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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Nov. 10, 2025 has been entered.
Claim Amendments
3. The amendment filed Nov. 10, 2025 has been entered. Claim 1 has 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 Claims 5-14 and 18 are withdrawn from consideration.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.
Maintained Grounds of Rejection
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.
5. 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 Weiner et al., (US 20120053509 published March 1, 2012; priority to Jan 2010).
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 antigen capable of generating an immune response in the subject, or an immunogenic fragment or variant thereof wherein the antigen is HPV, wherein the HPV antigen is E6 and E7 domains of 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].
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]. In a preclinical study 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]. Finally, 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].
Weiner et al., teach it is widely accepted that the principle producers of IFN-γ are T-cells, making IFN-γ production an acceptable mode of measuring the cellular immunogenicity of a given vaccine post-exposure to antigens [para 97]. DNA vaccines may be able to attain a level of immunogenicity. High levels of cellular responses measured in other similar E6 and E7-specific HPV DNA vaccine studies were associated with data suggestive of prophylactic and therapeutic anti-tumor efficacy. Thus, one can only infer the immunogenic efficacy of p6E6E7 and p11E6E7 by looking at the high levels of IFN-γ and cytokine production quantified by the ELISpot assays and intracellular cytokine staining [para 97]. Weiner et al., teach HPV types 16 and 18, which cause epithelial dysplasia and other lesions, are often associated with an increased risk of cancer, particularly in situ and invasive carcinomas of the cervix, vagina, vulva and anal canal. Nearly 88% of cervical cancers worldwide are the result of HPV subtypes 16, 18, 45, 31, 33, 52 and 58 [para 004]. DNA vaccines have many conceptual advantages over more traditional vaccination methods, such as live attenuated viruses and recombinant protein-based vaccines. DNA vaccines are safe, stable, easily produced, and well tolerated in humans [para 005].
Methods of inducing an immune response in individuals against an immunogen comprise administering to the individual the isolated nucleic acid molecule that encodes the amino acid sequence for a consensus immunogen selected from the group consisting of HPV 6 E6 and E7, HPV 11 E6 and E7, HPV 33 E6 and E7, HPV 58 E6 and E7, and fragments thereof [para 046]. Teaching claims 1 and 4. Figure 3 describes mice in combo group received both p6E6E7 and p11E6E7 per construct of DNA per immunization. DNA was administered via IM injection, followed by electroporation [para 17]. The vaccines elicit an immune response against HPV subtypes found predominantly to be associated with forms of head and neck cancer, and other forms of otolaryngologic diseases, in particular the vaccines include HPV 6 E6 and E7 and HPV 11 E6 and E7, and preferably both [para 047]. Based on these results from the phylogenic analyses, we developed two type-specific E6/E7 consensus DNA vaccines [para 82].
These vaccines elicit an immune response against HPV subtypes found predominantly to be associated with forms of cervical cancer, in particular the vaccines include HPV 33 E6 and E7 and HPV 58 E6 and E7, and preferably both [para 048]. Teaching claim 21. Genetic constructs may be administered by means including, but not limited to, electroporation methods and devices [para 70-72] which improves expression and immunogenicity of DNA vaccines [para 5]. Teaching claim 22. Figure 5 teach cytokine production by antigen-specific T-cells characterized by intracellular cytokine staining. Weiner et al., describe the HPV11 E6 and E7-specific T-cell immune response (FIG. 4B) [para 94]. Observation of the magnitude of cytokine production of CD4+ cells versus CD8+ T-cells, one can conclude that the immune responses elicited by p6E6E7 and p11E6E7 is heavily skewed towards driving CD8+ lymphocytes, which are associated in all models with their cell clearance [para 96]. Intracellular cytokine staining showed that vaccination with p6E6E7 and p11E6E7 was able to elicit a significant percentage of IFN-γ, TNF-α, and IL-2 producing T-cells [para 97]. TNF-α production may be of further interest given the potential tumor proliferative properties of HPV6 and HPV 11. IL-2 is another signaling molecule that has been observed to play a central role in the proliferation and differentiation of T-cells in the immune system. As a consequence, IL-2 is often examined in conjunction with other cytokines to gain further perspective on the magnitude and quality of a particular immune response. Given the above, the significant percentages of CD4+ and CD8+ cells producing IFN-γ, TNF-α, and IL-2 after vaccination with p6E6E7 suggests that the vaccine was successful in inducing a potent immune response [para 97].
Therefore, it would have been prima facie obvious at the time of applicants’ invention to have applied the teaching of Weiner 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 Weiner al., the improved immune response from DNA nucleic acid sequence encoding a synthetic HPV antigen as E6 and E7 domains of subtypes selected from the group consisting of HPV6, HPV11, HPV18, HPV31, HPV33, HPV52 and HPV58. Furthermore, Weiner et al., teach specific HPV subtypes are known to be associated with different forms of cancer. Moreover, it would have been prima facie obvious at the time of applicants’ invention to have applied the teaching of Weiner 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 Weiner teach using the synthetic antigens of the E6 and E7 domains from subtypes HPV 6, HPV 11, HPV 33 and HPV58 are safe, stable, easily produced, and well tolerated. One of ordinary skill in the art would have a reasonable expectation of success by incorporating the synthetic consensus antigens capable of generating an immune response. Finally, it would have been prima facie obvious to combine the invention of Fotin-Mleczek et al., and Weiner et al., to obtain the advantageous benefits of a vaccine which encodes an immunostimulatory 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
6. Applicant's arguments filed Nov. 10, 2025 have been fully considered but they are not persuasive. The rejection of 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 maintained for reasons of record.
