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 .
Claims 1-20 are pending.
Information Disclosure Statement
The references disclosed in the IDS filed on 9/25/2025 have been considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of the species of the first round of vaccination comprising two non-mutated peptides, one of 8-10 amino acids in length and one of 13-20 amino acids in length, the second round of vaccination comprising 5 peptides with affinity for MHCI alleles and 5 peptides with affinity for MHCII alleles, and wherein each round of vaccination comprises three applications of the array of peptides in the reply filed on 2/23/2026 is acknowledged.
Claims 12 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/23/2026.
Claims 1-11, 13-18, and 20 are currently under consideration as they read on the species of a method of treatment of a subject clinically presenting with a tumor comprising the first round of vaccination comprising two non-mutated peptides, one of 8-10 amino acids in length and one of 13-20 amino acids in length, the second round of vaccination comprising 5 peptides with affinity for MHCI alleles and 5 peptides with affinity for MHCII alleles, and wherein each round of vaccination comprises three applications of the array of peptides.
Claim Rejections - 35 USC § 112
Indefinite Language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 6-7, 10-12, 14-18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “non-mutated peptide derived from a tumor associated antigen”. “Non-mutated” and “derived from” are contradictory terms as “non-mutated” and “derived from” have opposite meanings. A person of ordinary skill in the art considers “non-mutated” to be defined as a non-altered or wild-type version and “derived from” to indicate the source of the peptide, but also indicates the presence of alterations in length of the peptide and specific amino acids in the peptide. Additionally, the claim does not recite limitations defining what is considered a “non-mutated” and “mutated” peptide since there is no indication that the peptide sequence is being compared to a reference wild-type sequence or to a patient’s reference genome. Given the broadest reasonable interpretation (BRI) of the limitation, the peptide can be anywhere from two to infinite amino acids in length with any amino acid substitution to be considered derived from a tumor associated antigen.
Claim 3 recites the limitation "the fraction" of “the DNA” and “the fraction of RNA” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 additionally recites, “determining the fraction of the DNA .. which encodes each of the mutated amino acid and the fraction of RNA transcribed .. expressing the mutated amino acids” AND “present in at least 10% of the DNA in the biopsy and expressed in at least 10% of the RNA transcribed”. It is unclear what the fraction of DNA and RNA represent and how the fraction of DNA and RNA are determined in relation to the mutated amino acids since there is no indication the DNA and RNA sequence are compared to a normal or reference genome. Additionally, it is unclear what the minimum measurement of 10% represents and how this correlates to the corresponding protein’s expression and implications in the tumor’s progression/prognosis. It is known in the field for DNA- and RNA-sequencing methods for mutation detection and calling, there must be a minimum filtering threshold to filter out low-frequency noise and separate true positive calls from sequencing errors and that differences in sequencing coverage depth and breadth have significant implications in mutation variant calling (Kobolt; PTO-892; page 2, Reference U). High confidence somatic SNV/indel calls should be identified by multiple somatic mutation calling tools at positions with sufficient sequencing coverage (>10x in both tumor and normal tissue). Additionally, higher sequencing depth can enable more sensitive detection of variants at low allele frequencies (Kobolt; PTO-892; page 2, Reference U).
Claims 6 and 7 recites the limitation "the T cell response" in line 2 of claim 6 and line 2 of claim 7. There is insufficient antecedent basis for this limitation in the claim.
Claims 10-12 recites limitations of the nucleic acids encoding the peptides defined by amino acid length (i.e. 8 to 10 amino acids long, 13-20 amino acids long, and 8-35 amino acids long). Nucleic acids are composed of DNA or RNA nucleotides and are not composed of amino acids. A person of ordinary skill in the art would know that nucleic acids only encode amino acids, so their length cannot be defined amino acids and only by nucleotide bases. It is unclear whether the claimed method of vaccination comprises nucleic acids or peptides.
Claim 13 recites limitations of the nucleic acids encoding the selected peptides administered in the second round of vaccination comprises at least 5 unique peptides. Similar to claims 10-12, nucleic acids are not peptides and are composed of nucleotide bases and not amino acids. It is unclear whether the claimed method of the second round of vaccination comprises nucleic acids or peptides.
Claims 14 and 15 recite limitations of the “desired predicted binding affinity to the one or more of the subject’s MHC alleles of selected peptides in the second round exceeds 85% and 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid”. It is unclear how the desired predicted binding affinity is being measure and what the % of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid represents. In light of the specification (page 21, lines 9-21), the binding affinity can be measured as a dissociation constant (Kd) or an inhibitory constant 50 (IC50). However, the two methods measure different concepts where the Kd is a direct measure of the energy of binding and IC50, where the concentration at which 50% of the peptide is displaced.
Claim 16 and 17 recite limitations of the desired predicted binding affinity of the selected peptide to the subject’s MHC allele to be less than 50 and 200 nanomolar. Similar to the rejection above over claims 14 and 15, it is unclear how the desired predicted binding affinity is being measure and what the unit (i.e. nanomolar) represents. In light of the specification (page 21, lines 9-21), the binding affinity can be measured as a Kd or an IC50. However, the two methods measure different concepts where the Kd is a direct measure of the energy of binding and IC50, where the concentration at which 50% of the peptide is displaced but both can have the same units of nanomolar.
Claim 18 recites limitations of administering peptides, or nucleic acids encoding them, which occur naturally in a tumor protein. It is unclear what the term “occur naturally in a tumor protein” means as there is no claimed measurement or comparison tool to determine what is naturally occurring in a tumor protein and what is not naturally occurring in a tumor protein. This term under broadest reasonable interpretation can encompass all peptides (i.e. mutant and wild-type peptides) as all proteins can be found to be naturally occurring in a tumor protein. Additionally, it is unclear how the wild-type naturally occurring peptides, or nucleic acids encoding them, can be generated into a 9-mer MHC-I or 15-mer MHC-II peptide since this method relies on exposing a mutated amino acid in the appropriate T cell exposed position.
Claim 20 recite limitations regarding the number of applications of the array of peptides, or the nucleic acids encoding them. It is unclear what the term “application” refers to as it can mean the number of times the claimed “vaccine” is administered to the subject or how the claimed “vaccine” is administered to the subject (i.e. intramuscularly, subcutaneously, orally, etc.).
Appropriate correction is required.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Written Description
Claims 1-11, 13-18, and 20 are 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.
Applicant is in possession of: a method of treating a subject clinically presenting with glioma or glioblastoma comprising: administering a first round of a pharmaceutical composition wherein the pharmaceutical composition comprises an array non-mutated peptides of VEGFR, WT-1, and Vimentin with SEQ ID NOs:1-118 and mutated peptides of EGFR, H3.3, IDH1, and BRAF with SEQ ID NOs: 154-183, 284-288, 294-298, 344-348, 392-396, 441-446, 468-472, and 512-514 and administering a second round of a personalized pharmaceutical composition comprising obtaining a biopsy of the tumor and of normal tissue of the subject and obtaining sequences for DNA, RNA, and protein in the biopsy; identifying proteins from the biopsy containing mutated amino acids by comparing the RNA fraction comprising the mutant amino acid (FPKM) and DNA tumor fraction encoding the gene mutation from the tumor biopsy and the normal tissue from the subject wherein the tumor specific mutations which can be targeted by T cells are selected from those with the RNA/DNA ratio exceeds 10%; generating an array of 9-mer MHC I peptides which expose the determined mutated amino acid at positions 4,5,6,7, or 8 and generating 15-mer MHC-II peptides which exposes the mutated amino acid at positions 2,3,5,7,8 of the 9-mer core for TCEM IIA peptide or -1,3,5,7,8 for TCEM IIB peptide; selecting a group of one or more selected peptides from the array of generated peptides which display a predicted dissociation constant (Kd) less than 200 and less than 50nM or within 1-2 standard deviations of the mean of the peptides that bind the tumor protein and synthesizing the group of peptides and administering the selected peptides as a second round of treatment.
Applicant is not in possession of: a method for treating a subject clinically presenting with a tumor comprising administering a first round of vaccination wherein the vaccination comprises an array of one or more peptides, or nucleic acids encoding them; selected from the group consisting of non-mutated peptides derived from tumor associated antigens appropriate to the tumors of the type diagnosed and peptides commonly found to be mutated in tumors of the type diagnosed; and administering a second round of personalized vaccination wherein the second round of vaccination comprises identifying proteins from the biopsy containing mutated amino acids and the peptide comprising each of the mutated amino acids; determining the predicted desired binding affinity to the subject’s MHC alleles; generating an array of alternative peptides not present in the tumor; selecting a group of one or more selected peptides from the generated array of alternative peptides which have a desired predicted binding affinity; and administering the selected peptides, or their encoded nucleic acids, as the second round of vaccination of instant claim 1; selecting the peptides commonly found to be mutated in tumors so as to position the mutated amino acid in a T cell exposed position and substituting one or more of the amino acids not in a T cell exposed position to provide a desired binding affinity of instant claim 2; selecting a sub array of alternative peptides in instant claim 3b; wherein the desired binding affinity to one or more of the subject’s MHC alleles of selected peptides in the second round of vaccination exceeds 85% and 95% of the binding affinity of all peptides in the tumor protein the comprises the mutated amino acid of instant claims 14 and 15; wherein the desired predicted binding affinity to the one or more of the subject’s MHC alleles of selected peptides in the second round is less than 50 and 200 nanomolar of instant claims 16 and 17; wherein the first and/or second rounds of vaccination further comprise administering peptides, or nucleic acids encoding them, which occur naturally in a tumor protein of instant claim 18.
The claims encompass any tumors, a first round “vaccine” comprising any non-mutated peptide(s) derived from tumor associated antigens appropriate to the tumors of the type diagnosed and any peptides commonly found to be mutated in tumors of the type diagnosed and a second round “vaccine” comprising any array of generated alternative peptides with any amino acid in a T cell exposed position and any amino acid substitution in a non-T cell exposed position to achieve any desired predicted binding affinity to the subject’s MHC alleles and any peptide occurring naturally in a tumor protein.
Regarding a subject clinically presenting with a tumor, the specification (page 15, lines 5-10) describes the use of the claimed peptides in treating cancer or tumor in a subject selected from the group consisting of nervous system, lung, breast, pancreas, liver, skin, prostate, genito-urinary tract, hematopoietic system, gastrointestinal, endocrine system, and musculoskeletal tissues with preferred embodiments being a tumor of the nervous system selected from the group consisting of glioma, glioblastoma, neuroblastoma, meningioma, schwannoma, and metastases to the brain from other sites. Examples 4-5 (page 76) describe EGFR variants (VIII, A289V/D/T, G598D, L858R) in glioblastoma and lung cancer and moderate-high affinity binding peptides for exemplar MHC I and II alleles. Examples 6-8 (pages 89, 94, 98) describe a common IDH1 R132H variant occurring in glioblastoma, H3.3 K27/28M variant occurring in glioma and glioblastoma, and BRAF V600E occurring in non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and lung adenocarcinoma; and bespoke peptides for all gene mutants with moderate – high binding affinity to MHC I and II alleles. However, there are no working examples or any description of other peptides for the first and second round of “vaccination”, how the generated peptides in Examples 4-8 offer therapeutic potential for a patient clinically presenting with a tumor or can be useable as a vaccine.
The specification does not reasonably convey possession of the full scope of the term tumor encompassed by the claims or that the broad genus of peptides in the first round of “vaccination” and the broad genus of generated array of alternative peptides in the second round of “vaccination” can be used to treat the broad genus of tumors. Absent a limiting definition for “tumor”, the genus opens up the claimed invention to all tumors including benign, malignant, solid, and liquid tumors.
Vaccines are used to prevent specific diseases caused by a specific agent and at minimum, the claims directed to using vaccines must be directed to specifically preventing a particular disease. The first criterion in judging a vaccine is the level of antibody (humoral immune response) before and after immunization. The success of the vaccination is judged by the extent of increase in the level of antigen - specific antibody. The second criterion for a vaccine is its ability to stimulate memory T lymphocytes (cell-mediated immune response) (See Kuby; PTO-892; page 4, Reference X). The art of Melief et al (PTO-892; page 5, Reference U) teaches must also exhibit clinical benefit in patients either by inducing a survival advantage or achieving cancer regression (Melief; whole document). The art of Liu et al (PTO-892; page 2, Reference V) teaches that cancer vaccines needs to be tumor specific and generated based upon tumor-specific antigen in order to produce an adaptive and humoral immune response against the tumor (Liu; Table 1; pages 8-9, section 4.1 Peptide Vaccines). Additionally, Pail et al (PTO-892; page 5, Reference V) teaches the effectiveness of cancer vaccines depends upon selection of optimal tumor antigens including vaccines with a higher total antigen content, selecting driver mutations over passenger mutations and tumor specific antigens over tumor-associated antigens, and peptide length (longer peptides are better than shorter peptides which are both better than whole proteins) which are all tumor and patient specific (Pail; page 198, left column, paragraph 3). All in all, it is unknown how non-specific or non-optimal peptide(s) will act in a tumor it was not designed to treat and how effective it will be in treating the tumor.
