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 .
The Applicant’s Amendment to the Claims filed on August 4, 2025 is entered.
Claims 3-9, 11, 14, 17-23, 25, 27, 31, 33-35, 40-45, 47-50, and 52-54 are canceled.
Claims 1-2, 10, 12-13, 15-16, 24, 26, 28-30, 32, 36-39, 46, 51, and 55-57 are pending and under examination.
Priority
This US17/788,651 filed on 06/23/2022 which is a 371 of PCT/US2022/030037 filed on 05/19/2022 which claims US Provisional 63/194,041 filed on 05/27/2021.
Information Disclosure Statement
The information disclosure statement filed October 2, 2025 has been considered by the examiner. The No IDS Size Fee Assertion box under 37 CFR 1.17(v) is checked.
Response to Amendments
All objections and rejection made in the previous office action and not repeated in this office action are withdrawn in view of the Applicant’s Amendment to the Claims filed on August 4, 2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-2, 10, 12-13, 15-16, 24, 26, 28-30, 32, 36-39, 46, 51, and 55-57 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This is a new grounds of rejection necessitated by amendment.
Regarding currently amended base claim 1, the newly added phrase: “and wherein bioinformatics algorithms select the tumor-specific neoantigen long peptides and the tumor-specific neoantigen short peptides based on a predicted immunogenicity and solubility” appears to require an active method step which is not consistent with the claim which is drawn to a product. The claim is indefinite because it is unclear whether the claim intends to require an active method step of selecting and what structure is implied by such method step and thus one of ordinary skill in the art would not be able to determine the metes and bounds of the claimed product composition.
Claims 2, 10, 12-13, 15-16, 24, 26, 28-30, 32, 36-39, 46, 51, and 55-57 are indefinite for the same reasoning as they depend from claim 1 and are not remedial.
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-2, 10, 12-13, 15-16, 24, 26, 28-30, 32, 36-39, 46, 51, and 55-57 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new grounds of rejection necessitated by amendment.
Claim 1 is currently amended to require the limitation of “wherein bioinformatics algorithms select the tumor-specific neoantigen long peptides and the tumor-specific neoantigen short peptides based on a predicted immunogenicity and solubility”. Thus the claims appear to require the critically essential element of tumor-specific neoantigen peptides selected by bioinformatics algorithms that possess the property/function of selecting the tumor-specific neoantigen long peptides and the tumor-specific neoantigen short peptides based on a predicted immunogenicity and solubility for treating any kind of cancer in a human subject.
The specification explicitly states in para 00121 that: “The vaccine will undergo final formulation “at-bedside” at the clinical site so as to be uniquely tailored to each patient’s tumor antigen profile and predicted immune responsiveness”. Claim 1 is drawn to a product rather than to a method. The present method claims are drawn to methods of using such product. In view of the instant specification it appears that the structure of the product is not known until final formulation “at-bedside” at the clinical site.
Further, a review of the instant specification does not appear to provide a representative set of such bioinformatics algorithms to show possession of this critically essential element of the claims. The term algorithm appears only twice in the specification. First, in para 00113, as follows:
Each personalized vaccine product will be composed of up to four patient-specific, non-complexed peptide-pools of up to five peptides each, combined at the time of administration with a ready-to-use adjuvant Poly ICLC (Hiltonol® (Oncovir, Inc., Washington, DC)). To determine the components of individualized peptide pools, as well as the number of pools, a tissue sample from each patient will undergo DNA and RNA sequencing, in addition to a patient blood sample for HLA typing. The resulting data will be analyzed using multiple bioinformatics algorithms to identify a patient-specific and unique set of neoantigenic peptides with a likelihood of targeting activity toward the patient’s disease. Up to four patient-specific peptide pools will be manufactured to include <5 peptides each, along with one pan-DR CD4-helper epitope (PADRE) (FIG. 1).
Secondly, the term algorithm appears in para 00123 as follows:
In order to dissolve as many peptides ranked as highly immunogenic by our
vaccine peptide prediction algorithm as possible, DMSO will be used. DMSO in low concentrations (approximately 4% v/v) is used as excipient in various approved drugs and has been shown to be safe when used as cryoprotectant in stem cell infusions.
