DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1, 8, 16-20 and 22 are pending and are under examination.
35 USC § 103(a) rejections withdrawn
The rejections of claims 1, 8, 16-20 and 22 under 35 U.S.C. 103(a) as being unpatentable over Parmiani et al (J Immunol, 178:1975-1979, 2007, IDS, cited previously), Nielsen et al (PloS one 2:e796, 2007, IDS, cited previously), Sjoblom et al (Science, 314:268-274, 2006, cited previously), Wood et al (Science, 318:1108-1113, 2007, IDS, cited previously) and Ley et al (Nature, 456:66-72, 2008, IDS, cited previously) in view of Lennerz et al (PNAS, 102:16013-16018, 2005, IDS, cited previously) Johnston et al (WO 2007/101227, published 7 September 2007, IDS, cited previously), Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS, cited previously) and Rammensee et al (US 2012/0082691, published 5 April 2012, effective filing date 14 December 2009, cited previously), Chiang et al (US 20060008468 published 12 January 2006, IDS, cited previously) Kozhich et al (J Immunol 158:4145-4151, 1997) and Baratin et al (J Peptide Sci 8:327-334, 2002) are withdrawn to include references that demonstrate the use of whole genome sequencing prior to the filing date of the present application.
35 USC § 101 rejections maintained
The rejections of claims 1, 8, 16-20 and 22 as not being directed to patent eligible subject matter under 35 USC § 101 are maintained.
The claims recite “judicial exceptions” as a limiting element or step without reciting additional elements/steps that integrate the judicial exceptions into the claimed inventions such that the judicial exceptions are practically applied, and are sufficient to ensure that the claims amount to significantly more than the judicial exceptions themselves. In the instant case, the “judicial exceptions” include the abstract ideas,
“identifying cancer-specific nucleic acids”, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding
prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject”, selecting a plurality of epitopes predicted in (d) that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150nM according to the validated HLA-peptide-binding prediction algorithm” and “comparing the first plurality of nucleic acid sequences from cancer cells of a subject to the second plurality of nucleic acid sequences from non-cancer cells of the same subject.
A.
Applicant argues that the amended claims contain a combination of active steps that represent additional elements that are not well-understood, routine, and conventional. Applicant argues that the Examiner's own cited art shows that this combination of active steps are not well-understood, routine and conventional. Parmiani merely mentions the possibility of sequencing a genome for individual tumors, which it does in future tense using the verb "will," and in a hedged tone using "potentially. Applicant argues that this description would surely not be used if this strategy was routine, well-known, or conventional.
Applicant’s argument has been considered but is not persuasive. First it is noted that Parmiani was published three years prior to the effective filing date of the present application. Parmiani recites that the ultimate strategy for targeting such types of Ags will imply sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Parmiani discloses that this would require a massive effort. Parmiani does not state that the sequencing of the whole genome was not well-understood, routine and conventional only that whole genome sequence for tumors for each individual cancer patient would be a massive effort. As disclosed by Ley (cited previously), Choi et al (PNAS, 106:19096-19101, 2009, IDS) and Gnirke et al, Nature Biotechnology 27:182-189, 2009, IDS) whole genome or exome sequencing was well-understood, routine and conventional by the time of Applicant’s effective filing date. Applicant has not pointed to any of limitations that was not well-understood, routine and conventional. Applicant’s method requiring a massive effort does not make that method not well-understood, routine and conventional. Furthermore, as the art discloses, whole genomic or whole exome sequencing were even more routine since Parmiani’s review article was published.
B.
Applicant submits that the Examiner has not met his burden of showing the claimed methods are "well-known, routine and conventional." The standard for "well-known, routine and conventional" under step 2B is not inventive concept as under 35 U.S.C. 103. Applicant citing Berkheimer v. HP Inc., 881 F.3d 1360 (Fed. Cir. 2018), argues that as the Federal Circuit recently noted, "the mere fact that something is disclosed in a piece of prior art, for example, does not mean it was well understood, routine, and conventional." Applicant argues that the appropriate art to demonstrate a feature is well-understood, routine, and conventional is a publication that describes the state of the art. Applicant argues that the Examiner, in pointing to primary literature to support the rejection under 35 U.S.C. 101, has failed to met his burden of showing the combination of active steps are well-known, routine and conventional.