The skilled artisan cannot envision all of the peptide variations in the first and second round “vaccine” possibilities recited in the instant claims and what the peptide variations are vaccinating for and/or against.
The specification does not reasonably convey possession of the full scope of the term “non-mutated peptides derived from tumor associated antigens appropriate to the tumor of the type diagnosed” and “peptides commonly found to be mutated in tumors of the type diagnosed” in the first round of vaccination AND “proteins from the biopsy containing mutated amino acids and the peptide comprising each of the mutated amino acids” which are then used to generate “an array of alternative peptides” in the second round of “vaccination” encompassed by the claims. Absent a limiting definition for “non-mutated peptides derived from tumor associated antigens appropriate to the tumor of the type diagnosed” and “peptides commonly found to be mutated in tumors of the type diagnosed”, and “array of alternative peptides”, the genus opens up the claimed invention to any non-mutated peptide derived from a tumor associated antigen (also see 112b rejection above) and any peptide commonly found to be mutated in tumors of the type diagnosed in the first round of vaccination AND any array of alternative peptides comprising the mutated amino acids found from the biopsy in the second round of personalized vaccination. The additional limitation recited in instant claim 18 of administering peptides, or nucleic acids encoding them, which occur naturally in a tumor protein broadens the scope of the claimed invention to include any and all proteins since any protein, mutated/non-mutated or contributes to normal cell functioning/contributes to tumorigenesis, is encompassed (see 112b rejection).
The specification does not adequately describe the genus of recited “non-mutated peptides derived from tumor associated antigens appropriate to the tumor of the type diagnosed” and “peptides commonly found to be mutated in tumors of the type diagnosed” in the first round of vaccination of instant claim 1 and the generated array of alternative peptides in the second round of vaccination of instant claim 1. The specification only describes the identification and generation of bespoke peptides (see Tables 1-15, SEQ ID NOs: 1-118, 154-183, 284-288, 294-298, 344-348, 392-396, 441-446, 468-472, and 512-514) for wild-type VEGFR1/2, vimentin, WT-1, EGFR, H3.3, IDH1, and BRAF and one mutant form of BRAF, IDH1, and EGFR for their use in only the first round of vaccination. Examples 9-10 do generally describe the method of selecting mutant peptides and generating better binding peptides for their use in a vaccine. However, there are no other specific working examples of generating other peptides for the first round of vaccination and specific personalized peptides for the second round of vaccination or how/if the generated peptides can be used to in a vaccine to treat a subject clinically presenting with a tumor or how effective the first and second round of vaccination peptides are for treating a subject clinically presenting with a tumor and eliciting an adaptive and/or humoral immune response.
The art of Feola et al (PTO-892; page 1, Reference X) teaches tumor associated antigens (TAAs) have a higher expression level in tumors compared to normal tissue; however, this poses a significant drawback in the development of therapeutics including cancer vaccines as there will be “on-target, off-tumor” toxicity and central and peripheral tolerance mechanisms eliminating the T and B cells’ ability to recognize self-antigens (i.e. onset of autoimmune disease) (Feola; page 4, paragraph 1). The art of Mehnath (PTO-892; page 2, Reference X) teaches that the selection of suitable tumor antigens is vital for the development of an effective vaccine candidate and that the ideal vaccine should exhibit a high level of tumor specificity because it is solely developed from the tumor and stimulate stronger immunogenicity (Mehanth; page 11, left column, paragraph 2). Peptides in cancer vaccine need to be tumor subtype specific and patient specific so that the patient’s immune response will be mounted against their specific cancer.
Additionally, the terms “mutant peptides” and “non-mutated peptides” for the first round of vaccination and “mutated amino acids” in the second round of personalized vaccination lack sufficient written description as there is insufficient disclosure of how “mutant peptides”, “non-mutant peptides”, and “mutant amino acids” are defined and what they encompass as there is no indication the DNA, RNA, or protein sequences are compared to a reference or “normal” genome. With how claims 1 and 3 are written for the second rounds of personalized vaccination, there is indication that the DNA and RNA sequences of the tumor biopsy and the DNA, RNA, and protein sequences of the normal tissue biopsy are being used in the claimed method. The art of Ballouz et al (PTO-892; page 1, Reference V) teaches that DNA, RNA, and protein sequencing always needs to be performed with consideration to a reference genome (standard hg19 genome or a patient specific genome) in order to perform mutation and variant calling or else one would not know what would be considered wild-type vs. mutant (Abstract; page 1, left column, paragraph 2; page 7, right column, paragraph 1).
There is insufficient written description for the recitation of “determining T cell exposed motifs which comprise mutated amino acids in each of the proteins” or what is considered a T cell exposed motifs and what is not a T cell exposed motif of instant claims 1 and 2 and how the positions correlate to efficiency of T cell recognition of the peptide and to the desired binding affinity to one or more of the MHC alleles of the subject. The additional limitation recited in instant claim 18 of administering peptides, or nucleic acids encoding them, which occur naturally in a tumor protein broadens the scope of the claimed invention to any and all proteins (see 112b rejection). Any protein, mutated/non-mutated or contributes to normal cell functioning/contributes to tumorigenesis, is encompassed by the claims.
The specification (Example 9) discloses that the T cell exposed motif (TCEM) depends on the length of the generated peptide and its MHC specificity. TCEM I (MHC I specificity) located in a 9-mer comprises 5 exposed amino acids with positions 4,5,6,7 or 8 and for TCEM II (MHC II specificity) located in a 15-mer comprises 5 exposed amino acids with positions 2,3,5,7,8 of the 9-mer core of the 15-mer peptide. The other positions are considered groove exposed positions that are not T cell exposed that determine and influence MHC binding affinity.
The art of Buonaguro et al (PTO-892; page 1, Reference W) teaches that immunodominance is key when considering a cancer vaccine formulation and immunodominance of T cell determinants results from the binding affinity to MHC molecules, the presence of appropriate MHC molecules and T cell receptors at the individual level, and competition between different epitopes of a given protein antigen for the available MHC binding sites (page 3, left column, section 2.1). Epitope specificity depends on peptides that are presented in the “peptide binding groove” of class I or class II MHC while the anchor residues mediate the anchoring of the peptide to the MHC molecule (page 3, left column, section 2.1). Although peptides can adopt optimal conformation in the groove of the MHC, there is no guarantee for the immunogenicity, so it is necessary to increase both the binding and the affinity to the MHC groove and to the T cell TCR (page 3, right column, section 2.1). Sequence length of the peptide vaccines are also important to promote strong immunogenic response and are typically short (8-11 amino acids; MHC class I) or long (11-30 amino acids; MHC class II) (page 3, right column, section 2.2).
Conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
The specification has neither demonstrated a structure function relationship nor provided a representative number of species of peptides in the first round of vaccination and the species of alternative peptides in the second round of vaccination with the mutated amino acids in a T cell exposed position and substitution of amino acid(s) not in a T cell exposed position with the recited function of treating a subject clinically presenting with a tumor.
The specification must set forth the structural features that would allow one of ordinary skill in the art to identify and produce the recited peptides. In the instant case, definition by function does not suffice to define the genus because it is only an indication of what the peptides do, rather than what they are.
The specification does not describe a correlation between the peptide structure and the function of being able to be used for treating a subject clinically presenting with a tumor such that a skilled artisan would have known what peptide variants possess the claimed function. "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 U.S.P.Q.2d 1410 (BPAI 2007)), at page 16. In this instant case, Applicants have not provided the requisite identifying structural features of the peptides encompassed. "Without a correlation between structure and function, the claim does little more than define the claimed invention by function" supra, at page 17.
The specification docs not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 U.S.P.Q.2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed invention.
Adequate written description requires more than a mere statement that it is part of the invention and a reference to a potential method of isolating it. In the instant application, the amino acid sequence itself or isolated protein is required. See Fiers V. Revel, 25 USPQ 2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Lts., 18 USPQ2d 1016. In view of the aforementioned problems regarding description of the claimed invention, the specification does not provide an adequate written description of the invention claimed herein. See The Regents of the University of California v. Eli Lilly and Company, 43 USPQ2d 1398, 1404-7 (Fed. Cir. 1997). In University of California V. Eli Lilly and Co., 39 U.S.P.Q.2d 1225 (Fed. Cir. 1995) the inventors claimed a genus of DNA species encoding insulin in different vertebrates or mammals, but had only described a single species of cDNA which encoded rat insulin. The court held that only the nucleic acids species described in the specification (i.e. nucleic acids encoding rat insulin) met the description requirement and that the inventors were not entitled to a claim encompassing a genus of nucleic acids encoding insulin from other vertebrates, mammals or humans, id. at 1240. The Federal Circuit has held that if an inventor is "unable to envision the detailed constitution of a gene so as to distinguish it from other materials...conception has not been achieved until reduction to practice has occurred", Amgen, Inc. V. Chugai Pharmaceutical Co, Ltd., 18 U.S.P.Q.2d 016 (Fed. Cir. 1991). Attention is also directed to the decision of The Regents of the University of California V. Eli Lilly and Company (CAFC, July 1997) wherein is stated: "The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 222 USPQ 369, 372-373 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, as we have previously held, a cDNA is not defined or described by the mere name "cDNA," even if accompanied by the name of the protein that it encodes, but requires a kind of specificity usually achieved by means of the recitation of the sequence of nucleotides that make up the cDNA." See Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606.
As such, there is insufficient written description of the required kind of structure identifying information about the corresponding makeup of the claimed peptides to demonstrate possession.
Regarding the term “desired predicted binding affinity”, the specification (page 21, lines 9-20) describes the term “affinity” to refer to a measurement of the strength of binding between two members of a binding pair which can be measured in terms of dissociation constant (Kd) or inhibitory constant 50 (IC50). The specification (page 21, lines 27-32; page 22, lines 1-17) describes the term “high affinity” to refer to binding pair or describe a binding pair that have an affinity of greater than 2 x 107 M-1 ( equivalent to a dissociation constant of 50nM Kd), “moderate affinity” to refer to a binding pair or describe a binding pair that have an affinity of from 2 x 107 M-1 to 2 x 106 M-1 and “low affinity” to refer to a binding pair or describe a binding pair that have an affinity of less than 2 x 106 M-1 (equivalent to a dissociation constant of 500nM Kd). Binding affinity can also be expressed by standard deviation from the mean binding found in the peptides making up a protein as "-lσ" or <-lσ and that analysis of a wide range of experimental results suggest that a criterion of standard deviation units can be used to discriminate between potential immunological responses and non-responses. Additionally, the specification (page 48, lines 6-15; page 104, lines 14-20) describes intermediate binding affinity may be most effective in stimulating a T cell response and good memory T cells while high affinity peptides do not generate the best cytotoxic T cell response and low affinity peptides may initiate but not sustain a CD8+ response. Strength of binding affinity (i.e. top 5% binders) may be a factor in determining whether the T cell response to a tumor leads to negative side effects of T cell exhaustion and tolerance.
However, there is no definition of the term “desired” or indication of what the Applicant deems to be a desired binding affinity. The specification does not provide adequate written description for the full scope of the recitation of an array of alternative peptides having a “desired predicted binding affinity” in instant claims 1-2 and 14-17 and how the “desired predicted binding affinity” correlates to the peptide’s ability to perform the recited function of treating a subject clinically presenting with a tumor or as a vaccine.
The additional recitation of “the desired predicted binding affinity to one or more of the subject’s MHC alleles of selected peptides in the second round of vaccination exceeds 85% … 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid” of instant claims 14-15 does not provide a sufficient definition of a “desired predicted binding affinity” as it is unclear how this is measured and what the % of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid represent (see 112b rejection). Additionally, the specification (Example 9) describes those peptides elected had a predicted binding affinity about 2 standard deviations below the mean of the protein, placing them at the 95% percentile, but not higher because very high affinity peptide may lead to immunosuppression or T cell exhaustion. This disclosure implies the limitations of the desired predicted binding affinity to exceed 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid is not even desired.