However, the specification does not appear to include any such algorithms.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Unpredictability is evidenced by the state of the prior art: Further, in the Applicants’ Arguments filed on 08/04/2025, the applicants argue that there was unpredictability in selecting tumor-specific neoantigens for use in cancer treatment. The applicants cite Feltkamp et al as evidence for such unpredictability and state in page 16 of “Remarks”:
Further, at the time of filing it had been established that immunogenicity of peptides in the context of MHC requires that the peptide bind MHC, but that binding MHC is not sufficient and is not an accurate predictor of immunogenicity. The examiner’s attention is respectfully directed to Feltkamp et al which clearly states that “immunogenicity is not guaranteed by efficient peptide-MHC class I binding, implying that additional factors are involved.” Thus, the art at the time of filing highlights the well-known challenge of identifying immunogenic peptides, creating significant uncertainty when predicting immunogenicity of identified patient-specific neoantigens.
(See Feltkamp et al “Efficient MHC class I-peptide binding is required but does not ensure MHC class I-restricted immunogenicity”: Molecular immunology Vol 31, No 18 pages 1391-401)
To satisfy the written description requirement, MPEP §2163 states, in part “...a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “...disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that the inventor(s) invented what is claimed.” (See Vas-Cath at page 1116).
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eh Lily & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) (‘In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. ..."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eh Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself.
Thus the claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed product invention.
Claim Rejections - 35 USC § 103 – new grounds necessitated by amendment
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.
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.
Currently amended claims 1-2, 10, 12-13, 15, 26, 28-30, 32, 36-39, 46, 51, and 55-57 are rejected under 35 U.S.C. 103 as being unpatentable over Flechtner et al (WO2020232408 published November 19, 2020; IDS ref, of record) in view of Soria-Guerra et al “An overview of bioinformatics tools for epitope prediction: Implications on vaccine development, Journal of Biomedical Informatics”, Volume 53, 2015, Pages 405-414), and Khurana et al: “A deep learning framework for sequence-based protein solubility prediction, Bioinformatics”, (Volume 34, Issue 15, August 2018, pages 2605-2613). This is a new grounds of rejection necessitated by amendment.
Regarding currently amended claim 1, Flechtner et al (WO2020231408) teaches methods and compositions for identifying tumor antigens of human lymphocytes, and for identifying subjects for cancer therapy. (See Abstract). Flechtner et al disclose a method comprising administering to the subject an immunogenic composition comprising one or more selected stimulatory antigens or immunogenic fragments thereof, wherein the immunogenic composition is administered according to a dosing regimen comprising an initial dose of the immunogenic composition and additional doses of the immunogenic composition. (See Abstract). Fletcher et al disclose that their immunogenic compositions contain a peptide epitope within an immunogenic polypeptide, and specifically suggest a peptide epitope bound by an MHC class I molecule, or MHC class II molecule. Fletcher recites: “As used herein, the term “antigen” encompasses both a full-length polypeptide as well as a portion or immunogenic fragment of the polypeptide, and a peptide epitope within the polypeptides (e.g., a peptide epitope bound by a Major Histocompatibility Complex (MHC) molecule (e.g., MHC class I, or MHC class II)”. (See para 0049). Regarding claim 1, parts a-b, Flechtner et al discloses the immunogenic composition may comprise (a) a plurality of tumor-specific neoantigen long and short peptides (para 0237). Fletcher et al discloses that the tumor-specific neoantigen long peptides in the immunogenic composition are about 15 to about 30 amino acids in length or less. (See para 0154; 0237). Further, regarding amended claim 1, part (b), Fletcher et al discloses that the tumor-specific neoantigen short peptides comprise between about 8 to about 14 amino acids. (See para 0154; 0237). Specifically, Fletcher et al discloses GEN-009, a personalized neoantigen vaccine for solid tumors. (See para 0237). Tumor-specific neoantigens that are shown to be stimulatory antigens, are incorporated into a patient's personalized vaccine in the form of synthetic long peptides (SLPs).
Regarding claim 1, part c, Flechtner et al discloses an adjuvant consisting of polyinosinic and polycytidylic acid, stabilized with poly-I-lysine and carboxymethylcellulose (poly ICLC). Specifically, Flechtner et al disclose the immunogenic compositions described may include an adjuvant. Adjuvants can be used as vaccine delivery systems and/or for their immunostimulatory properties. Vaccine delivery systems are often particulate formulations, e.g., emulsions, microparticles, immune stimulating complexes (ISCOMs), which may be, for example, particles and/or matrices, and liposomes. Immunostimulatory adjuvants include ISCOMS or may be derived from pathogens and can represent pathogen associated molecular patterns (P AMP), e.g., lipopolysaccharides (LPS), monophosphoryl lipid (MPL), or CpG-containing DNA, which activate cells of the innate immune system. Flechtner et al disclose that an exemplary adjuvant is Poly-ICLC. (See para 0159).