Applicants argue that Fotin-Mleczek et al., in view of Weiner et al. do not provide a skilled artisan with a reasonable expectation of success. In this case, the Office clearly and specifically pointed to: Combining prior art elements according to known methods to yield predictable results; substitution of one known element for another to obtain predictable results; Use of known technique to improve similar compositions in the same way; Applying a known technique to a known composition ready for improvement to yield predictable results; 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 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. In this case, all rationale employed provided 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 E6 and E7 domains of HPV subtypes selected from the group consisting of: HPV6, HPV11, HPV18, HPV31, HPV33, HPV52, and HPV58; and assert that Weiner does not teach or suggest the use of programmed death-ligand 1 (PDL1) antibody in combination with an HPV antigen.
In response to applicant's arguments against the Fotin-Mleczek et al., and Weiner et al., references 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 Weiner et al. Fotin-Mleczek et al., teach 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 antigen capable of generating an immune response in the subject, or an immunogenic fragment or variant thereof wherein the antigen is HPV, wherein the HPV antigen from E6 and E7; while Weiner et al., clearly teach the E6 or E7 domains of subtypes selected from the group consisting of HPV6, HPV11, HPV18, HPV31, HPV33, HPV52 and HPV58. Weiner et al., teach methods of inducing an immune response in individuals against an immunogen comprise administering to the individual the isolated nucleic acid molecule that encodes the amino acid sequence for a consensus immunogen selected from the group consisting of HPV 6 E6 and E7, HPV 11 E6 and E7, HPV 33 E6 and E7, HPV 58 E6 and E7, and fragments thereof. Furthermore, Weiner et al., teach the immunogenic efficacy of p6E6E7 and p11E6E7 by looking at the high levels of IFN-γ and cytokine production which would clearly provide a reasonable expectation of success.
Additionally, Fotin-Mleczek et al., in view of Weiner et al., clearly teach each and every instantly claimed limitations.
Applicants submit that Fotin-Mleczek in fact discloses HPV E6 and E7 domain antigens as two in a very long list that spans a page, i.e., from line 5 of page 62 to line 2 of page 63, and for which no actual data is offered to provide a skilled artisan with a reasonable expectation of successfully obtaining the claimed subject matter. The MPEP section 2123 teaches that patents are relevant as prior art for all they contain, “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir.1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
Applicant is reminded that reduction to practice is not teach standard. Rather a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art. Fotin-Mleczek et al’s teaching is not limited to specific examples, or even preferred embodiments. Furthermore, MPEP 2131 recites when a species is clearly named, the species claim is anticipated or rendered obvious no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. 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 Weiner et al., reinforces the teaching by evidencing Figure 5 showing cytokine production by antigen-specific T-cells characterized by intracellular cytokine staining. Weiner et al., describe the HPV11 E6 and E7-specific T-cell immune response (FIG. 4B). Observation of the magnitude of cytokine production of CD4+ cells versus CD8+ T-cells, allows one to conclude that the immune responses elicited by p6E6E7 and p11E6E7 are heavily skewed towards driving CD8+ lymphocytes, which are associated in all models with their cell clearance abilities. Therefore applicant’s argument is not persuasive especially when considering the advantageous and beneficial teachings of Fotin-Mleczek et al., in view of Weiner et al.
Applicants argue that prior art references do not teach the inclusion of PDL1 antibody, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, it would have been prima facie obvious at the time of applicants’ invention to have applied the teaching of Weiner et al., to the 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 Weiner teach using the synthetic antigens of the E6 and E7 domains from subtypes HPV 6, HPV 11, HPV 33 and HPV58 are safe, stable, easily produced, and well tolerated. Accordingly, this argument is not found persuasive.
In response to Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case,
it would have been prima facie obvious at the time of applicants’ invention to apply the teaching of Weiner 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 Weiner al., teach the improved immune response from DNA nucleic acid sequence encoding a synthetic HPV antigen as E6 and E7 domains of subtypes selected from the group consisting of HPV6, HPV11, HPV18, HPV31, HPV33, HPV52 and HPV58.
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 [para 19]. 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. Weiner et al., Figure 5 shows cytokine production by antigen-specific T-cells characterized by intracellular cytokine staining. Weiner et al., describe the HPV11 E6 and E7-specific T-cell immune response (FIG. 4B) [para 94]. Observation of the magnitude of cytokine production of CD4+ cells versus CD8+ T-cells, one can conclude that the immune responses elicited by p6E6E7 and p11E6E7 is heavily skewed towards driving CD8+ lymphocytes, which are associated in all models with their cell clearance [para 96]. Intracellular cytokine staining showed that vaccination with p6E6E7 and p11E6E7 was able to elicit a significant percentage of IFN-γ, TNF-α, and IL-2 producing T-cells [para 97]. TNF-α production may be of further interest given the potential tumor proliferative properties of HPV6 and HPV 11. IL-2 is another signaling molecule that has been observed to play a central role in the proliferation and differentiation of T-cells in the immune system. As a consequence, IL-2 is often examined in conjunction with other cytokines to gain further perspective on the magnitude and quality of a particular immune response. Given the above, the significant percentages of CD4+ and CD8+ cells producing IFN-γ, TNF-α, and IL-2 after vaccination with p6E6E7 suggests that the vaccine was successful in inducing a potent immune response [para 97]. Therefore Fotin-Mleczek et al., in view of Weiner et al., clear evidence that the improved results are neither surprising nor unexpected. Therefore none of Applicants arguments are not found persuasive and the rejection of record is maintained.
Conclusion
7. No claims allowed.
8. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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 Dan Kolker, can be reached on 571-272-3181. 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