The additional recitation of “the desired predicted binding affinity .. is less than 50 nanomolar and 200 nanomolar” of instant claims 16-17 do not provide a sufficient definition of a “desired predicted binding affinity” as it is unclear how this is being measured and what the units (% in instant claims 14-15 and nanomolar in instant claims 16-17) represent (see 112b rejection). Additionally, the specification (page 21, lines 26-33; page 22, lines 1-4) describes a 50 nM Kd to represent a high affinity binding pair and 500 nM Kd to represent a low affinity binding pair. However, the specification (Example 10) describes a very high affinity peptide (top 5% of binders) may lead to immunosuppression or exhaustion implying peptides with a desired predicted binding affinity equal to or less than 50nM is not even desired.
The art of Zhao et al (PTO-892; page 3, Reference V) teaches that strong MHC binding affinity is less than 50 nM and peptides that do exhibit binding to MHC have an affinity of less than 500 nM when measured with IC50 (Zhao; page 5, paragraph 1). The art of Apostolopoulos et al (PTO-892; page 1, Reference U) teaches the most appropriate peptides for immunization would be low to medium affinity binding peptides since high affinity peptides, specifically self-antigens or tumor-associated antigens, would lead to tolerance and are poorly immunogenic (Apostolopoulos; page 259, right column, paragraph 2; page 260, right column, paragraph 2).
As such, claims 1-11, 13-18, and 20 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims 1-11, 13-18, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While enabled for: a method for treating a subject clinically presenting with glioma and glioblastoma comprising administering a pharmaceutical composition wherein the pharmaceutical composition comprises an array non-mutated peptides of VEGFR, WT-1, and Vimentin with SEQ ID NOs:1-118 and mutated peptides of EGFR, H3.3, IDH1, and BRAF with SEQ ID NOs: 154-183, 284-288, 294-298, 344-348, 392-396, 441-446, 468-472, and 512-514 and administering a second round of treatment with a personalized pharmaceutical composition wherein the second round comprises the following steps: identifying proteins from the biopsy containing mutated amino by comparing the RNA fraction comprising the mutant amino acid (FPKM) and DNA tumor fraction encoding the gene mutation from the tumor biopsy and the normal tissue from the subject wherein the tumor specific mutations which can be targeted by T cells are selected from those with the RNA/DNA ratio exceeds 10%; generating an array of 9-mer MHC I peptides which expose the mutated amino acid at positions 4,5,6,7, or 8 and generating 15-mer MHC-II peptides which expose the mutated amino acid at positions 2,3,5,7,8 of the 9-mer core for TCEM IIA peptide or -1,3,5,7,8 for TCEM IIB peptide; selecting a group of one or more selected peptides from the array of generated peptides which display a predicted dissociation constant (Kd) less than 200 and less than 50nM or within 1-2 standard deviations of the mean of the peptides that bind the tumor protein and synthesizing the group of peptides and administering the selected peptides as a second round of treatment.
The specification does not reasonable provide enablement for: a method for treating a subject clinically presenting with a tumor comprising administering a first round of vaccination wherein the vaccination comprises an array of one or more peptides, or nucleic acids encoding them; selected from the group consisting of non-mutated peptides derived from tumor associated antigens appropriate to the tumors of the type diagnosed and peptides commonly found to be mutated in tumors of the type diagnosed; and administering a second round of personalized vaccination wherein the second round of vaccination comprises identifying proteins from the biopsy containing mutated amino acids and the peptide comprising each of the mutated amino acids; determining the predicted desired binding affinity to the subject’s MHC alleles; generating an array of alternative peptides not present in the tumor; selecting a group of one or more selected peptides from the generated array of alternative peptides which have a desired predicted binding affinity; and administering the selected peptides, or their encoded nucleic acids, as the second round of vaccination of instant claim 1; selecting the peptides commonly found to be mutated in tumors so as to position the mutated amino acid in a T cell exposed position and substituting one or more of the amino acids not in a T cell exposed position to provide a desired binding affinity of instant claim 2; selecting a sub array of alternative peptides in instant claim 3b; vaccination in instant claim 4-5 and 19-20; wherein the desired binding affinity to one or more of the subject’s MHC alleles of selected peptides in the second round of vaccination exceeds 85% and 95% of the binding affinity of all peptides in the tumor protein the comprises the mutated amino acid of instant claims 14 and 15; wherein the desired predicted binding affinity to the one or more of the subject’s MHC alleles of selected peptides in the second round is less than 50 and 200 nanomolar of instant claims 16 and 17; wherein the first and/or second rounds of vaccination further comprise administering peptides, or nucleic acids encoding them, which occur naturally in a tumor protein of instant claim 18.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The breadth of claims 1-11, 13-18, and 20 encompass treating subjects clinically presenting with any tumor including malignant/benign and liquid/solid tumors. Tumors all have different causes, affect different physiological processes, and are treated with different agents or surgical interventions.
The specification fails to provide guidance as how to treat any cancer with the recited “vaccines” and only provides working examples (Examples 1-8) disclosing the proposed peptides for VEGFR, Vimentin, WR1, EGFR, IDH R132H, H3.3 K27/28M, and BRAF V600E for the first round of vaccination and their predicted binding affinity to various MHC alleles.
The art of Feola et al (PTO-892; page 1, Reference X) teaches tumor associated antigens (TAAs) have a higher expression level in tumors compared to normal tissue; however, this poses a significant drawback in the development of therapeutics including cancer vaccines as there will be “on-target, off-tumor” toxicity and central and peripheral tolerance mechanisms eliminating the T and B cells’ ability to recognize self-antigens (i.e. onset of autoimmune disease) (Feola; page 4, paragraph 1). The art of Mehnath (PTO-892; page 2, Reference X) teaches that the selection of suitable tumor antigens is vital for the development of an effective vaccine candidate and that the ideal vaccine should exhibit a high level of tumor specificity because it is solely developed from the tumor and stimulate stronger immunogenicity (Mehanth; page 11, left column, paragraph 2). It is unpredictable how a cancer vaccine peptide that is not tumor or even patient specific will function in the patient’s tumor since it could effectively treat the tumor, create the onset of autoimmunity, or have no function, all of which depend on the MHC-peptide binding affinity as well as T cell receptor (TCR)-MHC-peptide binding (see McMahan et al, whole document; PTO-892; page 2, Reference W).
The breadth of claims 1-11, 13-18, and 20 encompass all peptides that are derived from tumor associated antigens appropriate to the type diagnosed (see 112b rejection above) and all peptides commonly found to be mutated in tumors of the type diagnosed for the first round of vaccination. The additionally recitation of the limitation of instant claim 18 of the first round of vaccination further comprising peptides, or their nucleic acids encoding them, which occur naturally in a tumor protein further broadens the scope of the claimed invention to all peptides expressed in the human body since all peptides can occur naturally in a tumor protein. The peptides have different structures and physiochemical properties and can elicit different anti-tumor and immune responses to varying degrees or have no impact on the course of the disease.
Regarding the terms “mutated” and “non-mutated” recited in instant claims 1 and 2, the specification discloses (page 28, lines 1-6) a “mutated amino acid” to refer to the appearance of an amino acid in a protein that is a result of a nucleotide change, a missense mutation, or an insertion, or deletion, or fusion. However, there is no discussion of how to determine if a protein is “mutated” and/or “nonmutated”. It is known in the art that in order to determine whether a protein is mutated or nonmutated, the DNA, RNA, and protein sequences need to be compared to a reference or a wild-type sequence and be present in the tumor with high confidence (See Ballouz; PTO-892; page 1, Reference V; Abstract; page 1, left column, paragraph 2; page 7, right column, paragraph 1). Additionally, individuals can possess unique short nucleotide polymorphisms (SNPs), a type of genetic variation which lends to normal DNA variation between individuals and population of individuals (See Piskol, whole document; PTO-892; page 3, Reference U). Depending on the reference sequence, the SNPs can be considered mutated even though they may not correlate to tumorigenesis. Additionally, after transcription, RNA can undergo alternative splicing leading to splice variants and varying protein sequences for the same protein which a person of ordinary skill in the art would consider “non-mutated” (See Piskol, whole document). However, with splice variants producing different protein sequences could be considered “mutated” when compared to a reference sequence. With how the claims are written it is unpredictable what amino acids and how many amino acids need to be altered to be considered “mutated” and “non-mutated”.
The breadth of claims 1-11, 13-18, and 20 encompass all peptides with any amino acid exposed in a T cell exposed position and any amino acid substitution in a non-T cell exposed position to achieve any defined desired predicted binding affinity to the subject’s MHC alleles in the second round of personalized treatment. The peptides have different physiochemical properties and can elicit different immune responses (CD4+ or CD8+) to varying degrees.
The specification (page 52, line 3) discloses TCEMs comprise 5 amino acids, or 205 = 3.2 million possible configurations in a 9-mer or 15-mer peptide. There is no disclosure of if the TCEM would also encompass bigger genomic changes such as insertions/deletions, gene fusions, etc. and how these genomic changes would be translated into a protein structure and which amino acids would be in the peptide’s TCEM. These larger genomic changes then additionally broaden the scope of what the claimed invention encompasses. With the different configurations, it would be unpredictable as to how efficient a T cell recognizes the peptide and how it functions as a “vaccine” to induce an immune response against said peptide. With the addition of substituting one or more of the amino acids not in a T cell exposed position as recited in instant claim 2, the possibilities of peptides becomes billions. It is unpredictable how the substitution would alter MHC binding affinity or if it would alter it at all and would require undue experimentation to then measure the billions of peptides binding affinity to a patient’s MHC alleles.
With the additional recitation of selecting an array of peptides with a predicted MHC binding affinity that exceeds 85% and 95% of the binding affinity of all of the peptides in the tumor protein that comprises the mutated amino acid as recited in instant claims 14 and 15 and the desired predicted binding affinity is less than 50 nanomolar and 200 nanomolar of instant claims 16 and 17. As stated above the specification discloses that there are millions of possible peptides for one given protein and then to add in substituting one or more amino acids in a position not in a T cell exposed position, the possible peptides becomes billions. It would require undue experimentation to measure the MHC binding affinity of all the billions of possible peptides to know which peptides exceeds 85% and 95% of the binding affinity of all the peptides in the tumor protein and which peptides have a predicted MHC binding affinity of less than 50nM and 200 nM. The specification also discloses (page 104, lines 19-20) that the top 5% binders (including peptides with an MHC binding affinity of less than 50nM) are not even desirable or chosen for further study in Examples 1-8 because very high affinity peptide may lead to immunosuppression or T cell exhaustion (see 112b rejection). It would then be unpredictable which of these billions of possible peptides bind to a TCR with high affinity to elicit an immune response against the mutated peptide found in the tumor (see McMahan et al; PTO-892, page 2, Reference W).
In view of the absence of a specific and detailed description in Applicant’s specification of how to effectively use the genus of peptides claimed, absence of working examples providing evidence which is reasonably predictive that the genus of the claimed peptides are effective for in vivo use for treating a subject clinically presenting with a tumor, and the lack of predictability in the art at the time the invention was made, an undue amount of experimentation would be required to practice the claimed “vaccine” compositions with a reasonable expectation of success.
In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the first and second round “vaccinations” for a treatment for subjects clinically presenting with a tumor.
At issue is whether or not the claimed compositions could be used as vaccines. Vaccines are used to prevent specific diseases caused by a specific agent. The claims 1-20 do not recite any disease to be prevented by the use of the claimed vaccines. At a minimum, claims directed to using vaccines must be directed to specifically preventing a particular disease. A method of using a “vaccine” to treat an unspecified disease or tumor is not enabled as the vaccine composition would be unsuccessfully used to treat any other tumor than the one that it is formulated to prevent. One of ordinary skill in the art would be required to perform undue experimentation to make and use a vaccine formulated for preventing tumor X to prevent tumor Y.
Furthermore, the specification does not provide sufficient guidance on how to sufficiently prevent tumors (vaccination) by administering the claimed compounds. The first criterion in judging a vaccine is the level of antibody (humoral immune response) before and after immunization. The success of the vaccination is judged by the extent of increase in the level of antigen - specific antibody. The second criterion for a vaccine is its ability to stimulate memory T lymphocytes (cell-mediated immune response) (See Kuby; PTO-892; page 4, Reference X). As such one of ordinary skill in the art would be required to perform undue experimentation to make and use the genus of vaccines encompassed for pharmaceutical use in preventing tumor.