Regarding claim 1, part d, Flechtner et al discloses (d) an immune checkpoint inhibitor that is an inhibitor of the programmed death-1 (PD-1) pathway. (See para 0021; 0192, 0217).
Regarding claim 2, Fletcher et al discloses that the immunogenic composition comprises up to about 19 tumor-specific neoantigen long peptides and/or short peptides. (See para 0237). Fletcher et al discloses a personalized vaccine, consisting of 4 to 20 SLPs, is generated for each patient.
Regarding claim 10, Fletcher et al discloses that each of the tumor-specific neoantigen long peptides in the immunogenic composition are different and/or each of the tumor-specific short peptides in the immunogenic composition are different. (para 0237).
Regarding claim 12, Fletcher et al discloses that the immunogenic composition comprises one or more tumor-specific frameshift peptides and/or a neoantigen resulting from a non-synonymous mutation. (See para 0069; 0074).
Regarding claim 13, Fletcher et al discloses that the tumor- specific neoantigen long peptides and/or short peptides are divided into about four peptide pools. (See para 0209). The SLPs are divided into 4 pools, with each pool containing 1 to 5 SLPs. The 4 pools are administered subcutaneously (SC) in each of the patient's limbs. Collectively, these pools of SLPs are the GEN 009 drug product. Each pool of GEN 009 drug product consists of 100 to 1500 Ug total peptide administered with 0.45 mg poly ICLC adjuvant per injection ([0209]).
Regarding claim 15, Fletcher et al discloses that each peptide pool comprises about 5 or less tumor-specific neoantigen long peptides and/or short peptides. (See para 0209).
Regarding claims 26 and 32, Fletcher et al discloses that the peptide pools further comprise 300 µg tumor-specific neoantigen long peptides and/or short peptides and 500 mcg Poly ICLC per 1 mL peptide pool. For example, Fletcher et al disclose that the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials (para 0158). The immunogenic composition is administered to a subject according to a dosing regimen or dosing schedule. The amount of antigen in each immunogenic composition dose (e.g., a vaccine, vaccine formulation and/or pharmaceutical composition) is selected to be a therapeutically effective amount, which induces a prophylactic or therapeutic response, in either a single dose or over multiple doses. A single dose will comprise about 100 to about 1500 ug total peptide. The total volume of a single dose is 0.5 mL to 1.0 mL. A single dose may comprise more than one antigen, for example, 2, 3, 4, 5 or more. A dosing regimen comprises an initial dose of an immunogenic composition and at least one additional dose of the immunogenic composition. After an initial dose is administered, an additional dose is administered about 3, 6, 12 or 24 weeks following the initial dose. The dosing regimen may comprise administration of different immunogenic compositions, e.g., 2, 3, 4, 5, 6, 7, 8, or more different immunogenic compositions comprising antigens. A dosing regimen can include an initial dose of 2, 3, 4, 5, 6, 7, 8, or more different immunogenic compositions, and at least one additional dose of the 2, 3, 4, 5, 6, 7, 8, or more different immunogenic compositions. An immunogenic composition may comprise one antigen or 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antigens (See paragraphs 0177-0180).
Regarding claims 36-37 Fletcher et al disclose that the administering may be by various routes to the subject. It is considered that it would have been prima facie obvious to administer doses to different extremities of the subject or to the same extremity of the subject at each administration depending on the type and condition and location of the cancer to be treated. (See para 0048; 0158).
[0158] Immunogenic compositions can be prepared as formulations suitable for route of administration. Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, intranasal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
Further, Fletcher et al disclose that the SLPs are divided into 4 pools, with each pool containing 1 to 5 SLPs. The 4 pools are administered subcutaneously (SC) in each of the patient's limbs. Collectively, these pools of SLPs are the GEN 009 drug product. Each pool of GEN 009 drug product consists of 100 to 1500 Ug total peptide administered with 0.45 mg poly ICLC adjuvant per injection ([0209]).