Applicant’s arguments have been considered but are not persuasive. It is noted, as discussed above, that the limitations “identifying cancer-specific nucleic acids”, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject”, selecting a plurality of epitopes predicted in (d)” are drawn to abstract ideas.
It is not clear which of the remaining steps in not well-understood, routine and conventional. The citation in Berkheimer v. HP Inc., 881 F.3d 1360 (Fed. Cir. 2018) is a follows.
While patent eligibility is ultimately a question of law, the district court erred in concluding there are no underlying factual questions to the § 101 inquiry. Id. At 642. Whether something is well-understood, routine, and conventional to a skilled artisan at the time of the patent is a factual determination. Whether a particular technologyis well-understood, routine, and conventional goes beyond what was simply known in the prior art. The mere fact that something is disclosed in a piece of prior art, for example, does not mean it was well-understood, routine, and conventional.
Thus, the determination of whether the other method steps are well-understood, routine and conventional is a factual question which was not addressed by the district court in granting summary judgement. As described above, the steps of obtaining the cancer cells and non-cancer cells and isolating the nucleic acids for whole genome or whole exome sequencing was known in the art. It is not clear what other step besides steps involving an abstract idea was not well-known. The algorithms used in the present invention, the NetMHC prediction algorithm (Nielsen et al. PLoS One. 2007, 2(8):e796) and IEDB predictive algorithm IEDB (Vita R et al. Nucleic Acids Res. 2010, 3 8 :D854-62) were known in the art. As discussed by Sette, Kozhich and Baradin, increasing the binding affinity to the MHC molecule resulted in stronger immunogenicity. Thus, using an algorithm with the parameter, IC50 of less than 150nM, to select a set of epitopes, was well-known at the time of the effective filing date of the present application.
Parmiani recited that the methods paralleling the methods of the present claims would require a massive effort. As discussed above, requiring a massive effort does not indicate that the combination of steps were not well understood, conventional and routine.
NEW REJECTIONS:
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 8, 16, 18-20 and 22 under 35 U.S.C. 103(a) as being unpatentable over Parmiani et al (J Immunol, 178:1975-1979, 2007, IDS, cited previously), Nielsen et al (PloS one 2:e796, 2007, IDS, cited previously), Sjoblom et al (Science, 314:268-274, 2006, cited previously), Wood et al (Science, 318:1108-1113, 2007, IDS, cited previously), Ley et al (Nature, 456:66-72, 2008, IDS, cited previously), Choi et al (PNAS, 106:19096-19101, 2009, IDS) and Gnirke et al, Nature Biotechnology 27:182-189, 2009, IDS) in view of Lennerz et al (PNAS, 102:16013-16018, 2005, IDS, cited previously) Johnston et al (WO 2007/101227, published 7 September 2007, IDS, cited previously), Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS, cited previously) and Kozhich et al (J Immunol 158:4145-4151, 1997) and Baratin et al (J Peptide Sci 8:327-334, 2002).
Parmiani teaches the identification of unique human tumor antigens and their use in tumor immunotherapy. Parmiani discloses a method for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor (page 1977, 1st column).
Nielsen disclose using the NetMHCpan algorithm to determine the predicted IC50 values for several peptides binding with multiple HLA alleles (page 2; Figure 1).
It would have prima facie obvious to substitute Neilsen’s method of using NetMHCpan algorithm to determine the predicted IC50 values for several peptides binding with multiple HLA alleles for Parmiani’s method for selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor because both Parmini and Neilson disclosed methods for determining selection of peptides whose motifs are predicted to be presented by specific HLA alleles for use in development of vaccines.