PDQ (PTO-892; page 4, Reference W) teaches that prevention of cancer can be accomplished by avoiding a carcinogen, pursuing a healthy lifestyle or dietary practices, medical interventions (e.g. chemoprevention) or surgical procedures, or early detection strategies (PDQ; page 1; paragraph 4). PDQ additionally teaches that there are only two proven, efficacious cancer vaccines targeting HPV and hepatitis B (PDQ; pages 4-5, paragraph 4).
The specification fails to provide guidance as to how to prevent (100% prevention) a tumor using any of the recited agents. The art is highly unpredictable as to what will be a therapy for tumors, so it would require an undue amount of experimentation for one of ordinary skill in the art to practice the claimed invention commensurate in the scope with the claims. The invention may encompass pharmaceutical compositions which treat tumors, but the specification does not disclose how to totally prevent tumors using a “vaccine” composition.
Since no in vivo studies were used as model system to prevent any disorder it is not clear that reliance on the in vitro data accurately reflects the relative animal efficacy of the claimed therapeutic strategy. The specification does not adequately teach how to effectively treat any tumors or reach any therapeutic endpoint in animals by administrating the vaccine, much less any tumor as encompassed by the instant claims. The specification does not teach how to extrapolate data obtained from the in vitro studies to the development of effective in vivo animal therapeutic treatment, commensurate in scope with the claimed invention. There must be a rigorous correlation of biological activity between the disclosed in vitro activity and an in vivo effectiveness to establish a method of preventing disease using a “vaccine”.
Although, the specification describes in vitro experiments, there is no correlation on this record between the in vitro studies and the preventing tumors in currently available form for humans or animals. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to efficacy in humans or animals (emphasis added). Ex parte Maas, 9 USPQ2d 1746
In view of the absence of a specific and detailed description in Applicant's specification of how to effectively use the genus of “vaccine” compositions claimed, absence of working examples providing evidence which is reasonably predictive that the genus of claimed agents are effective for in vivo use for prevention of tumors, and the lack of predictability in the art at the time the invention was made, an undue amount of experimentation would be required to practice the claimed vaccine compositions with a reasonable expectation of success.
Substantiating evidence may be in the form of animal tests, which constitute recognized screening procedures with clear relevance to efficacy in humans. See Ex parte Krepelka, 231 USPQ 746 (Board of Patent Appeals and Interferences 1986) and cases cited therein. Ex parte Maas, 9 USPQ2d 1746.
Priority
This application is a 371 of PCT/US2021/062147 effectively filed on 12/7/2021 which claims benefit to U.S. Provisional Application 63/122,192 effectively filed on 12/7/2020.
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 1-2, 4, 6-11, 16-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hilf et al (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") and U.S. Patent No. US 10,815,273 B2 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 30; “Dao”).
Hilf teaches a phase I clinical trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC) that integrates highly individualized vaccinations with both unmutated antigens and neoepitopes into standard care to optimally exploit the limited target space (i.e. limited intratumoural infiltration of immune cells) for patients with newly diagnosed glioblastoma who were HLA-A*02:01+ or HLA-A*24:02+ (Hilf; Abstract; page 242, left column, paragraph 2). The GAPVAC approach includes two rounds of vaccination with the first being APVAC1 which was derived from a premanufactured library of unmutated GBM associated antigens/peptides and composed of the seven best-ranking HLA class I peptides (9-10 amino acid length), two peptides binding promiscuously to different HLA-DR (class II) molecules (pan-DR antigens) (14-18 amino acid length) and a viral marker peptide (Hilf; Abstract; page 240, right column, paragraph 2; Fig. 3; Extended Data Fig. 2a). The specific peptides included in APVAC1 were chosen based on a ranking score considering individual-peptide presentation data, mRNA expression data and immunogenicity data and ensured strong tumor association (Hilf; page 260, right column, paragraph 1; Extended Data Fig.1a). The APVAC1 vaccine was administered eleven times within 21 weeks at regular intervals (Hilf; Fig. 1 and 5; Extended Fig.2a). Some patients in the clinical trial received surgical intervention (i.e. re-resection) after receiving APVAC1 (Hilf; Fig. 5). Ex vivo multimer analysis revealed vaccine induced CD8+ T cell responses to at least one APVAC1 HLA class I peptide in 12/13 patients and vaccine induced CD4+ T cell responses to one or both APVAC1 unmutated pan-DR antigens in 9/13 patients (Hilf; page 243, left column, paragraphs 2-3). The second round of vaccination, APVAC2, followed which preferentially targeted neoepitopes in three strategies including (1) mutation containing peptides natural presentation shown by mass spectrometry (HLA class I or class II); (2) mutation containing peptides with a predicted high likelihood for HLA class I binding and immunogenicity (peptides with a length of 19 amino acids with the mutation at position 10 were used); and (3) unmutated GBM-associated HLA class I epitopes that were identified in the individual immunopeptidome that were not part of the APVAC1 warehouse were selected (Hilf; page 241, paragraph 1; page 242, paragraph 1; Fig. 1; Extended Fig. 2a). To identify mutation containing peptides, DNA and RNA were extracted from a biopsy of the patient’s tumor and compared to DNA from normal blood cells from the same patient using next-generation sequencing, specifically whole exome sequencing wherein, for mutation detection, the DNA reads were aligned to the reference genome hg19 with BWA and only high confidence calls were retained for single-nucleotide variants. For RNA-sequencing analysis, RNA reads were aligned to the hg19 reference genome and transcriptome using Bowtie, gene expression determined by comparing known transcript and exon coordinates of genes of the UCSC followed by normalization to RPKM units. Additionally, high sensitivity liquid chromatography-tandem mass spectrometry data was analyzed against a personalized proteome library that contained all SNVs to identify HLA class I- and II-presented mutation containing peptides. HLA binding affinity was predicted via IEDB T cell prediction tools using all variant-containing 8-11 amino acid containing peptides for HLA-A/B-binding estimations where the best IEDB consensus score was associated with the respective variant and potential immunogenicity was assessed by calculating the difference between the predicted HLA-binding affinity of the mutant peptide and the wild-type counterpart along with absolute predicted HLA binding and variant expression (Hilf; page 246, right column “APVAC2 selection and manufacturing”). From this method, only the highest-ranking ones as judged by HLA-binding, expression, and immunogenicity were considered or APVAC2 as 19 amino acid peptides (mutation flanked by 9 amino acids of the natural sequence on each side to cover all potential mutation-containing HLA-binding 9-10 amino acid peptides) and only two candidates per patient were de novo synthesized and administered (Hilf; page 247, right column “APVAC2 selection and manufacturing”). The APVAC2 vaccine was administered eight times within nine weeks starting day 15 of the 4th TMZ cycle (Hilf; Extended Data Fig.2a). 8/10 patients developed neoepitope specific, dominantly CD4+ T cell responses and 11/13 vaccinated, mutated APVAC2 peptides induced a CD4+ T cell response (Hilf; page 243, right column, paragraph 1; Figs. 3-4). Although none of the mutated APVAC2 peptides evoked an isolated CD8+ T cell response, ex vivo multimer staining confirmed a CD8+ T cell response for the 19-mer peptide 14-M09 (Hilf; page 243, right column, paragraph 1; Fig. 4).
Hilf does not teach the limitation in instant claim 1 wherein the amino acids not within the T cell exposed motif are substituted to change the predicted MHC binding affinity; instant claim 2 wherein the method further comprising selecting the peptides commonly found to be mutated in tumors so as to position the mutated amino acid in a T cell exposed position and substituting one or more of the amino acids not in a T cell exposed position to provide a desired binding affinity to one or more of the MHC alleles of the subject; instant claim 16 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round is less than 50 nanomolar; and instant claim 17 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round is less than 200 nanomolar.
However, Dao teaches methods of identifying new epitopes derived from WT1 to expand the potential use of WT1 as a target for immunotherapy by using computer-based MHC-binding algorithms and in vitro validation of the T cell responses specific for the identified peptides (Dao; Abstract). Dao teaches affinity for MHC molecules is necessary for peptide presentation and T cell recognition in order to elicit a peptide-specific immune response (Dao; page 36, column 50, lines 64-65). The 15-mer overlapping peptides were designed by altering a single amino acid in the anchor residues of the native peptides for class I, which resulted in a higher predicted binding than its native sequences. The class II peptides were designed by adding flanking residues to the class I peptides, in order to simultaneously stimulate both CD4 and CD8 T cells (Dao; Example 1-2, columns 47, peptide design, peptide synthesis). To generate peptides with strong immunogenicity, amino acid substitutions were introduced to positions 2 and 9 (class I anchor residues) (Dao; [66]-[70]; Example 2, page 36, columns 49-50). Peptides were also derived to bind to HLA-B35, A0101, A0301, A1101 class I and HLA-DR class II molecules in order induce T cell responses in the context of other HLA haplotypes (Dao; Example 9, page 41, columns 59-60). The MHC binding affinity is measured as an IC50 where high affinity refers to a concentration of 0.5 - 500nM (Dao; page 20, column 17, lines 26-27). Additionally, MHC binding prediction scores of the native and analog peptides were screened using three online available databases (BIMAS, RANKPEP, and SYFPEITHI) (Dao; Example 1, column 47, Peptide Design).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the claimed invention, to have modified the method of treating a subject clinically presenting with a tumor comprising a first round of vaccination (APVAC1) and a second round of personalized vaccination (APVAC2) wherein APVAC2 comprises generating an array of peptides not present in the tumor of Hilf with the method of substituting amino acids not within the T cell exposed motif to change to predicted MHC binding affinity of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches the array of generated peptides in APVAC2 to already successfully elicit a CD4+ and CD8+ immune response in a patient and Dao teaches substituting an amino acid not within the T cell exposed motif in a peptide can further strengthen MHC-peptide binding and elicit a stronger immune response compared to the peptide’s native analog. Therefore, it would have been obvious to combine the array of generated peptides in APVAC2 of Hilf with method of substituting amino acids not within a T cell exposed motif of Dao in order to yield predictable results of enhancing MHC-peptide binding and eliciting a stronger peptide-specific immune response in a subject.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method of treating a subject clinically presenting with a tumor comprising a first round of vaccination (APVAC1) and a second round of personalized vaccination (APVAC2) wherein APVAC2 comprises a generated peptides chosen in part for their MHC binding affinity to the subject’s MHC alleles of Hilf with the predicted MHC binding affinity to be between 0.5 – 500 nM of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches the array of generated peptides in APVAC2 to successfully bind to the subject’s MHC alleles and successfully elicit a CD4+ and CD8+ immune response and Dao teaches a high MHC binding affinity to be between 0.5 – 500 nM which is correlated to a stronger immune response. Therefore, it would have been obvious to combine the predicted MHC binding affinity of Hilf to be a high predicted binding affinity (0.5 – 500 nM) of Dao in order to yield a predictable result of enhancing MHC-peptide binding and elicit a stronger peptide-specific immune response in a patient.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hilf in view of Dao as applied to claim 1 above, and further in view of Rabizadeh et al (IDS filed on 9/25/2025; Non-Patent Literature Documents, Reference 132; “Rabizadeh”) and Malcikova et al (PTO-892; page 5, Reference W; "Malcikova").
Hilf and Dao have been discussed above. Hilf and Dao differ from the claimed invention in regards to instant claim 3 wherein the method further comprises a. determining the fraction of the DNA in the tumor biopsy which encodes each of the mutated amino acids and the fraction of RNA transcribed from that gene locus and expressing the mutated amino acids; and b. selecting a sub array of the alternative peptides from the proteins in the biopsy which are present in at least 10% of the DNA in the biopsy and expressed in at least 10% of the RNA transcribed from that gene locus in the biopsy.
However, Rabizadeh teaches improved methods of identifying clinically druggable mutations in patients with cancer by simultaneously analyzing both tumor and germline sequences to reduce the risk of mistakenly identifying germline mutation as somatically-derived genetic changes and potential cancer driver mutations (i.e. false positive (Rabizadeh; Abstract; page 19223, left column, paragraph 1; page 19224, right column, paragraphs 1-2). Rabizadeh teaches the differences in precision and sensitivity of tumor-only sequencing methods versus tumor and normal DNA sequencing methods where the former method results in the elimination of false positive results and analysis of the DNA or both the normal germline and the tumor genome is necessary for accurate identification of molecule targets for cancer therapy. Even higher precision is achieved through both tumor-normal DNA and RNA sequencing analysis as RNA sequencing provides data on the relative expression levels of DNA variants and specific tumor somatic variants as mRNA (Rabizadeh; page 19230, right column, paragraphs 1-3). Rabizadeh also teaches treatment decision based on tumor-only DNA sequencing or in the absence of RNA sequencing results in administration of ineffective therapeutic while also increasing the risk of negative drug-related side effects (Rabizadeh; page 19230, right column, paragraph 3).