Regarding claims 28-30 and 38, Flechtner et al discloses that the immunogenic composition is administered according to a dosing regimen comprising an initial dose of the immunogenic composition and additional doses of the immunogenic composition, wherein after an initial dose is administered, an additional dose is administered 3 weeks following the initial dose, an additional dose is administered 6 weeks following the initial dose, an additional dose is administered 12 weeks following the initial dose, and an additional dose is administered 24 weeks following the initial dose. (See Abstract; Figure 1). The dosing of Fletcher is construed to meet the limitation of wherein the subject is administered about six doses of the immunogenic composition, and each dose of the immunogenic composition is administered about 4 weeks after administration of the prior dose of the immunogenic composition. (See Abstract; Fig 1; para 0246).
Regarding claim 39 Fletcher et al disclose that the subject is administered about six doses of the immunogenic composition, further comprising administering an adjuvant between each dose of the immunogenic composition. (See para Abstract; Fig 1; para 0246).
Regarding claim 46 Fletcher et al disclose that cancers of the patients screened and treated with the GEN 009 neoantigen vaccination included melanoma, breast cancer, ovarian cancer, prostate cancer, kidney cancer, gastric cancer, colon cancer, testicular cancer, head and neck cancer, pancreatic cancer, brain cancer, B-cell lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, T-cell lymphocytic leukemia, colon cancer, urothelial cancer, or lung cancer. (See Table 5).
Regarding claim 51 Fletcher et al discloses that the immunogenic composition is administered by intramuscular administration. Fletcher et al states that the “immunogenic compositions can be prepared as formulations suitable for route of administration”, and continue “Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, intranasal, and subcutaneous routes..”. (See para 0048; 0158).
Regarding claim 55 Fletcher et al discloses that the immune checkpoint inhibitor of the programmed death-1 (PD-1) pathway is Nivolumab. (See para 0021; 0217).
Regarding claim 56 Fletcher et al discloses that the melanoma is metastatic melanoma. (See page 77, right col of Table).
Regarding claim 57 Fletcher et al discloses that the breast cancer is stage IV HR positive, HER2 negative breast cancer. (See page 78).
However, while Fletcher et al discloses the elements of the presently claimed compositions and methods, they do not explicitly disclose that the tumor-specific neoantigens were selected by bioinformatic algorithms. Fletcher discloses that bioinformatic algorithms were known in the art for selecting tumor-specific neoantigens but disclose that “tools for predicting MHC class II epitopes are under-developed and more variable”. (See para 0071). In para 0074, Fletcher et al disclose that their methods identified tumor-specific antigens that are not identified by “known algorithms”. (para 0074). In para 0102-0103, Fletcher et al describe tumor-specific antigens (aka, neoantigens). In para 0105, Fletcher et al state that neoantigens may be selected by sequencing the genome or exome of tumor tissue versus healthy tissue from a patient with cancer and that “genes that are selected based on their frequency of mutation and ability to encode a potential or putative neoantigen” are selected for further sequencing and analysis. Thus, the neoantigens of Fletcher et al are selected using mathematical comparisons of frequency of mutation.
The reference of Soria-Guerra et al discloses selection of tumor-specific neoantigens for use in an immunogenic composition where the selection is by bioinformatic algorithms. Khurana et al specifically disclose use of bioinformatic algorithms to predict peptide composition solubility.
For example, Soria-Guerra et al recite (abstract):
Exploitation of recombinant DNA and sequencing technologies has led to a new concept in vaccination in which isolated epitopes, capable of stimulating a specific immune response, have been identified and used to achieve advanced vaccine formulations; replacing those constituted by whole pathogen-formulations. In this context, bioinformatics approaches play a critical role on analyzing multiple genomes to select the protective epitopes in silico. It is conceived that cocktails of defined epitopes or chimeric protein arrangements, including the target epitopes, may provide a rationale design capable to elicit convenient humoral or cellular immune responses. This review presents a comprehensive compilation of the most advantageous online immunological software and searchable, in order to facilitate the design and development of vaccines. An outlook on how these tools are supporting vaccine development is presented. HIV and influenza have been taken as examples of promising developments on vaccination against hypervariable viruses. Perspectives in this field are also envisioned.
Further, Khurana et al disclose bioinformatics algorithms for in silico sequence-based protein solubility predictors. They disclose DeepSol, a novel Deep Learning-based protein solubility predictor. (See Abstract).
The skill level in the art of making and using immunogenic compositions comprising neoantigen peptides was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to combine the tumor-specific neoantigens with the adjuvant and PD-1 inhibitor in an immunogenic composition for treating cancer in a subject for the rationale of making of boosting antibody responses in the subject receiving the composition. It would have been prima facie obvious to do such because Fletcher et al explicitly suggests combining these elements to make effective immunogenic compositions for treating cancer in a subject.
