DETAILED ACTION
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 .
Priority
The application claims priority to foreign applications DKPA 2021 00317, filed on 26 March 2021, and DKPA 2021 70182, filed on 21 April 2021. The application is 371 of application PCT/EP2022/057955, filed on 25 March 2022. The effective filing date is 26 March 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 09 January 2024, 12 March 2024, 15 January 2025, and 20 October 2025 were considered by the examiner.
Election/Restrictions
In response to the restriction/election of species requirement, issued on 27 February 2026, the applicant has elected Group 1:
Claims 1-7, 9, 12, 15-23, and 48, drawn to a method of treating a subject having cancer, the method comprising administering to the subject (a) an anticancer vaccine comprising a polynucleotide comprising a nucleotide sequence encoding a targeting unit that targets antigen-presenting cells, a multimerization unit, and an antigenic unit comprising one or more cancer antigens or parts thereof; and (b) one or more checkpoint inhibitors.
Furthermore, the applicant has elected to prosecute the claims of Group 1, drawn to methods for treating a subject having cancer, as they relate to the following species:
Chemokine receptor CCR1 as the surface molecule;
anti-PD-L1 antibody as the one or more checkpoint inhibitor; and
HNSCC as the tumor type.
Claims 1-7, 9, 12, and 15-23 read on the elected invention. After performing the prior art search, the examiner has decided to rejoin claim 24 . Claims 1-7, 9, 12, and 15-24 are the subject of this office action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 15, 17, and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), which was cited in the IDS, filed on 09 January 2024.
Krauss et al presents the first interim clinical response data from 14 heavily pre-treated patients, enrolled in clinical trial NCT03548467. This trial uses a DNA vaccine (Relevant to instant claim 17), VB10.NEO, which as shown in the following figure taken from Krauss et al teaches several limitations, regarding the vaccine component, established in instant claim 1 of the current application, such as a dimerization domain (Relevant to instant claim 15), a targeting unit, and an antigenic unit :
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The antigenic unit of the individualized vaccine is taught to comprise up to 20 unique neoantigens (Relevant to instant claims 2 and 3) (Background). In this trial, participants with locally advanced or metastatic solid tumors (Relevant to instant claim 23), including melanoma, non-small-cell lung carcinoma (NSCLC), clear renal cell carcinoma (RCC), urothelial cancer, and squamous cell carcinoma of the head and neck (SCCHN), received the VB10.NEO vaccine, administered via intramuscular injection (Relevant to instant claim 21), with 12 out of 14 patients receiving the vaccine in combination with checkpoint inhibitors (Relevant to instant claims 1 and 22) (Background and VB N-01 Study). Prior to vaccine administration, the participants received at least 12 weeks of checkpoint inhibition therapy, often in addition to other lines of anti-cancer treatments (VB N-01 Study).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 12, 15-19, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017118695 A1 (herein Granum) in view of Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss).
In regard to claim 1, Granum teaches an anticancer cancer vaccine comprising polynucleotides or polypeptides, methods of treatment of cancer wherein such an anticancer vaccine is used, as well as methods for producing the vaccine (Abstract). In the abstract section it is also disclosed that “the vaccine comprises a polynucleotide comprising a nucleotide sequence coding a targeting unit, a dimerization unit, a first linker and an antigenic unit, wherein said antigenic unit comprises n-1 antigenic subunits, each subunit comprising at least part of a cancer neoepitope sequence and a second linker and said antigenic unit further comprising a final cancer neoepitope sequence wherein n is an integer of from 3 to 50, or the vaccine comprises the polypeptide encoded by the polynucleotide or a dimeric protein consisting of two polypeptides encoded by the polynucleotide.” This disclosure teaches the limitations presented in instant claim 1, regarding the anticancer vaccine component of the claim. The authors also suggest that a treatment using the disclosed vaccine may be used in combination with checkpoint blockade inhibitor treatment (Page 28 lines 9-10).
Although Granum et al do suggest the possibility of combining the disclosed method of treating cancer with a checkpoint-blockade therapy, they do not provide any example embodiments or details as to how the combined therapy would be implemented. Krauss teaches these deficiencies.