Malcikova additionally teaches European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) recommendations for TP53 mutation analysis to ensure the data is analyzed and interpreted in a consistent, standardized, and accurate way (Malcikova; Abstract). Malcikova teaches that the limit of detection (LOD) for next generation sequencing (NGS), or the lowest variant allele frequency (VAF) that is reproducibly detectable by a particular method under specific well-defined conditions, should be set above the Sanger Sequencing detection limit (minimum LOD is 10% VAF) to reliably identify variants and avoid false positive calls (Malcikova; page 1074, right column, paragraph 2). The LOD is a function of both the initial DNA input and the sequencing coverage achieved (Malcikova; page 1074, right column, paragraph 2). Additionally, Malcikova teaches variants with <10% VAF are considered low burden or low-level variants (Malcikova; page 10176, left column, paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the two rounds of vaccination of Hilf and Dao with the motivation to perform both RNA and DNA sequencing of tumor and normal tissue as a basis for treatment decision of Rabizadeh with selecting a variant with a VAF ≥ 10% of Malcikova with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Rabizadeh teaches that both tumor-normal DNA and RNA sequencing is necessary for accurate identification of molecule targets for cancer therapy and can lead to more effective treatments for patients and Malcikova teaches that a variant with ≥10% VAF is a higher confidence disease causing variant that has a higher probability of full clonality compared to a low VAF. Therefore, it would have been obvious to identify targetable gene variants through tumor-normal DNA and RNA sequencing of Rabizadeh with a high VAF (≥10%) Malcikova in the two rounds of vaccination of Hilf and Dao to yield predictable results of more effective targeting true positive oncogenic gene mutations and improve therapeutic outcomes for patients.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Hilf in view of Dao as applied to claim 1 above, and further in view of Fisher et al (PTO-892; page 3, Reference W; "Fisher").
Hilf and Dao have been discussed above. Hilf and Dao differ from the claimed invention in regards to instant claim 5 wherein the first round of vaccination is administered prior to surgical intervention.
However, Fisher teaches that surgery is widely used as a therapy for common solid tumors but it is not curative and cancer vaccination prior to surgery is a viable option to treat patients (Fisher; Abstract; page 1-2, Background). Fisher teaches neoadjuvant anti-tumor vaccination combined with partial debulking surgery is capable of inducing effective CD8 T cell dependent anti-tumor immunity and that depletion of CD4 T cells during vaccination provided complete tumor eradication and established immunological memory that could protect against subsequent tumor growth (Fisher; page 7, left column, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with the selected peptides in the second round of vaccination to have the mutated amino acids in a T cell exposed position of Dao with a cancer vaccine administration prior to surgery of Fisher with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modified the timing of the two rounds of vaccination of Hilf to be prior to surgery of Fisher in order to yield a predictable result of enhancing tumor eradication and establishing immunological memory that could protect against subsequent tumor growth.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Hilf in view of Dao as applied to claim 1 above, and further in view of Walter et al (PTO-892; page 4, Reference V; "Walter").
Hilf and Dao have been discussed above. Hilf and Dao differ from the claimed invention in regards to instant claim 13 wherein the group of one or more selected peptides, or the nucleic acids encoding them, administered in the second round of vaccination comprises at least 5 unique peptides not present in the proteins sequenced in the tumor.
However, Walter teaches a renal cell carcinoma vaccine, IMA901, that consists of eleven peptides, nine HLA_A*02-restricted tumor associated peptides (TUMAPs), one HLA-DR-restricted TUMAP used to treat patients with renal cell carcinoma, and one viral marker not present in the proteins sequenced in the tumor (Walter; Abstract; Table 1; page 1255, right column, paragraph 1). Identification of TUMAPs were based on natural presentation from primary tumor tissues using XPRESIDENT, an antigen discovery platform (Walter; page 1255, left column, paragraph 2). Walter teaches that clinically relevant antigens were identified by comparing mRNA expression profiles of 42 RCC samples to those of 35 different healthy tissues and subsequent in vitro priming using artificial antigen presenting cells to detect antigen specific T cells in peripheral blood cells of healthy donors (Walter; page 1255, left column, paragraph 3). Among the 27 immune-evaluable subjects taking IMA901, 20 showed vaccine induced T cell response to at least one TUMAP and 8 responded to multiple TUMAPs (Walter; page 1255, right column, paragraph 2). Walter additionally teaches that these patients had a large breadth of T cell responses attributed to the number of different specific antigens in IMA901 which was significantly associated with clinical benefit implying that the targeting of multiple antigens in immunotherapy is required for clinical efficacy (Walter; page 1259, left column, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the cancer vaccine composition of Hilf and Dao with the motivation to use multiple unique peptides in a cancer vaccine not present within proteins sequenced in the tumor of Walter with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have to use multiple unique peptides in a cancer vaccine since Walter teaches targeting multiple specific antigens induces a breadth of T cell responses and is associated with improved clinical efficacy. Therefore, it would have been obvious to combine the cancer vaccine composition of Hilf and Dao with the motivation to use multiple unique peptides in a cancer vaccine of Walter in order to yield a predictable result of widening the breadth of T cell responses and increasing the clinical efficacy of the vaccine.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hilf in view of Dao as applied to claim 1 above, and further in view of US 2017/0161430 A1 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 050; "Bremel").
Hilf and Dao have been discussed above. Hilf and Dao differ from the claimed invention in regards to instant claim 14 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 85% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid and instant claim 15 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid.
However, Bremel teaches methods and systems for identifying and classifying epitopes that can be used to design synthetic peptides and protein for vaccines (Bremel, Abstract; [0004]). Bremel teaches that there is a need to predict peptide sequences which comprise motifs that are likely to be recognized by T-cells and which are likely to give rise to down-regulation or suppression of the immune response or up-regulation or activation of the immune response (Bremel; [0004]). The peptides that bind to MHC class molecules in the groove exposed motif (GEM) can be altered in order to increase peptide-MHC binding affinity which can help lead to downstream stimulation of an immune response (Bremel; [0011]-[0012]). Bremel teaches binding affinity can be measured with an IC50 or Kd where a strong binder has a Kd of 50nM and a weak binder has a Kd of 500nM (Bremel; [0154]-[0159]). Bremel teaches binding affinity to also be expressed by the standard deviation from the mean binding found in all the peptides making up a protein where peptides with a standard deviation ≥ 1 below the mean represents the 85th percentile of MHC-peptide binding affinity (i.e. stronger binder) which is useful for discrimination between potential immunological responses and non-responses (Bremel; [0159]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating a subject clinically presenting with a tumor comprising a first round of vaccination (APVAC1) and a second round of personalized vaccination (APVAC2) wherein APVAC2 comprises a generated peptides chosen in part for their MHC binding affinity to the subject’s MHC alleles of Hilf and Dao with the predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches the array of generated peptides in APVAC2 to successfully bind to the subject’s MHC alleles and successfully elicit a CD4+ and CD8+ immune response and Dao teaches a high MHC binding affinity to be between 0.5 – 500 nM which is correlated to a stronger immune response. Bremel teaches peptides with a predicted MHC binding affinity at or below 1 standard deviation (85th percentile or above) of all peptides making up a protein can help discriminate between peptides that provide an immunological response and peptides that do not and peptides associated with higher binding affinity lead to an immunological response. Therefore, it would have been obvious to combine the APVAC2 peptides with strong predicted MHC binding affinity of Hilf and Dao with peptides with a predicted MHC binding affinity at or below 1 standard deviation (85th percentile or above) of the mean of all peptides making up a protein of Bremel in order to yield a predictable result of selecting peptides with strong MHC binding affinity to elicit a stronger immune response in a patient.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
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Claims 1-2, 4, 6-11, 16-18, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7 of U.S. Patent No. 12,569,546 B2 (PTO-892; page 1, Reference A; “’546”) in view of Hilf et al (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") and U.S. Patent No. US 10,815,273 B2 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 30; “Dao”).
‘546 teaches in reference claim 1 a method for treating cancer in a subject comprising designing a group of ten or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject comprising the following steps: obtaining a biopsy of the subject's tumor; obtaining sequences for proteins in said biopsy; identifying proteins from the biopsy containing mutated amino acids and the peptide comprising each of said mutated amino acids; determining T cell exposed motifs which comprise mutated amino acids in each of the proteins; determining the predicted binding affinity to the subject's MHC alleles of peptides which comprises each of said T cell exposed motifs which comprise mutated amino acids and identifying MHC allele-T cell exposed motif combinations which bind with an affinity greater than the mean for the protein from which the peptide is derived; generating an array of alternative peptides not present in the tumor from the identified MHC allele-T cell exposed motif combinations which bind with an affinity greater than the mean for the protein from which the peptide is derived, wherein each peptide in the array comprises the amino acids of one of said T cell exposed motifs which comprise mutated amino acids, and in which one or more of the amino acids not within the T cell exposed motif are substituted to change the predicted MHC binding affinity; selecting a group of ten or more selected peptides from said array of alternative peptides, wherein the group of selected peptides comprises peptides collectively predicted to bind to at least 4 different MHC alleles carried by the subject and further wherein the desired predicted binding affinity of each of the ten selected peptides is from 100 to 500 nM; synthesizing said group of ten or more selected peptides, or nucleic acids encoding the selected peptides; and treating cancer in the subject by a process selected from the group consisting of 1) administering the peptides or nucleic acids to the patient to stimulate a tumor specific T cell response; wherein said MHC alleles are MHC type I and said T cell response is a CD8+ response in reference claim 2; wherein said MHC alleles are MHC type I and said T cell response is a CD4+ response in reference claim 3; wherein the selected peptides are less than 20 amino acids in length in reference claim 4; wherein said group of ten or more selected peptides, or nucleic acids encoding them, is administered to a subject as a vaccine in reference claim 7.
‘546 does not teach administering a first round of administering a first round of vaccination, wherein the vaccination comprises an array of one or more peptides, or nucleic acids encoding the peptides, selected from the group consisting of non-mutated peptides derived from tumor associated antigens appropriate to tumors of the type diagnosed and peptides commonly found to be mutated in tumors of the type diagnosed; and a second round of personalized vaccination comprising the following steps of obtaining sequences for DNA and RNA in the biopsy and administering the selected peptides or their encoding nucleic acids as the second round of vaccination in instant claim 1; the method further comprising determining the MHC alleles of the subject prior to the first round of vaccination in instant claim 4; wherein the MHC alleles are a combination of MHC type I alleles and MHC type II alleles of instant claim 8; wherein the MHC I allele in the first round of vaccination is not A0201 or A2402 in instant claim 9; wherein the first and/or second rounds of vaccination further comprise administering peptides, or the nucleic acids encoding them, which occur naturally in a tumor protein in instant claim 18; and wherein each round of vaccination comprises 3 or more applications of the array of peptides, or the nucleic acids encoding them in instant claim 20.
