to combine PD-L1 antibodies with encoded synthetic antigens, where there is no change in the respective function of the antibodies or the antigen, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
7. Applicant's arguments filed July 9, 2025 with respect to the rejection of claims -12, 4 and 20-22 under Fotin-Mleczek et al., in view of Weiner et al., have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Yan et al.
Applicants argue that Fotin-Mleczek et al., do not provide a skilled artisan with a reasonable expectation of success. Here, the Office clearly and specifically pointed to: 1) Combining prior art elements according to known methods to yield predictable results; substitution of one known element for another to obtain predictable results;
2) Use of known technique to improve similar compositions in the same way;
3) Applying a known technique to a known composition ready for improvement to yield predictable results;
4) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; and teaching, suggestion; or 5) 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 invention. There office action pointed to all rationales thereby providing a clear link between the factual findings and the legal conclusion of obviousness.
Applicants argue that Fotin-Mleczek does not teach or suggest the use of synthetic consensus antigens comprising the E6 and E7 domains of HPV subtypes HPV18.
In response to applicant's arguments against the Fotin-Mleczek et al., reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the rejection is based upon Fotin-Mleczek et al., in view of Yan et al. Fotin-Mleczek et al., teach an immunogenic composition and method for enhancing a T cell response against an antigen in a subject in need thereof, comprising: a) programmed death-ligand 1 (PD-L1) antibody, or combination thereof, and b) an encoded HPV synthetic antigen; while Yan et al., clearly teach the HPV synthetic/engineered consensus antigen comprising E6 and E7 domains of the HPV18 subtype. Yan et al., teach the advantage that this construct induces a strong cellular immune responses against HPV18 E6 and E7 antigens and elicits cellular immunity in the context of immunotherapy for HPV-associated cancers. Thus, Fotin-Mleczek et al., in view of Yan et al., clearly teach each and every instantly claimed limitations.
Applicants urge that the instant specification teaches a 30% increase in HPV specific T cells responses compared to DNA vaccines alone. In response to applicant's argument regarding the 30% increase in T cell responses, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this case, Fotin-Mleczek et al., teach an immunogenic composition and method for enhancing a T cell response against an antigen in a subject in need thereof, comprising: a) programmed death-ligand 1 (PD-L1) antibody, or combination thereof, and b) an encoded HPV synthetic antigen; and Yan et al., teach the consensus HPV antigen elicits are strong immune response. Therefore the prior art teach the combination was already known to elicit a strong immune response.
With respect to the argued level immune response from a host receiving the combination composition is not a claim limitation; therefore this aspect of the argument is not found persuasive.
Applicants argue that an enhanced immune response would not have been predicted. Contrary to Applicants argument, an enhanced immune response is not required or recited by the instant claims. Instead the method claims only requires an increased immune response as compared to a subject administered a vaccine not including PDL1 antibody. In this case, the administration of a composition comprising the synthetic HPV consensus antigen comprising the E6 and E7 domains will increase the immune response; thereby meeting the instantly claimed limitation. Fotin-Mleczek et al. showed the beneficial combination of a tumour vaccine based on mRNA and an antibody directed against the CTLA4 receptor which attenuates the signaling of T cells.
Accordingly, this argument is not found persuasive because an increased immune response was previously taught by the prior art.
Therefore, because Fotin-Mleczek et al., clearly recite HPV E6 and E7 as DNA molecules comprising a DNA sequence encoding synthetic antigen capable of generating an immune response in the subject, clearly and obviously provides one of ordinary skill in the art a reasonable expectation of success to use the HPV E6 and E7 antigens; especially when an increased and beneficial immune response was known in the art.
Again Applicants argue surprising and unexpected results. However, Fotin-Mleczek et al. showed the beneficial combination of an immunogenic tumour vaccine based on a nucleic acid sequence and an antibody directed against the CTLA4 receptor which attenuates the signaling of T cells. Fotin-Mleczek et al., found that the combination of a vaccine and a PD-1 pathway inhibitor shows extremely advantageous inhibition of tumour growth resulting in enhanced survival which could not be expected from the prior art. Yan et al., teach that among the most striking advances for plasmid delivery in vivo has been that of electroporation (EP). Studies have shown that EP is a feasible method for DNA vaccine delivery to enhance both cellular and humoral responses. The immunogenicity of this construct was examined in mice by quantitative T-cell assays. Yan et al., observed that this construct was able to elicit important cellular immunity in rhesus macaques. Yan et al., described specific stimulation of the IFN-γ release. Yan et al., showed the phylogenic analyses indicated advantages in using a type-specific E6/E7 consensus DNA vaccine. Therefore Fotin-Mleczek et al., in view of Yan et al., provide clear evidence that the improved immune response results are neither surprising nor unexpected. Therefore none of Applicants arguments are not found persuasive and the rejection of record is maintained.
Pertinent Art
8. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Shin et al., (Hum Vaccin Immunother. 2012 Apr 1;8(4):470-478) teach induction of robust cellular immunity against HPV6 and HPV11 in mice by DNA vaccine encoding for E6/E7 antigen.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645