Krauss et al presents the first interim clinical response data from 14 heavily pre-treated patients, enrolled in clinical trial NCT03548467. This trial uses a DNA vaccine, VB10.NEO, that closely resembles the vaccine described by Granum, as shown in the following figure taken from Krauss et al:
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In this trial, participants with locally advanced or metastatic solid tumors, including melanoma, non-small-cell lung carcinoma (NSCLC), clear renal cell carcinoma (RCC), urothelial cancer, and squamous cell carcinoma of the head and neck (SCCHN), received the VB10.NEO vaccine, with 12 out of 14 patients receiving the vaccine in combination with checkpoint inhibitors (Background and VB N-01 Study). Prior to vaccine administration, the participants received at least 12 weeks of checkpoint inhibition therapy, often in addition to other lines of anti-cancer treatments (VB N-01 Study). The authors teach that most responses to checkpoint inhibitors occur within the first 3-5 months, after which decreases in lesion size are unexpected and the lesions usually grow without additional therapeutic intervention (Efficacy Panel 2). The authors demonstrate that the method resulted in a clinical response in 7 of the 14 patients, with 4 of the responsive patients representing SCCHN (Efficacy Panel 2 and Figure 2).
It would have been obvious, to one skilled in the art, to combine the teachings of Granum (methods of treating cancer comprising the administration of neoantigen vaccine) with the method taught by Krauss. Granum suggests combining the disclosed method with checkpoint inhibitors, and Krauss’ data indicating that such a combination would be successful (Figures 2 and 3) provides clear motivation.
In regard to claim 2, Granum teaches that “mutations found in a tumor are normally highly individual, and accordingly, the vaccine according to the present invention is personalized for use only in the patient having the mutation in question” (Page 9 lines 11-13). The use of the term “personalized”, as stated in the reference, is functionally equivalent to the term “individualized”, as used in the current application.
In regard to claims 3 and 4, Granum teaches that between 5 to 50 neopepitopes may be included in the vaccine, in order to obtain the most efficient immune response without diluting the T cells (Page 12 lines 32-36). It is taught that a preferred embodiment includes at least 10 neoepitopes (Page 12 lines 28-29). It is stated that each neoepitope is part of an antigenic subunit, consisting of a neoepitope and a linker, and that a plurality of these subunits constitutes the antigenic unit (Page 11 lines 27-32).
In regard to claim 12, Granum teaches that the targeting unit, which is defined as “a unit that delivers the polypeptide/protein with its antigen to an antigen presenting cell for MHC class II-restricted presentation to CD4+ T cells or for providing cross presentation to CD8+ T cells by MHC class I restriction”, may target surface molecules such as HLA, CD14, CD40, chemokine receptors, and TLRs (Page 17 line 11 – Page 18 line 16). Additionally, the authors state that a preferred embodiment comprises a targeting unit with affinity towards a chemokine receptor selected from CCR1, CCR3, and CCR5 (Page 18 lines 7-10).
In regard to claims 15, 16, 18, and 19, Granum provides an example embodiment of the disclosed neoantigen vaccines, which is comprised of the following structure (Page 34 lines 5-8):
Signal peptide (human LD78b) - Targeting unit (Full-length LD78b) - Dimerization unit (Hinge-region 1 IgG3 - Hinge-region 4 from IgG3 – Gly/Leu linker- CH3 domain from IgG3) - First linker (Gly/Leu linker) - Antigenic unit.
This exemplary embodiment teaches the limitations established in claims 15 (dimerization domain), claim 16 (flexible/non-immunogenic liner connecting dimerization unit to the antigenic unit), claim 18 (a signal peptide), and claim 19, which establishes the source of the polynucleotide/protein sequences of the various structural components of the vaccine.
In regard to claim 17, Krauss teaches a therapeutic anticancer neoepitope vaccine comprising a polynucleotide encoding a targeting unit, a dimerization unit, a linker, and an antigenic unit (Page 28 lines 14-27).