Hilf teaches a phase I clinical trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC) that integrates highly individualized vaccinations with both unmutated antigens and neoepitopes into standard care to optimally exploit the limited target space (i.e. limited intratumoural infiltration of immune cells) for patients with newly diagnosed glioblastoma who were HLA-A*02:01+ or HLA-A*24:02+ (Hilf; Abstract; page 242, left column, paragraph 2). The GAPVAC approach includes two rounds of vaccination with the first being APVAC1 which was derived from a premanufactured library of unmutated GBM associated antigens/peptides and composed of the seven best-ranking HLA class I peptides (9-10 amino acid length), two peptides binding promiscuously to different HLA-DR (class II) molecules (pan-DR antigens) (14-18 amino acid length) and a viral marker peptide (Hilf; Abstract; page 240, right column, paragraph 2; Fig. 3; Extended Data Fig. 2a). The specific peptides included in APVAC1 were chosen based on a ranking score considering individual-peptide presentation data, mRNA expression data and immunogenicity data and ensured strong tumor association (Hilf; page 260, right column, paragraph 1; Extended Data Fig.1a). The APVAC1 vaccine was administered eleven times within 21 weeks at regular intervals (Hilf; Fig. 1 and 5; Extended Fig.2a). Some patients in the clinical trial received surgical intervention (i.e. re-resection) after receiving APVAC1 (Hilf; Fig. 5). The second round of vaccination, APVAC2, followed which preferentially targeted neoepitopes in three strategies including (1) mutation containing peptides natural presentation shown by mass spectrometry (HLA class I or class II); (2) mutation containing peptides with a predicted high likelihood for HLA class I binding and immunogenicity (peptides with a length of 19 amino acids with the mutation at position 10 were used); and (3) unmutated GBM-associated HLA class I epitopes that were identified in the individual immunopeptidome that were not part of the APVAC1 warehouse were selected (Hilf; page 241, paragraph 1; page 242, paragraph 1; Fig. 1; Extended Fig. 2a). To identify mutation containing peptides, DNA and RNA were extracted from a biopsy of the patient’s tumor and compared to DNA from normal blood cells from the same patient using specifically whole exome sequencing wherein, for mutation detection, the DNA reads were aligned to the reference genome hg19 with BWA and only high confidence calls were retained for single-nucleotide variants. For RNA-sequencing analysis, RNA reads were aligned to the hg19 reference genome and transcriptome using Bowtie, gene expression determined by comparing known transcript and exon coordinates of genes of the UCSC followed by normalization to RPKM units. Additionally, high sensitivity liquid chromatography-tandem mass spectrometry data was analyzed against a personalized proteome library that contained all SNVs to identify HLA class I- and II-presented mutation containing peptides. HLA binding affinity was predicted via IEDB T cell prediction tools using all variant-containing 8-11 amino acid containing peptides for HLA-A/B-binding estimations where the best IEDB consensus score was associated with the respective variant and potential immunogenicity was assessed by calculating the difference between the predicted HLA-binding affinity of the mutant peptide and the wild-type counterpart along with absolute predicted HLA binding and variant expression (Hilf; page 246, right column “APVAC2 selection and manufacturing”). From this method, only the highest-ranking ones as judged by HLA-binding, expression, and immunogenicity were considered or APVAC2 as 19 amino acid peptides (mutation flanked by 9 amino acids of the natural sequence on each side to cover all potential mutation-containing HLA-binding 9-10 amino acid peptides) and only two candidates per patient were de novo synthesized and administered (Hilf; page 247, right column “APVAC2 selection and manufacturing”). The APVAC2 vaccine was administered eight times within nine weeks starting day 15 of the 4th TMZ cycle (Hilf; Extended Data Fig.2a).
Dao teaches methods of identifying new epitopes derived from WT1 to expand the potential use of WT1 as a target for immunotherapy by using computer-based MHC-binding algorithms and in vitro validation of the T cell responses specific for the identified peptides (Dao; Abstract). Dao teaches affinity for MHC molecules is necessary for peptide presentation and T cell recognition in order to elicit a peptide-specific immune response (Dao; page 36, column 50, lines 64-65). The 15-mer overlapping peptides were designed by altering a single amino acid in the anchor residues of the native peptides for class I, which resulted in a higher predicted binding than its native sequences. The class II peptides were designed by adding flanking residues to the class I peptides, in order to simultaneously stimulate both CD4 and CD8 T cells (Dao; Example 1-2, columns 47, peptide design, peptide synthesis). To generate peptides with strong immunogenicity, amino acid substitutions were introduced to positions 2 and 9 (class I anchor residues) (Dao; [66]-[70]; Example 2, page 36, columns 49-50). Peptides were also derived to bind to HLA-B35, A0101, A0301, A1101 class I and HLA-DR class II molecules in order induce T cell responses in the context of other HLA haplotypes (Dao; Example 9, page 41, columns 59-60). The MHC binding affinity is measured as an IC50 where high affinity refers to a concentration of 0.5 - 500nM (Dao; page 20, column 17, lines 26-27). Additionally, MHC binding prediction scores of the native and analog peptides were screened using three online available databases (BIMAS, RANKPEP, and SYFPEITHI) (Dao; Example 1, column 47, Peptide Design).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the first round of vaccination (APVAC1) wherein the peptides occur naturally in a tumor protein and wherein the MHC alleles of the subject are determined prior to the first round of vaccination of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as ‘546 teaches a personalized cancer vaccination specifically targeting neoepitopes of a specific cancer patient is effective at treating a cancer and Hilf teaches supplementing the targeting of neoepitopes with the T cell responses of unmutated and/or overrepresented antigens to achieve a broad anti-tumor response directed towards a specific T cell response depending on the patient’s MHC alleles can more effectively treat a cancer patient. Therefore, it would have been obvious to combine the APVAC1 vaccination of Hilf with the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 in order to yield a predictable outcome of more effectively treating a cancer patient by targeting both unmutated, overrepresented antigens and neoepitopes to achieve a broad anti-tumor response.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with APVAC1 and APVAC2 vaccinations administered more than once of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as ‘546 teaches the method of treat cancer comprising group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity can treat a patient with cancer and Hilf teaches multiple administrations of both APVAC1 and APVAC2 vaccines led to sustained CD4+ and CD8+ immune responses in patients. Therefore, it would have been obvious to combine the method of treating cancer of ‘546 with the number of administrations of APVAC1 and APVAC2 of Hilf in order to yield a predictable result of sustained CD4+ and CD8+ response in patients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC alleles are a combination of MHC type I and MHC type II alleles of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches the class II peptides being designed by adding flanking residues to the class I peptides in order to simultaneously stimulate both CD4 and CD8 T cells. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of simultaneously stimulating both CD4 and CD8 T cells.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC I allele in not A0201 or A2402 of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches peptides derived to bind to HLA-B35, A0101, A0301, A1101 class I and HLA-DR class II molecules induce T cell responses in the context of other HLA haplotypes that are present in a broader range of patients. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of inducing T cell responses in the context of other HLA haplotypes and broadening a patient’s response to the peptide.
Claims 1 and 3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7 of U.S. Patent No. 12,569,546 B2 (PTO-892; page 1, Reference A; “’546”) in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Rabizadeh et al (IDS filed on 9/25/2025; Non-Patent Literature Documents, Reference 132; “Rabizadeh”) and Malcikova et al (PTO-892; page 5, Reference W; "Malcikova").
‘546 and Hilf have been discussed above. ‘546 and Hilf differ from the claimed invention in regards to instant claim 3 wherein the method further comprises a. determining the fraction of the DNA in the tumor biopsy which encodes each of the mutated amino acids and the fraction of RNA transcribed from that gene locus and expressing the mutated amino acids; and b. selecting a sub array of the alternative peptides from the proteins in the biopsy which are present in at least 10% of the DNA in the biopsy and expressed in at least 10% of the RNA transcribed from that gene locus in the biopsy.
However, Rabizadeh teaches improved methods of identifying clinically druggable mutations in patients with cancer by simultaneously analyzing both tumor and germline sequences to reduce the risk of mistakenly identifying germline mutation as somatically-derived genetic changes and potential cancer driver mutations (i.e. false positive (Rabizadeh; Abstract; page 19223, left column, paragraph 1; page 19224, right column, paragraphs 1-2). Rabizadeh teaches the differences in precision and sensitivity of tumor-only sequencing methods versus tumor and normal DNA sequencing methods where the former method results in the elimination of false positive results and analysis of the DNA or both the normal germline and the tumor genome is necessary for accurate identification of molecule targets for cancer therapy. Even higher precision is achieved through both tumor-normal DNA and RNA sequencing analysis as RNA sequencing provides data on the relative expression levels of DNA variants and specific tumor somatic variants as mRNA (Rabizadeh; page 19230, right column, paragraphs 1-3). Rabizadeh also teaches treatment decision based on tumor-only DNA sequencing or in the absence of RNA sequencing results in administration of ineffective therapeutic while also increasing the risk of negative drug-related side effects (Rabizadeh; page 19230, right column, paragraph 3).
Malcikova additionally teaches European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) recommendations for TP53 mutation analysis to ensure the data is analyzed and interpreted in a consistent, standardized, and accurate way (Malcikova; Abstract). Malcikova teaches that the limit of detection (LOD) for next generation sequencing (NGS), or the lowest variant allele frequency (VAF) that is reproducibly detectable by a particular method under specific well-defined conditions, should be set above the Sanger Sequencing detection limit (minimum LOD is 10% VAF) to reliably identify variants and avoid false positive calls (Malcikova; page 1074, right column, paragraph 2). The LOD is a function of both the initial DNA input and the sequencing coverage achieved (Malcikova; page 1074, right column, paragraph 2). Additionally, Malcikova teaches variants with <10% VAF are considered low burden or low-level variants (Malcikova; page 10176, left column, paragraph 5).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with o perform both RNA and DNA sequencing of tumor and normal tissue as a basis for treatment decision of Rabizadeh with selecting a variant with a VAF ≥ 10% of Malcikova with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Rabizadeh teaches that both tumor-normal DNA and RNA sequencing is necessary for accurate identification of molecule targets for cancer therapy and can lead to more effective treatments for patients and Malcikova teaches that a variant with ≥10% VAF is a higher confidence disease causing variant that has a higher probability of full clonality compared to a low VAF.
Therefore, it would have been obvious to combine the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with the motivation identify targetable gene variants through tumor-normal DNA and RNA sequencing of Rabizadeh with a high VAF (≥10%) Malcikova to yield predictable results of more effective targeting true positive oncogenic gene mutations and improve therapeutic outcomes for patients.
Claims 1 and 5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,569,546 B2 (PTO-892; page 1, Reference A; “’546”) in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Fisher et al (PTO-892; page 3, Reference W; “Fisher”).
‘546 and Hilf have been discussed above. ‘546 and Hilf differ from the claimed invention in regards to instant claim 5 wherein the first round of vaccination is administered prior to surgical intervention.
However, Fisher teaches that surgery is widely used as a therapy for common solid tumors but it is not curative and cancer vaccination prior to surgery is a viable option to treat patients (Fisher; Abstract; page 1-2, Background). Fisher teaches neoadjuvant anti-tumor vaccination combined with partial debulking surgery is capable of inducing effective CD8 T cell dependent anti-tumor immunity and that depletion of CD4 T cells during vaccination provided complete tumor eradication and established immunological memory that could protect against subsequent tumor growth (Fisher; page 7, left column, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with a cancer vaccine administration prior to surgery of Fisher with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modified the timing of the APVAC1 vaccine of Hilf to be prior to surgery of Fisher in order to yield a predictable result of enhancing tumor eradication and establishing immunological memory that could protect against subsequent tumor growth.
Claims 1 and 13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,569,546 B2 (PTO-892; page 1, Reference A; “’546”) in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Walter et al (PTO-892; page 4, Reference V; "Walter").
‘546 and Hilf have been discussed above. ‘546 and Hilf differ from the claimed invention in regards to instant claim 13 wherein the group of one or more selected peptides, or the nucleic acids encoding them, administered in the second round of vaccination comprises at least 5 unique peptides not present in the proteins sequenced in the tumor.
However, Walter teaches a renal cell carcinoma vaccine, IMA901, that consists of eleven peptides, nine HLA_A*02-restricted tumor associated peptides (TUMAPs), one HLA-DR-restricted TUMAP used to treat patients with renal cell carcinoma, and one viral marker not present in the proteins sequenced in the tumor (Walter; Abstract; Table 1; page 1255, right column, paragraph 1). Identification of TUMAPs were based on natural presentation from primary tumor tissues using XPRESIDENT, an antigen discovery platform (Walter; page 1255, left column, paragraph 2). Walter teaches that clinically relevant antigens were identified by comparing mRNA expression profiles of 42 RCC samples to those of 35 different healthy tissues and subsequent in vitro priming using artificial antigen presenting cells to detect antigen specific T cells in peripheral blood cells of healthy donors (Walter; page 1255, left column, paragraph 3). Among the 27 immune-evaluable subjects taking IMA901, 20 showed vaccine induced T cell response to at least one TUMAP and 8 responded to multiple TUMAPs (Walter; page 1255, right column, paragraph 2). Walter additionally teaches that these patients had a large breadth of T cell responses attributed to the number of different specific antigens in IMA901 which was significantly associated with clinical benefit implying that the targeting of multiple antigens in immunotherapy is required for clinical efficacy (Walter; page 1259, left column, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with the motivation to use multiple unique peptides in a cancer vaccine not present within proteins sequenced in the tumor of Walter with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have to use multiple unique peptides in a cancer vaccine since Walter teaches targeting multiple specific antigens induces a breadth of T cell responses and is associated with improved clinical efficacy. Therefore, it would have been obvious to have modified the cancer vaccine composition of ‘546 and Hilf with the motivation to use multiple unique peptides in a cancer vaccine of Walter in order to yield a predictable result of widening the breadth of T cell responses and increasing the clinical efficacy of the vaccine.