Further, one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have been motivated to use available bioinformatic algorithms to select neoantigen peptides for the immunogenic composition for the rationale of Soria-Guerra et al that bioinformatics approaches play a critical role on analyzing multiple genomes to select the protective epitopes in silico. Soria-Guerra et al state that “it is conceived that cocktails of defined epitopes or chimeric protein arrangements, including the target epitopes, may provide a rationale design capable to elicit convenient humoral or cellular immune responses”. Soria-Guerra et al “presents a comprehensive compilation of the most advantageous online immunological software and searchable, in order to facilitate the design and development of vaccines”.
It would have been obvious to select neoantigens using bioinformatic algorithms because Fletcher et al states these are known in the art and Fletcher discloses that bioinformatic algorithms were known in the art for selecting tumor-specific neoantigens and Soria-Guerra et al explicitly suggest using such for making immunogenic compositions.
In view of the high skill level in the art it is considered that one of ordinary skill in the art would have had a reasonable expectation of success to combine the elements of Fletcher et al to arrive at the presently claimed invention.
Thus the invention as a whole is considered obvious over the cited references.
Response to Arguments
The Applicants’ response filed on August 4, 2025 have been fully considered but are unpersuasive as they may pertain to this new grounds of rejection. The applicants argue that the neoantigen peptides of GEN-009 do not meet the limitation of long or short peptides. However, this argument is unpersuasive because Fletcher et al discloses that the immunogenic composition comprises up to about 19 tumor-specific neoantigen long peptides and/or short peptides. (See para 0237). Fletcher et al discloses a personalized vaccine, consisting of 4 to 20 SLPs, is generated for each patient.
The applicants argue that Fletchner does not meet all of the claim limitations (selecting by algorithms) and that Fletchner teaches away from the presently amended claims because “Fletcher believes using bioinformatic algorithms is unreliable for predicting tumor-specific neoantigens for inclusion in an immunogenic composition”, citing Flechtner at paragraph [0071]. The applicants argue that “cited art will teach away when it suggests that the developments flowing from its disclosure are unlikely to produce the objective of the Applicant’s invention. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).”
The Applicant asserts Flechtner teaches away from the claimed invention, as amended. Fletchner discloses a system called Antigen Lead Acquisition System (ATLAS) that is used to identify neoantigens in each patient’s tumor by identifying antigens from next generation sequencing of subject tumor samples, generating a library comprising either bacteria expressing antigens or beads displaying antigens, then introducing a subject’s peripheral blood mononuclear cells (PMBCs) to identify neoantigens that induce activation of subject-specific T cells by measuring expression of immune modulators. The claimed invention now requires use of bioinformatics algorithms to predict patient-specific neoantigens based on immunogenicity and, according to Fletchner, this would not result in an immunogenic composition. Flechtner discloses computational modeling used to predict epitopes is limited as “greater than 12,000 HLA alleles encoding MHC molecules, with each subject expressing as many as 14 of them, all with different epitope affinities” would need to be taken into account and “predicted epitopes fail to be found presented by tumors when they are evaluated using mass spectrometry.” Flechtner at Paragraph [0071]. Flechtner goes on to teach “the predictive algorithms do not take into account T cell recognition of the antigen, and the majority of predicted epitopes are incapable of eliciting T cell responses even when they are present.” Therefore, from the teachings of Fletchner, a person of ordinary skill in the art would not arrive at the claimed invention but instead would be motivated to use ATLAS or to seek other in vitro assays solutions to identify patient-specific neoantigens for inclusion in an immunogenic composition.
However, this argument is unpersuasive because Fletcher et al state in para 0071 state that there are limitations to computational methods to predict what is an antigen but that such methods need improvement. Fletcher discloses that bioinformatic algorithms were known in the art for selecting tumor-specific neoantigens but disclose that “tools for predicting MHC class II epitopes are under-developed and more variable”. (See para 0071). In para 0074, Fletcher et al disclose that their methods identified tumor-specific antigens that are not identified by “known algorithms”. (para 0074). In para 0102-0103, Fletcher et al describe tumor-specific antigens (aka, neoantigens). In para 0105, Fletcher et al state that neoantigens may be selected by sequencing the genome or exome of tumor tissue versus healthy tissue from a patient with cancer and that “genes that are selected based on their frequency of mutation and ability to encode a potential or putative neoantigen” are selected for further sequencing and analysis. Thus, the neoantigens of Fletcher et al are selected using mathematical comparisons of frequency of mutation.