In regard to claim 21, Granum teaches that the vaccine may comprise a pharmaceutically acceptable carrier, diluent, adjuvant, or buffer (Page 26 lines 3-4).
In regard to claim 22, Krauss teaches that the checkpoint inhibitor therapy is administered for at least 12 weeks, prior to the administration of the vaccine, after which the two treatments are administered concurrently (VB N-01 Study).
In regard to claim 23, Krauss teaches a method of treating cancer in patients with locally advanced or metastatic solid tumors (Background).
In regard to claim 24, Granum and Krauss teach a method for treating cancer in a subject, comprising the administration of a personalized anti-cancer vaccine, comprising multiple neoepitopes, and one or more checkpoint inhibitors, as discussed above.
Since Granum and Krauss teach a method that comprise the administration of both a personalized vaccine and a checkpoint inhibitor, a kit comprising both components, in separate containers, would have been obvious to one skilled in the art. By combining the components into a kit, one is able simplify the logistics, regarding ordering, transportation, storage, and insurance billing, as the kit would ensure that all the necessary components for the treatment are accounted for while ordering, shipping, storing, or billing.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017118695 A1 (herein Granum) and Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss) in view of Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
In regard to claims 5 and 6, Granum and Krauss teach a method for treating cancer in a subject, comprising the administration of a personalized anti-cancer vaccine, comprising multiple neoepitopes, and one or more checkpoint inhibitors, as discussed for the 35 U.S.C. rejections of claims 1-3.
Neither Granum nor Krauss teach that the antigenic unit of the vaccine further comprises one or more patient-present shared cancer antigens or parts thereof. Cafri teaches this deficiency.
Carfi relates to a clinical trial involving the administration of mRNA vaccines, comprising validated neoantigens, predicted neoantigens, and patient-present shared cancer antigens (driver genes), concatenated into single constructs (Abstract). In this study, 4 patients were treated with mRNA vaccines, comprising a shared mRNA backbone, and 20 epitopes, comprised of validated autologous tumor neoantigens, any mutations found in driver genes (TP53, KRAS, or PIK3CA), and HLA-I-predicted neoepitopes (Results and Figures 2). T cells isolated from one of the three patients, immunized with vaccine containing epitopes for driver gene products, showed the development of reactivity towards an oncogenic KRAS mutant after vaccination (Results: Immunogenicity of mRNA-4650 in patient 4271). When designing this patient’s vaccine, exome and RNA-seq analysis identified the KRAS G12D mutation, a common oncogenic mutation shared between many forms of cancer, and an epitope corresponding to this mutation was included in the administered mRNA vaccine, as well as 13 predicted neoantigens and 5 validated neoantigens. The authors note that initial screens, collected before vaccination, showed no KRAS G12D reactivity, however following vaccination mutant-specific reactivity was observed. In addition to developing reactivity towards the oncogenic KRAS mutant, the patient also showed reactivity towards 5 candidate antigens (3 were reactive only towards the mutant form of the antigen). These results demonstrate that the personalized mRNA vaccine were able to stimulate an immune response towards their intended/predicted targets, although it must be noted that no clinical response was observed in the trial. Furthermore, the authors suggest that this vaccine design strategy could be combined with other immune modulators, such as checkpoint inhibitors (Discussion).
It would have been obvious, to one skilled in the art, to combine the teachings of Cafri (cancer vaccines comprising shared cancer antigens and personalized neoepitopes) with those of Granum and Krauss (a method of treating cancer comprising administration of an anti-cancer vaccine and a checkpoint inhibitor). In addition to directly suggesting the combination of the disclosed vaccine with checkpoint inhibitors, Cafri also demonstrates the immunogenicity of the shared cancer antigen, in the context of a neoantigen vaccine (Results: Immunogenicity of mRNA-4650 in patient 4271). These findings establish a reasonable expectation of success, when considering incorporating patient-present shared cancer antigens into the teachings of Granum and Krauss. Additional motivation for this combination comes from the fact that common oncogenes, such as KRAS, PIK3CA, and TP53, are mutated in a large percentage of assayed cancers and are genetic drivers of multiples cancers, a commonly known fact, which has sparked decades of research investigating methods targeting these genes and their products. For example, the RAS proto-oncogenes (HRAS, KRAS, and NRAS) are found to harbor mutations in ~30% of malignant human cancers, as taught by Zhang (Introduction). Thus, by adding patient-present shared cancer antigens to the vaccine, taught by Granum, one is ensuring that the vaccine-induced immune-response is targeting a driver of cancer.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri) in view of Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
Granum, Krauss, and Cafri teach a method for treating cancer in a subject, comprising the administration of a personalized anti-cancer vaccine, comprising multiple neoantigens and shared antigens, and one or more checkpoint inhibitors, as discussed for the 35 U.S.C. rejections of claims 5 and 6.