Claims 1 and 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,569,546 B2 (PTO-892; page 1, Reference A; “’546”) in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of US 2017/0161430 A1 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 050; "Bremel").
‘546 and Hilf have been discussed above. ‘546 and Hilf differ from the claimed invention in regards to instant claims 14 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 85% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid and instant claim 15 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid.
However, Bremel teaches methods and systems for identifying and classifying epitopes that can be used to design synthetic peptides and protein for vaccines (Bremel, Abstract; [0004]). Bremel teaches that there is a need to predict peptide sequences which comprise motifs that are likely to be recognized by T-cells and which are likely to give rise to down-regulation or suppression of the immune response or up-regulation or activation of the immune response (Bremel; [0004]). The peptides that bind to MHC class molecules in the groove exposed motif (GEM) can be altered in order to increase peptide-MHC binding affinity which can help lead to an increase in stimulation of an immune response (Bremel; [0011]-[0012]). Bremel teaches binding affinity can be measured with an IC50 or Kd where a strong binder has a Kd of 50nM and a weak binder has a Kd of 500nM (Bremel; [0154]-[0159]). Bremel teaches binding affinity to also be expressed by the standard deviation from the mean binding found in all the peptides making up a protein where peptides with a standard deviation ≥ 1 below the mean represents the 85th percentile of MHC-peptide binding affinity (i.e. stronger binder) which is useful for discrimination between potential immunological responses and non-responses (Bremel; [0159]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel with reasonable expectation of success. One of ordinary skill in the art would have been motivated to select peptides with a predicted MHC binding affinity in the 85th percentile or above compared to all other peptides making up a protein since Bremel teaches a strong MHC-peptide bond can elicit a stronger immune response. Therefore, it would have been obvious to combine the method of treating cancer in a subject comprising designing a group of 10 or more tumor-specific T -cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides, which have a desired predicted MHC binding affinity of ‘546 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel to yield a predictable result of selecting peptides with a strong MHC binding affinity to elicit a stronger immune response in a patient.
Claims 1-4, 6-11, 16-18, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-10, 13, 15, and 17 of copending Application No. 18/256,243 in view of Hilf et al ((IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") and U.S. Patent No. US 10,815,273 B2 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 30; “Dao”).
‘243 teaches in reference claim 1 a method for producing a personalized composition to treat a subject with cancer comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject, comprising the following steps: obtaining a biopsy of the subject's tumor and a normal tissue sample; obtaining DNA sequences from the tumor biopsy and normal tissue and RNA sequences from the tumor biopsy obtaining sequences for proteins in the biopsy; identifying proteins from the biopsy containing mutated amino acids and the peptide comprising each of the mutated amino acids; determining T cell exposed motifs which comprise mutated amino acids in each of the proteins; determining the predicted binding affinity to the subject's MHC alleles of peptides which comprises each of the T cell exposed motifs, or a subset thereof; generating an array of alternative peptides not present in the tumor, wherein each peptide in the array comprises the amino acids of one of the T cell exposed motifs, and in which the amino acids not within the T cell exposed motif are substituted to change the predicted MHC binding affinity; selecting a group of one or more selected peptides from the array of alternative peptides which have a desired predicted binding affinity for one or more of the subject's MHC alleles; selecting from the array of alternative peptides those peptides in which those amino acids not located within the T cell exposed motif provide desired characteristics for formulation and delivery; and synthesizing the group of one or more selected peptides, or nucleic acids encoding the selected peptides; wherein the method further comprises: a. determining the fraction of the DNA in the tumor biopsy comprising genes that encode each of the proteins containing mutated amino acids, and the fraction of RNA transcribed from that gene locus and expressing the protein containing mutated amino acids; b. selecting from the proteins containing mutated amino acids in the biopsy those which are present in at least 10% of the DNA in the biopsy and expressed in at least 10% of the RNA transcribed from that gene locus in the biopsy; and c. generating the array of alternative peptides from these selected proteins in reference claim 2; wherein the MHC alleles are MHC I alleles wherein the selected 8 to 10 amino acids in length in reference claims 5-6; wherein the MHC alleles are MHC II alleles wherein the selected peptides are from 11 to 22 amino acids in length in reference claims 7-8; wherein the T cell response is a cytotoxic T cell response in reference claim 9; wherein the T cell response is a T helper response in reference claim 10; wherein the desired binding affinity to an MHC allele is less than 200 nM in reference claim 13; wherein the desired binding affinity to an MHC allele is less than 50 nM in reference claim 15; and wherein the T cell exposed motif comprising the mutated amino acid is absent from the normal human proteome in reference claim 17.
‘243 does not teach not teach administering a first round of vaccination, wherein the vaccination comprises an array of one or more peptides, or nucleic acids encoding the peptides, selected from the group consisting of non-mutated peptides derived from tumor associated antigens appropriate to tumors of the type diagnosed and peptides commonly found to be mutated in tumors of the type diagnosed; and a second round of personalized vaccination in instant claim 1; the method further comprising determining the MHC alleles of the subject prior to the first round of vaccination of instant claim 4; wherein the MHC I allele in the first round of vaccination is not A0201 or A2402 of instant claim 9; wherein the first and/or second rounds of vaccination further comprise administering peptides, or the nucleic acids encoding them, which occur naturally in a tumor protein of instant claim 18; wherein each round of vaccination comprises 3 or more applications of the array of peptides, or the nucleic acids encoding them of instant claim 20.
Hilf and Dao have been discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the first round of vaccination (APVAC1) wherein the MHC alleles of the subject are determined prior to the first round of vaccination of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches supplementing the targeting of neoepitopes with the T cell responses of unmutated and/or overrepresented antigens to achieve a broad anti-tumor response directed towards a specific T cell response depending on the patient’s MHC alleles and can more effectively treat a cancer patient. Therefore, it would have been obvious to combine the APVAC1 vaccination of Hilf with method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 in order to yield a predictable result of more effectively treating a cancer patient by targeting both unmutated, overrepresented antigens and neoepitopes to achieve a broad anti-tumor response.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with APVAC1 and APVAC2 vaccinations administered more than once of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches multiple administrations of both APVAC1 and APVAC2 vaccines led to sustained CD4+ and CD8+ immune responses in patients. Therefore, it would have been obvious to combine the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the multiple administrations of APVAC1 and APVAC2 of Hilf in order to yield a predictable result of a sustained CD4+ and CD8+ response in patients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC alleles are a combination of MHC type I and MHC type II alleles of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches the class II peptides being designed by adding flanking residues to the class I peptides in order to simultaneously stimulate both CD4 and CD8 T cells. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of simultaneously stimulating both CD4 and CD8 T cells.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC I allele in not A0201 or A2402 of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches peptides derived to bind to HLA-B35, A0101, A0301, A1101 class I and HLA-DR class II molecules induce T cell responses in the context of other HLA haplotypes that are present in a broader range of patients. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of inducing T cell responses in the context of other HLA haplotypes and broaden a patient’s response to the peptide.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/256,243 in view Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Fisher et al (PTO-892; page 3, Reference W; “Fisher”)
‘243 and Hilf have been discussed above. ‘243 and Hilf differ from the claimed invention in regards to instant claim 5 wherein the first round of vaccination is administered prior to surgical intervention.
However, Fisher teaches that surgery is widely used as a therapy for common solid tumors but it is not curative and cancer vaccination prior to surgery is a viable option to treat patients (Fisher; Abstract; page 1-2, Background). Fisher teaches neoadjuvant anti-tumor vaccination combined with partial debulking surgery is capable of inducing effective CD8 T cell dependent anti-tumor immunity and that depletion of CD4 T cells during vaccination provided complete tumor eradication and established immunological memory that could protect against subsequent tumor growth (Fisher; page 7, left column, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with a cancer vaccine administration prior to surgery of Fisher with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modified the timing of the APVAC1 vaccine of Hilf to be prior to surgery of Fisher in order to yield a predictable result of enhancing tumor eradication and establishing immunological memory that could protect against subsequent tumor growth.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/256,243 in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Walter et al (PTO-892; page 4, Reference V; "Walter").
‘243 and Hilf have been discussed above. ‘243 and Hilf differ from the claimed invention in regards to instant claim 13 wherein the group of one or more selected peptides, or the nucleic acids encoding them, administered in the second round of vaccination comprises at least 5 unique peptides not present in the proteins sequenced in the tumor.
However, Walter teaches a renal cell carcinoma vaccine, IMA901, that consists of eleven peptides, nine HLA_A*02-restricted tumor associated peptides (TUMAPs), one HLA-DR-restricted TUMAP used to treat patients with renal cell carcinoma, and one viral marker not present in the proteins sequenced in the tumor (Walter; Abstract; Table 1; page 1255, right column, paragraph 1). Identification of TUMAPs were based on natural presentation from primary tumor tissues using XPRESIDENT, an antigen discovery platform (Walter; page 1255, left column, paragraph 2). Walter teaches that clinically relevant antigens were identified by comparing mRNA expression profiles of 42 RCC samples to those of 35 different healthy tissues and subsequent in vitro priming using artificial antigen presenting cells to detect antigen specific T cells in peripheral blood cells of healthy donors (Walter; page 1255, left column, paragraph 3). Among the 27 immune-evaluable subjects taking IMA901, 20 showed vaccine induced T cell response to at least one TUMAP and 8 responded to multiple TUMAPs (Walter; page 1255, right column, paragraph 2). Walter additionally teaches that these patients had a large breadth of T cell responses attributed to the number of different specific antigens in IMA901 which was significantly associated with clinical benefit implying that the targeting of multiple antigens in immunotherapy is required for clinical efficacy (Walter; page 1259, left column, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with the motivation to use multiple unique peptides in a cancer vaccine not present within proteins sequenced in the tumor of Walter with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have to use multiple unique peptides in a cancer vaccine since Walter teaches targeting multiple specific antigens induces a breadth of T cell responses and is associated with improved clinical efficacy. Therefore, it would have been obvious to have modified the cancer vaccine of ‘243 and Hilf with the motivation to use multiple unique peptides in a cancer vaccine of Walter in order to yield a predictable result of widening the breadth of T cell responses and increasing the clinical efficacy of the vaccine.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/256,243 in view of Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of US 2017/0161430 A1 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 050; "Bremel").
‘243 and Hilf have been discussed above. ‘243 and Hilf differ from the claimed invention in regards to instant claim 14 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 85% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid and instant claim 15 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid.
However, Bremel teaches methods and systems for identifying and classifying epitopes that can be used to design synthetic peptides and protein for vaccines (Bremel, Abstract; [0004]). Bremel teaches that there is a need to predict peptide sequences which comprise motifs that are likely to be recognized by T-cells and which are likely to give rise to down-regulation or suppression of the immune response or up-regulation or activation of the immune response (Bremel; [0004]). The peptides that bind to MHC class molecules in the groove exposed motif (GEM) can be altered in order to increase peptide-MHC binding affinity which can help lead to downstream stimulation of an immune response (Bremel; [0011]-[0012]). Bremel teaches binding affinity can be measured with an IC50 or Kd where a strong binder has a Kd of 50nM and a weak binder has a Kd of 500nM (Bremel; [0154]-[0159]). Bremel teaches binding affinity to also be expressed by the standard deviation from the mean binding found in all the peptides making up a protein where peptides with a standard deviation ≥ 1 below the mean represents the 85th percentile of MHC-peptide binding affinity (i.e. stronger binder) which is useful for discrimination between potential immunological responses and non-responses (Bremel; [0159]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel with reasonable expectation of success. One of ordinary skill in the art would have been motivated to select peptides with a predicted MHC binding affinity in the 85th percentile or above compared to all other peptides making up a protein since Bremel teaches a strong MHC-peptide bond can elicit a stronger immune response. Therefore, it would have been obvious to combine the method for producing a personalized composition to treat a subject with cancer comprising a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T-cell stimulating peptides which have a desired predicted binding affinity as a vaccine of ‘243 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel to yield a predictable result of selecting peptides with a strong MHC binding affinity to elicit a stronger immune response in a patient.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4, 6-11, 13, 16-18, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10, and 13 of copending Application No. 19/539,385 in view of Hilf et al (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") and U.S. Patent No. US 10,815,273 B2 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 30; “Dao”).