However, this argument of teaching away is unpersuasive because nowhere does Fletcher disclose that algorithms should not be used. Further, this new grounds of rejection is over a combination of references and the reference of Soria-Guerra et al disclose selection of tumor-specific neoantigens for use in an immunogenic composition where the selection is by bioinformatic algorithms. Khurana et al specifically disclose use of bioinformatic algorithms to predict peptide composition solubility.
In addition, the applicants argue there is no teaching, suggestion, or motivation to modify Flechtner to arrive at the claimed invention.”
However, this argument is unpersuasive because this new grounds of rejection is over the combination of references and the reference of Soria-Guerra et al disclose selection of tumor-specific neoantigens for use in an immunogenic composition where the selection is by bioinformatic algorithms. Khurana et al specifically disclose use of bioinformatic algorithms to predict peptide composition solubility.
Further, the applicant argues that Fletcher fails to disclose neoantigens of varying length, which the instant Specification teaches leads to both MHC class I and II presentation, a skilled artisan would not arrive at the claimed invention.
However, this argument is unpersuasive because Fletcher et al disclose that their immunogenic compositions contain a peptide epitope within an immunogenic polypeptide, and specifically suggest a peptide epitope bound by an MHC class I molecule, or MHC class II molecule. Fletcher recites: “As used herein, the term “antigen” encompasses both a full-length polypeptide as well as a portion or immunogenic fragment of the polypeptide, and a peptide epitope within the polypeptides (e.g., a peptide epitope bound by a Major Histocompatibility Complex (MHC) molecule (e.g., MHC class I, or MHC class II)”. (See para 0049). Fletcher et al discloses that the tumor-specific neoantigen long peptides in the immunogenic composition are about 15 to about 30 amino acids in length or less. (See para 0154; 0237). Further, regarding amended claim 1, part (b), Fletcher et al discloses that the tumor-specific neoantigen short peptides comprise between about 8 to about 14 amino acids. (See para 0154; 0237). Specifically, Fletcher et al discloses GEN-009, a personalized neoantigen vaccine for solid tumors. (See para 0237). Tumor-specific neoantigens that are shown to be stimulatory antigens, are incorporated into a patient's personalized vaccine in the form of synthetic long peptides (SLPs).
Further, the applicants argue that there is no reasonable expectation of success because Fletchner teaches that there is “significant uncertainty predicting immunogenicity”.
However, this argument is unpersuasive because this new grounds of rejection is over the combination of references and the reference of Soria-Guerra et al disclose selection of tumor-specific neoantigens for use in an immunogenic composition where the selection is by bioinformatic algorithms. Khurana et al specifically disclose use of bioinformatic algorithms to predict peptide composition solubility.
Claims 1, 13, 16 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Flechtner et al in view of Soria-Guerra et al, and Khurana et al as applied to claims 1 and 13 above, and further in view of Franke et al. (Pan DR binding sequence provides T-cell help for induction of protective antibodies against Plasmodium yoelii sporozoites. Vaccine, 17, 1201-1205, 1999; of record). This is a new grounds of rejection.
The references of Flechtner et al in view of Soria-Guerra et al, and Khurana et al render obvious claim 1 and 13 for reasons provided above.
Regarding claim 16, Fletcher et al discloses peptide pools and/or one or more neoantigens resulting from a non-synonymous mutation but do not explicitly include a helper peptide.
Regarding claim 24, Flechtner et al does not disclose using the PADRE epitope as a CD4 helper peptide.
Franke et al disclose that using the PADRE epitope as a CD4 helper peptide was a known and successful technique to boost antibody responses in vivo. Franke et al. disclosed that the Pan-DR epitope (PADRE) peptides have demonstrated the capacity to deliver significant helper T-cell activity in vivo (abstract).
The skill level in the art of making and using immunogenic compositions comprising neoantigen peptides was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to include a PADRE epitope as a CD4 helper peptide in an immunogenic composition comprising neoantigens comprising peptides for the rationale of boosting antibody responses to subject receiving the composition. It would have been obvious to one of ordinary skill in the art to do such because Franke et al disclose that it was a known and successful technique to boost antibody responses in vivo. Franke et al. disclosed that the Pan-DR epitope (PADRE) peptides have demonstrated the capacity to deliver significant helper T-cell activity in vivo (abstract).