Granum, Krauss, and Cafri do not teach a method for treating cancer in a subject, comprising the administration of a non-personalized anti-cancer vaccine, comprising shared antigens, and one or more checkpoint inhibitors. Li teaches this deficiency.
Li et al is an editorial, discussing reported interim data from a phase 1 clinical trial, NCT02410733 (Paragraph 1). The referenced trial is a multicenter, non-randomized, open-label, dose-escalation trial designed to evaluate the safety and tolerability of BNT111, a vaccine targeting four shared melanoma tumor antigens (Paragraph 4). In this trial, patients with advanced melanoma, that express at least one of the four targeted shared antigens, were administered BNT111 (Paragraph 4). 78% of the treated patients showed immune responses against at least one of the shared antigens (Paragraph 5). From a subset of 42 patients, who had previously been treated with checkpoint inhibitors, 25 were treated with the vaccine alone and the remaining 17 were treated with vaccine in combination with a checkpoint inhibitor (Paragraph 6). Of the patients receiving mono-vaccine therapy three experienced a partial response, and of the patients receiving the combination therapy six developed a partial response (Paragraph 6). This finding shows a clear advantage of the combination therapy over the mono-vaccine therapy, although the authors do note that the response rate of the combination therapy is equivalent to patients receiving mono-checkpoint blockade therapy. The authors note that the results of this study highlight the potential of such vaccines for the treatment of various cancers, beyond just melanoma, in combination with checkpoint inhibitors (Paragraph 10). The authors also discuss the pros and cons of using shared tumor antigens compared to neoantigens and make it clear that meaningful comparisons between the efficacy of either approach were difficult to make at the time of writing, due to limited clinical data (Paragraph 10). Thus, at the time of writing, 2020, it was impossible to determine if vaccines comprising neoantigens, shared tumor antigens, or a combination of antigens were the best strategy to pursue.
Considering the teachings of Li, it would have been obvious to one skilled in the art to modify the method, taught by Granum, Krauss, and Cafri, to only include shared tumor antigens. As taught by Li, the art, at the time of filing, was unclear as to the best strategy to employ for anti-cancer vaccine design, regarding the nature of the included antigens. The results discussed by Li, show that there was a reasonable expectation of success for the use of a vaccine comprising shared tumor antigens, as shown by the robust immune response, to such a vaccine (Paragraphs 5 and 6).
Claims 9, 20, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017118695 A1 (herein Granum) and Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss) in view of Lopez J, et al. A Phase Ib Study to Evaluate RO7198457, an Individualized Neoantigen-Specific Immunotherapy (iNeST), in Combination with Atezolizumab in Patients With Locally Advanced or Metastatic Solid Tumors. Cancer Res 15 August 2020; 80 (16_Supplement): CT301. https://doi.org/10.1158/1538-7445.AM2020-CT301 (herein Lopez).
In regard to claims 9 and 20, Granum and Krauss teach a method for treating cancer in a subject, comprising the administration of a personalized anti-cancer vaccine, comprising multiple neoepitopes, and one or more checkpoint inhibitors, as discussed for the 35 U.S.C. rejections of claim 1.
Neither Granum nor Krauss teach that the checkpoint inhibitor is either one or more inhibitors selected from the group consisting of anti-PD-L1 antibody, anti-TIGIT antibody, and anti-CTLA-4 antibody. Lopez teaches this deficiency.