‘385 teaches a method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject, comprising the following steps: obtaining a biopsy of the subject’s tumor, obtaining sequences for proteins in said biopsy, identifying proteins from the biopsy containing mutated amino acids and the peptide comprising each of said mutated amino acids, determining T cell exposed motifs which comprise mutated amino acids in each of the proteins, determining the predicted binding affinity to the subject's MHC alleles of peptides which comprises each of said T cell exposed motifs, or a subset thereof, generating an array of alternative peptides not present in the tumor, wherein each peptide in the array comprises the amino acids of one of said T cell exposed motifs, and in which one or more of the amino acids not within the T cell exposed motif are substituted to change the predicted MHC binding affinity, selecting a group of one or more selected peptides from said array of alternative peptides which have a desired predicted binding affinity for one or more of the subject's MHC alleles; and synthesizing said group of one or more selected peptides, or nucleic acids encoding the selected peptides of reference claim 1; wherein said MHC alleles are MHC type I and said T cell response is a CD8+ response of reference claim 2; wherein said MHC alleles are MHC type II and said T cell response is a CD4+ response of reference claim 3; wherein said selected peptides are less than 20 amino acids long of reference claim 4; wherein said group of one or more selected peptides comprises at least 5 unique peptides not present in the proteins sequenced in the tumor of reference claim 5; wherein said desired predicted binding affinity is less than 100 nanomolar of reference claim 6; wherein said group of one or more selected peptides, or the nucleic acids encoding them, is administered to a subject as a vaccine of reference claim 10; A vaccine for administration to a subject with cancer comprising a group of peptides, or nucleic acids encoding the same peptides, selected according to the method of claim 1 of reference claim 13.
‘385 does not teach not teach administering a first round of vaccination, wherein the vaccination comprises an array of one or more peptides, or nucleic acids encoding the peptides, selected from the group consisting of non-mutated peptides derived from tumor associated antigens appropriate to tumors of the type diagnosed and peptides commonly found to be mutated in tumors of the type diagnosed; and a second round of personalized vaccination comprising obtaining sequences for DNA and RNA in the biopsy in instant claim 1; further comprising determining the MHC alleles of the subject prior to the first round of vaccination of instant claim 4; wherein the MHC alleles are a combination of MHC type I alleles and MHC type II alleles of instant claim 8; wherein the MHC I allele in the first round of vaccination is not A0201 or A2402 of instant claim 9; wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round is less than 200 nanomolar of instant claim 17; wherein the first and/or second rounds of vaccination further comprise administering peptides, or the nucleic acids encoding them, which occur naturally in a tumor protein of instant claim 18; wherein each round of vaccination comprises 3 or more applications of the array of peptides, or the nucleic acids encoding them of instant claim 20.
Hilf has been discussed above. Dao has been discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the APVAC1 vaccination of 243 with the first round of vaccination (APVAC1) wherein the MHC alleles of the subject are determined prior to the first round of vaccination of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches supplementing the targeting of neoepitopes with the T cell responses of unmutated and/or overrepresented antigens to achieve a broad anti-tumor response directed towards a specific T cell response depending on the patient’s MHC alleles and can more effectively treat a cancer patient. Therefore, it would have been obvious to combine the APVAC1 vaccination of Hilf with the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 in order to yield a predictable outcome of more effectively treating a cancer patient by targeting both unmutated, overrepresented antigens and neoepitopes to achieve a broad anti-tumor response.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the DNA and RNA sequencing methods of the patient’s tumor and normal tissue samples to determine patient specific mutations for the generation of APVAC2 of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as ‘385 teaches that a biopsy is obtained and protein sequences are identified in order to determine the patient specific mutations and Hilf teaches that DNA and RNA sequencing can also identify patient specific mutations and these can successfully guide personalized cancer vaccine generation and can elicit CD4+ and CD8+ immune responses in patients. Therefore, it would have been obvious to combine the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the DNA and RNA sequencing methods of the patient’s tumor and normal tissue samples to determine patient specific mutations for the generation of APVAC2 of Hilf in order to successfully identify patient specific gene mutations and generate a personalized cancer vaccine to successfully elicit a CD4+ and CD8+ immune response in a patient.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the APVAC1 and APVAC2 vaccinations administered more than once of Hilf with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification as Hilf teaches multiple administrations of both APVAC1 and APVAC2 vaccines led to sustained CD4+ and CD8+ immune responses in patients. Therefore, it would have been obvious to combine the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the number of administrations of APVAC1 and APVAC2 of Hilf in order to yield a predictable result of a sustained CD4+ and CD8+ response in patients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC alleles are a combination of MHC type I and MHC type II alleles of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches the class II peptides being designed by adding flanking residues to the class I peptides in order to simultaneously stimulate both CD4 and CD8 T cells. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of simultaneously stimulating both CD4 and CD8 T cells.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with APVAC1 and APVAC2 vaccinations of Hilf with the MHC I allele in not A0201 or A2402 of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches peptides derived to bind to HLA-B35, A0101, A0301, A1101 class I and HLA-DR class II molecules induce T cell responses in the context of other HLA haplotypes that are present in a broader range of patients. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of inducing T cell responses in the context of other HLA haplotypes and broaden the patient’s response to the peptide.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with APVAC1 and APVAC2 vaccinations of Hilf with the desired predicted MHC binding affinity to be between 0.5 – 500 nM of Dao with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Dao teaches a high affinity binder will have a 0.5 – 500 nM MHC binding affinity which elicits a peptide-specific immune response. Therefore, one of ordinary skill in the art would have been motivated to make this modification in order to yield a predictable result of selecting a peptide with a high MHC binding affinity and produce a peptide-specific immune response.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1of copending Application No. 19/539,385 in view Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Rabizadeh et al (IDS filed on 9/25/2025; Non-Patent Literature Documents, Reference 132; “Rabizadeh”) and Malcikova et al (PTO-892; page 5, Reference W; "Malcikova").
‘385 and Hilf have been discussed above. ‘385 and Hilf differ from the claimed invention in regards to instant claim 3 wherein the method further comprises a. determining the fraction of the DNA in the tumor biopsy which encodes each of the mutated amino acids and the fraction of RNA transcribed from that gene locus and expressing the mutated amino acids; and b. selecting a sub array of the alternative peptides from the proteins in the biopsy which are present in at least 10% of the DNA in the biopsy and expressed in at least 10% of the RNA transcribed from that gene locus in the biopsy.
However, Rabizadeh teaches improved methods of identifying clinically druggable mutations in patients with cancer by simultaneously analyzing both tumor and germline sequences to reduce the risk of mistakenly identifying germline mutation as somatically-derived genetic changes and potential cancer driver mutations (i.e. false positive (Rabizadeh; Abstract; page 19223, left column, paragraph 1; page 19224, right column, paragraphs 1-2). Rabizadeh teaches the differences in precision and sensitivity of tumor-only sequencing methods versus tumor and normal DNA sequencing methods where the former method results in the elimination of false positive results and analysis of the DNA or both the normal germline and the tumor genome is necessary for accurate identification of molecule targets for cancer therapy. Even higher precision is achieved through both tumor-normal DNA and RNA sequencing analysis as RNA sequencing provides data on the relative expression levels of DNA variants and specific tumor somatic variants as mRNA (Rabizadeh; page 19230, right column, paragraphs 1-3). Rabizadeh also teaches treatment decision based on tumor-only DNA sequencing or in the absence of RNA sequencing results in administration of ineffective therapeutic while also increasing the risk of negative drug-related side effects (Rabizadeh; page 19230, right column, paragraph 3).
Malcikova additionally teaches European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) recommendations for TP53 mutation analysis to ensure the data is analyzed and interpreted in a consistent, standardized, and accurate way (Malcikova; Abstract). Malcikova teaches that the limit of detection (LOD) for next generation sequencing (NGS), or the lowest variant allele frequency (VAF) that is reproducibly detectable by a particular method under specific well-defined conditions, should be set above the Sanger Sequencing detection limit (minimum LOD is 10% VAF) to reliably identify variants and avoid false positive calls (Malcikova; page 1074, right column, paragraph 2). The LOD is a function of both the initial DNA input and the sequencing coverage achieved (Malcikova; page 1074, right column, paragraph 2). Additionally, Malcikova teaches variants with <10% VAF are considered low burden or low-level variants (Malcikova; page 10176, left column, paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with with the motivation to perform both RNA and DNA sequencing of tumor and normal tissue as a basis for treatment decision of Rabizadeh with selecting a variant with a VAF ≥ 10% of Malcikova with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Rabizadeh teaches that both tumor-normal DNA and RNA sequencing is necessary for accurate identification of molecule targets for cancer therapy and can lead to more effective treatments for patients and Malcikova teaches that a variant with ≥10% VAF is a higher confidence disease causing variant that has a higher probability of full clonality compared to a low VAF. Therefore, it would have been obvious to combine modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with identify targetable gene variants through tumor-normal DNA and RNA sequencing of Rabizadeh with a high VAF (≥10%) Malcikova to yield predictable results of more effective targeting true positive oncogenic gene mutations and improve therapeutic outcomes for patients.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1of copending Application No. 19/539,385 in view Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of Fisher et al (PTO-892; page 3, Reference W; “Fisher”).
‘385 and Hilf have been discussed above. ‘385 and Hilf differ from the claimed invention in regards to instant claim 5 wherein the first round of vaccination is administered prior to surgical intervention.
However, Fisher teaches that surgery is widely used as a therapy for common solid tumors but it is not curative and cancer vaccination prior to surgery is a viable option to treat patients (Fisher; Abstract; page 1-2, Background). Fisher teaches neoadjuvant anti-tumor vaccination combined with partial debulking surgery is capable of inducing effective CD8 T cell dependent anti-tumor immunity and that depletion of CD4 T cells during vaccination provided complete tumor eradication and established immunological memory that could protect against subsequent tumor growth (Fisher; page 7, left column, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with a cancer vaccine administration prior to surgery of Fisher with reasonable expectation of success. One of ordinary skill in the art would have been motivated to have modified the timing of the APVAC1 vaccine of Hilf to be prior to surgery of Fisher in order to yield a predictable result of enhancing tumor eradication and establishing immunological memory that could protect against subsequent tumor growth.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 14-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1of copending Application No. 19/539,385 in view Hilf (IDS filed on 9/25/2025; NPL Documents, Reference 66; "Hilf") in further view of US 2017/0161430 A1 (IDS filed on 9/25/2025; U.S. Patent Documents, Reference 050; "Bremel").
‘385 and Hilf have been discussed above. ‘385 and Hilf differ from the claimed invention in regards to instant claim 14 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 85% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid and instant claim 15 wherein the desired predicted binding affinity to the one or more of the subject's MHC alleles of selected peptides in the second round of vaccination exceeds 95% of the binding affinity of all peptides in the tumor protein that comprises the mutated amino acid.
However, Bremel teaches methods and systems for identifying and classifying epitopes that can be used to design synthetic peptides and protein for vaccines (Bremel, Abstract; [0004]). Bremel teaches that there is a need to predict peptide sequences which comprise motifs that are likely to be recognized by T-cells and which are likely to give rise to down-regulation or suppression of the immune response or up-regulation or activation of the immune response (Bremel; [0004]). The peptides that bind to MHC class molecules in the groove exposed motif (GEM) can be altered in order to increase peptide-MHC binding affinity which can help lead to downstream stimulation of an immune response (Bremel; [0011]-[0012]). Bremel teaches binding affinity can be measured with an IC50 or Kd where a strong binder has a Kd of 50nM and a weak binder has a Kd of 500nM (Bremel; [0154]-[0159]). Bremel teaches binding affinity to also be expressed by the standard deviation from the mean binding found in all the peptides making up a protein where peptides with a standard deviation ≥ 1 below the mean represents the 85th percentile of MHC-peptide binding affinity (i.e. stronger binder) which is useful for discrimination between potential immunological responses and non-responses (Bremel; [0159]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel with reasonable expectation of success. One of ordinary skill in the art would have been motivated to select peptides with a predicted MHC binding affinity in the 85th percentile or above compared to all other peptides making up a protein since Bremel teaches a strong MHC-peptide bond can elicit a stronger immune response. Therefore, it would have been obvious to combine the method for treating cancer in a subject comprising designing a group of one or more tumor-specific T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject of ‘385 with the two rounds of vaccination (APVAC1 and APVAC2) of Hilf with selecting peptides with a predicted MHC binding affinity to be below 1 standard deviation below the mean (85th percentile) of all peptides making up a protein of Bremel to yield a predictable result of selecting peptides with a strong MHC binding affinity to elicit a stronger immune response in a patient.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641 /NORA M ROONEY/Primary Examiner, Art Unit 1641
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