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to include a PADRE epitope as a CD4 helper peptide in an immunogenic composition comprising neoantigens comprising peptides to arrive at the presently claimed invention.
Thus the invention as a whole is considered obvious over the cited references.
Response to Arguments
The Applicants’ response filed on August 4, 2025 have been fully considered but are unpersuasive as they may pertain to this new grounds of rejection. The applicants argue that Fletchner does not render obvious claims 16 and 24 for the reasons outlined above. This argument is persuasive because claims 16 and 24 were not rejected over Fletchner alone.
In addition, the applicants argue against the Franke reference stating:
Further, Franke discloses the inclusion of PADRE in a vaccine for Plasmodium yoelii sporozoites. The immunological response needed to generate long-term immune memory (i.e., memory T-cells) is fundamentally different for a parasitic infection compared to cancer. For instance, pathogen-driven inflammation can support T-cell priming, while the tumor microenvironment suppresses these functions, including T-cell survival. The memory T cell subsets generated are also substantially different between a Plasmodium spp. infection and subsets generated due to cancer immunotherapies. Thus, a person of ordinary skill would not be motivated to look to Franke to combine with Fletchner as it is directed to cancer immunogenic compositions.
However, this argument regarding the Franke reference is unpersuasive because arguments of counsel cannot take the place of evidence on the record. Attorney arguments are not considered to be evidence.
Currently amended claims 1-2, 10, 12-13, 15, 16, 24, 26, 28-29, 30, 32, 36-39, 46, 51, 55, 56, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over in view of WO-2015095811A2 to Hacohen et al (made of record in the IDS filed on 10/02/2025, priority to US Provisional 61/919576; US Patent 11,452,768)
Regarding claims 1, 46, and 56, Hacohen et al teach a neoplasia vaccine or immunogenic composition administered in combination with checkpoint blockade inhibitors including anti-PDL1 for treatment of neoplasia including melanoma, in a subject. (See Abstract and FIG 5.) Hacohen et al teach including a poly-ICLC adjuvant in the immunogenic composition. (See para 0014). Further, Hacohen et al teaches the neoantigenic peptide ranges from about five to about 50 amino acids in length. (See ref claims 3) which meets the limitations of a combination of long and short peptides. Also, in one embodiment the neoantigenic peptide ranges from about 15 to about 35 amino acids in length. (see para 0012, lines 4-5) which meets the limitation of between about 15 to about 30 amino acids in length. Further, Hacohen et al teach selection of the “neoplasia/tumor specific neoantigens using bioinformatic analysis using validated algorithms to predict which tumor-specific mutations create epitopes that could bind to the patient’s HLA allotype”. Based on this analysis, Hacohen et al teach that a plurality of peptides corresponding to a subset of these mutations “may be designed and synthesized for each patient, and pooled together for use as a cancer vaccine or immunogenic composition in immunizing the patient”. (See para 0081). Hacohen et al disclose long and short neoantigen peptides in the range of about 8 to about 14 amino acids in length and in the range of about 15 to about 30 amino acids in length. In one embodiment the neoantigen peptide ranges from about 5 to about 50 amino acids in length. Also, Hacohen et al teach neoantigen peptides in the range from about 15 to about 35. And from about 20 to about 35 amino acids in length (See para 0093.)
Regarding claim 2, Hacohen et al teach the immunogenic composition comprising at least five neoantigenic peptides. (see para 0012, lines 102). (See ref claims 2). Further, Hacohen et al teach one tumor-specific antigen to 20. (see para 0093, line 5-7).
Regarding claim 10, Hacohen et al teach selection of the “neoplasia/tumor specific neoantigens using bioinformatic analysis using validated algorithms to predict which tumor-specific mutations create epitopes that could bind to the patient’s HLA allotype”. Based on this analysis, Hacohen et al teach that a plurality of peptides corresponding to a subset of these mutations “may be designed and synthesized for each patient, and pooled together for use as a cancer vaccine or immunogenic composition in immunizing the patient”. (See para 0081). Thus the peptides in the composition are different amino acid sequences.
Regarding claim 12, Hacohen et al disclose a neoantigen resulting from a frameshift or non-synonymous mutation. (See para 0038 part(iii)).
Regarding claims 13 and 32, Hacohen et al disclose that the tumor- specific neoantigen long peptides and/or short peptides are divided into about four peptide pools (see para 0049; 00501.)