Lopez relates to a phase 1b study evaluating R07198457, an individualized neoantigen vaccine candidate, in combination with the atezolizumab, an anti-PD-L1 antibody-based checkpoint inhibitor, for the treatment of locally advanced or metastatic solid tumors (Background). It is taught that this combination has a manageable safety profile and induces significant levels of neoantigen-specific immune response (Discussion).
It would have been obvious, to one skilled in the art, to combine the teachings of Granum and Krauss (a method of treating cancer comprising administration of an anti-cancer vaccine and a checkpoint inhibitor) with those of Lopez (a similar method, in which the checkpoint inhibitor is atezolizumab). Lopez establishes that combination therapies, comprising administering a personalized neoantigen vaccine in combination with atezolizumab, have manageable safety profiles, and as such provides motivation for the use of anti-PD-L1 antibodies, as checkpoint inhibitors.
In regard to claim 48, Granum and Krauss teach a method for treating cancer in a subject, comprising the administration of a personalized anti-cancer vaccine, comprising multiple neoepitopes, and one or more checkpoint inhibitors, as discussed for the 35 U.S.C. rejections of claim 1.
Granum also provides guidance on dosing regimens (Page 27 line 24 – Page 28 line 2). Granum teaches that the vaccine should be administered in a “immunologically effective amount”, which can be determined by a physician. Granum also provides dose ranges for both DNA and RNA vaccines, 0.3 mg – 6.0 mg or 5μg – 5 mg, respectively (Page 28 lines 1-2). The amounts referenced in the current claim, 3mg or 6mg, overlap with the range taught by Granum for DNA vaccines, and as highlighted in MPEP 2144.05, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. It is also taught that the vaccine may be administered using at least three-week intervals, to avoid T cell exhaustion (Page 27 lines 24-26).
Lopez provides guidance regarding the dosing regimen of atezolizumab (Methods). Lopez teaches a regimen, in which atezolizumab is administered on day 1 of a 21-day cycle, at a dose of 1200 mg. This is identical to the limitation established in instant claim 48, regarding the administration of atezolizumab.
The dosing regimens described in the instant claim would result from routine optimization, using the initial guidance provided by Granum and Lopez. One skilled in the art would be motivated, with an expectation of success, to optimize the method disclosed by performing routine optimization (including recited dosages and dose schedules), to optimize dosages, dosing methods, and repetition rates. It is not inventive to discover optimal or workable ranges by routine experimentation. An administering physician can easily determine optimum dosages, dosing methods and repetition rates (see in re Aller, 220 F.2d 454, 456 (CCPA 1955)).
The instant claim also establishes efficacy limitations of the invention. MPEP 2121 states: “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability.” Since each element of claim 48 is taught by prior art, efficacy similar to that illustrated in the instant application and set out in claims 48 is presumed (see In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 12691165
Claims 1-4, 6, 7, 12, 15-19, and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12691165 (herein ‘165) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li).
The claims of ‘165 are drawn to an individualized anticancer vaccine, comprising an identical structure to the vaccine referenced in the methods described in instant claims 1, 2, 6, 7, 12, 15, 16, 17, 18, 19, and 21. The teachings of Granum and Krauss, as discussed for 35 U.S.C. 103 rejections of claims 1-4, 12, 15-19, and 21-24, render obvious a method for treating cancer, comprising the administration of checkpoint inhibitors and a vaccine, which is similar in structure to that described in the claims of ‘165, but differs in the nature of the comprised antigens. The claims of ‘165 refer to patient-present shared antigens, whereas the teachings of Granum and Krauss refer to individualized neoantigens. The teachings of Li et al render obvious the substitution of the neoantigens with patient-present shared antigens, as discussed for the 35 U.S.C. 103 rejection of instant claim 7. Thus, by combining the teachings of Granum, Krauss, and Li to the invention encompassed by claims 1-19 of ‘165, one would arrive at a method identical to that described by instant claims 1, 2, 6, 7, 12, 15, 16, 17, 18, 19, and 21. Furthermore, such a combination would also render obvious a the limitations of instant claims 3, 4, and 22-24, as discussed in their corresponding 35 U.S.C. 103 rejections.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12691165 (herein ‘165) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
As discussed for the non-statutory double patenting rejection of instant claim 3, claims 1-19 of ‘165, Granum, Krauss, and Li teach method for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the vaccine further comprises one or more patient-present shared cancer antigen. This deficiency is taught by Cafri, as discussed in the 35 U.S.C. 103 rejections of instant claims 5 and 6. In short, Cafri et al demonstrate that a cancer vaccine, comprising both neoantigens and patient-present shared antigens, was capable of inducing a significant immunogenic response, and that this response was directed to both neoantigens and patients-present shared antigens(Results: Immunogenicity of mRNA-4650 in patient 4271). This demonstration provides ample motivation to combine this antigen selection strategy with the above-mentioned treatment method.
Claims 9, 20, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12691165 (herein ‘165) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li), and Lopez J, et al. A Phase Ib Study to Evaluate RO7198457, an Individualized Neoantigen-Specific Immunotherapy (iNeST), in Combination with Atezolizumab in Patients With Locally Advanced or Metastatic Solid Tumors. Cancer Res 15 August 2020; 80 (16_Supplement): CT301. https://doi.org/10.1158/1538-7445.AM2020-CT301 (herein Lopez).
As discussed for the non-statutory double patenting rejection of instant claim 1, claims 1-19 of ‘165, Granum, Krauss, and Li teach method for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the checkpoint inhibitor targets PD-L1. This deficiency is taught by Lopez, as discussed in the 35 U.S.C. 103 rejections of instant claims 9, 20, and 48. In short, Lopez demonstrates that a neoantigen vaccine administered in combination with atezolizumab to cancer patients displayed a manageable toxicity profile and induced a significant immune response (Discussion). This provides motivation to combine the above-mentioned method with atezolizumab, as it presents a reasonable expectation of success, in terms of safety and immunogenicity.
U.S. Patent No. 12059459
Claims 1-4, 12, 15-19, and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12059459 (herein ‘459) in view of WO2017118695 A1 (herein Granum) and Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss).
Claim 21 of ‘459 refers to a method of treating cancer, comprising the administration of a neoantigen vaccine composition, as described in claim 1 of ‘459. This method is encompassed by claims of the instant application, with the sequence identity limitations of claim 1 of ‘459 merely defining a species of the genus claimed in the current application (see instant claims 12 and 19). The only difference between the two methods is the inclusion of an additional limitation, that being the additional administration of a checkpoint inhibitor, in the current application. This additional limitation is taught by Granum and Krauss, as discussed in the 35 U.S.C. 103 rejection of instant claim 1.
Claims 9, 20, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12059459 (herein ‘459) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Lopez J, et al. A Phase Ib Study to Evaluate RO7198457, an Individualized Neoantigen-Specific Immunotherapy (iNeST), in Combination with Atezolizumab in Patients With Locally Advanced or Metastatic Solid Tumors. Cancer Res 15 August 2020; 80 (16_Supplement): CT301. https://doi.org/10.1158/1538-7445.AM2020-CT301 (herein Lopez).
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-22 of ‘459, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the checkpoint inhibitor targets PD-L1. This deficiency is taught by Lopez, as discussed in the 35 U.S.C. 103 rejections of instant claims 9, 20, and 48. In short, Lopez demonstrates that a neoantigen vaccine administered in combination with atezolizumab to cancer patients displayed a manageable toxicity profile and induced a significant immune response (Discussion). This provides motivation to combine the above-mentioned method with atezolizumab, as it presents a reasonable expectation of success, in terms of safety and immunogenicity.