Regarding claim 15, Hacohen et al renders obvious that each peptide pool comprises about 5 or less tumor-specific neoantigen long peptides and/or short peptides because Hacohen et al 20 peptides and four peptide pools.
Regarding claim 16 and 24, Hacohen et al disclose a neoantigen resulting from a frameshift or non-synonymous mutation and a helper peptide, specifically an HLA-DR restricted helper peptide used in melanoma vaccines to activate CD4+ T cells non-specifically. (See para 0038 part(iii); 00296).
Regarding claim 26, Hacohen et al disclose that peptide pools comprise 300 ug neoantigen and 500 mcg Poly ICLC per 1mL peptide pool. (See para 00276).
Regarding claim 30, Hacohen et al disclose that the subject is administered at least six doses of the immunogenic composition. (See para 0029.)
Regarding claim 32, Hacohen et al disclose that the immunogenic composition is administered as about four peptide pools at each dose.(para 00501)
Regarding claims 32, and 37, Hacohen et al disclose that the subject is administered each peptide pool on a different extremity of the subject or the same extremity of the subject. (See para 0381; 509-510).
Regarding claim 32, Hacohen et al disclose that the subject is administered about six doses of the immunogenic composition, and each dose of the immunogenic composition is administered about 4 weeks after administration of the prior dose of the immunogenic composition. (See para 00276; 00382; 00383)
Regarding claim 39, Hacohen et al disclose that the subject is administered about six doses of the immunogenic composition, further comprising administering an adjuvant between each dose of the immunogenic composition. (See para 00276; 00382; 00383)
Regarding claim 51, Hacohen et al disclose intramuscular administration. (See para 0022).
Regarding claim 55, Hacohen et al disclose nivolumab. (See Title; Abstract).
Regarding claim 56, Hacohen et al disclose metastatic melanoma. (See para 0052.)
Regarding claim 57, Hacohen et al disclose breast cancer. (See para 0025; 0137; 0360.)
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to combine the elements of Hacohen et al for the rationale of making and using a successful immunogenic composition comprising neoantigens selected using bioinformatic algorithms for treating cancer in a patient. It would have been obvious to do such because the elements of the present claims are preferred embodiments disclosed in Hacohen et al
In view of the high skill level in the art it is considered that one of ordinary skill in the art would have had a reasonable expectation of success to combine the elements of Hacohen et al to arrive at the presently claimed invention.
Currently amended claims 1-2, 10, 12-13, 15, 16, , 28-29, 46, and 55, are rejected under 35 U.S.C. 103 as being unpatentable over Bassani-Sternberg et al in “A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma – A Proof of Antigen Discovery Feasibility in Three Patients” (Frontiers in Immunology Original Research published August 8, 2019),
Regarding claims 1, 28-29, and 46, Bassani-Sternberg et al disclose an immunogenic composition comprising tumor-specific neoantigen peptides used in a pharmaceutical form for treating cancer in a human patient having pancreatic cancer. (See Title, Abstract, entire article). Specifically, they disclose a combination of dendritic cells loaded with personalized neoantigen peptides (PEP-DC). These PEP-DC are selected using bioinformatic algorithms. See Abstract; page 5, right col., para headed: Prediction and Prioritization of Neoantigens”; Figure 2; and page 4, para 2, which states that “the selection of long peptides is done in silico by the NeoDisc pipeline. Note that the term “in silico” means that the scientific experiments or research are conducted by means of computer modeling or computer simulation. Further, Bassani-Sternberg et al disclose a PD-1 inhibitor. specifically nivolumab. (See Title; Abstract). Further, regarding claim 1, Bassani-Sternberg et al disclose 31-mer peptides with mutations in the middle position was then generated and subjected to binding predictions of HLA class I (9-12 mers) and class II (12-19 mers). See Table 1 and Figure 4 for detailed information about the 10 optimally designed “long peptides” for each patient. Note that Bassani-Sternberg et al refers to long peptides as 15-31 amino acid peptides. Note that a 15-mer amino acid peptide is construed to meet the limitation of about 14 amino acids which meets the limitation of a short peptide of the present claims.
Further regarding claim 2, Bassani-Sternberg et al disclose selection of top 10 optimally designed long peptides (see Fig 2; Fig 4).
Regarding claim 10, Bassani-Sternberg et al discloses that each of the tumor-specific neoantigen long peptides in the immunogenic composition are different and/or each of the tumor-specific short peptides in the