Claims 5 and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12059459 (herein ‘459) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-22 of ‘459, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the vaccine comprises one or more patient-present shared antigens. This deficiency is taught by Cafri, as discussed in the 35 U.S.C. 103 rejections of instant claims 5 and 6. In short, Cafri et al demonstrate that a cancer vaccine, comprising both neoantigens and patient-present shared antigens, was capable of inducing a significant immunogenic response, and that this response was directed to both neoantigens and patients-present shared antigens(Results: Immunogenicity of mRNA-4650 in patient 4271). This demonstration provides ample motivation to combine this antigen selection strategy with the above-mentioned treatment method.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12059459 (herein ‘459) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri), and Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-22 of ‘459, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the vaccine is non-individualized, comprising one or more shared antigens. This deficiency is taught by Li, as discussed in the 35 U.S.C. 103 rejections of instant claim 7.
U.S. Patent No. 12697377
Claims 1-4, 12, 15-19, and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12697377 (herein ‘377) in view of WO2017118695 A1 (herein Granum) and Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss).
Claim 19 of ‘377 refers to a method of treating cancer, comprising the administration of a neoantigen vaccine composition, as described in claim 1 of ‘377. This method is encompassed by claims of the instant application. The only difference between the two methods is the inclusion of an additional limitation, that being the additional administration of a checkpoint inhibitor, in the current application. This additional limitation is taught by Granum and Krauss, as discussed in the 35 U.S.C. 103 rejection of instant claim 1.
Claims 9, 20, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12697377 (herein ‘377) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Lopez J, et al. A Phase Ib Study to Evaluate RO7198457, an Individualized Neoantigen-Specific Immunotherapy (iNeST), in Combination with Atezolizumab in Patients With Locally Advanced or Metastatic Solid Tumors. Cancer Res 15 August 2020; 80 (16_Supplement): CT301. https://doi.org/10.1158/1538-7445.AM2020-CT301 (herein Lopez).
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-19 of ‘377, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the checkpoint inhibitor targets PD-L1. This deficiency is taught by Lopez, as discussed in the 35 U.S.C. 103 rejections of instant claims 9, 20, and 48. In short, Lopez demonstrates that a neoantigen vaccine administered in combination with atezolizumab to cancer patients displayed a manageable toxicity profile and induced a significant immune response (Discussion). This provides motivation to combine the above-mentioned method with atezolizumab, as it presents a reasonable expectation of success, in terms of safety and immunogenicity.
Claims 5 and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of US Patent No .12697377 (herein ‘377)) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-19 of ‘377, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the vaccine comprises one or more patient-present shared antigens. This deficiency is taught by Cafri, as discussed in the 35 U.S.C. 103 rejections of instant claims 5 and 6. In short, Cafri et al demonstrate that a cancer vaccine, comprising both neoantigens and patient-present shared antigens, was capable of inducing a significant immunogenic response, and that this response was directed to both neoantigens and patients-present shared antigens(Results: Immunogenicity of mRNA-4650 in patient 4271). This demonstration provides ample motivation to combine this antigen selection strategy with the above-mentioned treatment method.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12697377 (herein ‘377) in view of WO2017118695 A1 (herein Granum), Krauss. J, et al. (2019) P424 VB10.NEO, and individualized neoepitope cancer vaccine, induces positive clinical responses in patients with locally advanced or metastatic solid tumors. 34th Annual Meeting SITC, 9 November 2019 (herein Krauss), and Cafri G, et al. (2020) mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988 (herein Cafri), and Li L, et al. (2020) Cancer vaccines: shared tumor antigens return to the spotlight. Signal Transduct Target Ther. 2020 Oct 30;5(1):251 (herein Li) with Zhang Y, Ma JA, Zhang HX, Jiang YN, Luo WH. Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020 Feb;19(2):163-173 (herein Zhang) providing additional evidentiary value.
As discussed for the non-statutory double patenting rejection of instant claims 1-4, 12, 15-19, and 21-24, claims 1-19 of ‘377, Granum, and Krauss teach methods for treating cancer comprising the administration of a checkpoint inhibitor and a vaccine, comprising one or more neoantigens. This combination of teachings does not teach that the vaccine is non-individualized, comprising one or more shared antigens. This deficiency is taught by Li, as discussed in the 35 U.S.C. 103 rejections of instant claim 7.
Conclusion
No claims allowed.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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