Sjoblom disclose a high-throughput identification of somatic mutations in cancer (page 268, 3rd column). Sjoblom identified somatic mutations in exomes from colorectal and breast cancer cell by comparing the nucleic acid sequences from the cancer cells in the subject to the nucleic acid sequences from non-cancer cells of the subject (page 268, 3rd column to page 269 3rd column).
Ley disclose the use of parallel sequencing to sequence the genomic DNA of tumor cells and normal cell to identify cancer-associated mutations (page 66, 1st column; page 67, 1st column to page 69 2nd column).
Choi disclose whole-exome capture on single arrays on a Roche/NimbleGen platform to the Illumina sequencing platform to illustrate the utility of this approach by identification of a rare mutation in a patient (pages 19096-19097). Choi demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants (Abstract; page 19097, 1st column; Table 1). Choi demonstrated a protocol of sufficient sensitivity and specificity to be highly useful for detecting rare sequence variants across the whole exome (page 19097, 2nd column).
Gnirke developed a capture method that uses RNA “baits” to “fish” targets out of a “pond” of DNA fragments (page 3, 1st paragraph to page 4, 3rd paragraph).Gnirke disclose that there is substantial economy in targeting the protein-coding fraction, the “exome”, which represents only ~1% of the human genome (page 2, 1st paragraph). Gnirke disclose that coding exons were captured by complementary oligonucleotides using hybrid selection and then sequenced (Id). Gnirke disclose that RNA libraries were generated and sequenced using next-generation sequencing instruments (Id).
Wood disclose that of the 18,191 genes analyzed, 1718 had at least one nonsilent mutation in either a breast or colorectal cancer. (page 1109, 3rd column). Wood recites that any gene that was mutated in the tumor but not in normal tissue from the same patient was analyzed (page 1108, 1st column).Wood disclose that the mutations include single-base substitutions, substitutions with missense changes, alteration of splice sites and insertions, deletions or duplications (Id). Wood disclose that many of these cancer mutations were unique and not present in the tumors of other cancer patients (Figure 3.).
Lennerz disclose that the tumor response of a patient with cancer was primarily driven by T cells that recognize mutated tumor antigens (page 16014, 2nd paragraph to page 16016, 2nd paragraph; Table 1).
One of ordinary skill in the art would have been motivated to combine Parmiani, Wood, Sjoblom, Ley and Lennerz because they all disclose the presence of cancer-specific peptides comprising neo-epitopes in cancer cells. Lennerz disclose that tumor responses to tumor was primarily driven by T cells that recognize mutated tumor antigens indicating the importance of these mutated tumor antigens in generating vaccines. Ley and Sjoblom disclose the feasibility of sequencing the whole genome of individual tumor cells and normal cells and selecting mutated peptides. Wood discloses the prevalence of subject-specific mutations in tumor cells compared to normal cells. It would have been prima facie obvious to combine the large scale sequencing of tumor cells in Ley, Sjoblom and Wood to identify subject and tumor specific mutations to Parmiani and Nielsen’s disclosure of the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor to have a method of identifying a plurality of nucleic acid sequences from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells and that do not include nucleic acid sequences from non-cancer cells of the subject, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, wherein each of the two or more different peptide sequences are expressed by the cancer cells and comprise a cancer specific mutation, predicting which epitopes of the two or more different peptide sequences form a complex with an expressed protein encoded by an HLA allele of the subject by an HLA peptide binding analysis; selecting at least two epitopes predicted in (b) based on the HLA peptide binding analysis and making a composition of the selected peptides to the subject.
In addition, one of ordinary skill in the art would have been motivated to apply Choi and Gnirke’s whole genome sequencing to Parmiani, Wood, Sjoblom, Ley and Lennerz’s method for selecting neoantigenic peptides because Wood, Sjoblom, Ley, Choi and Gnirke all disclose whole transcriptome, whole exome or whole genome sequencing from a subject. It is noted that Ott also assessed the expression of mutated alleles by RNA sequencing of the tumour to determine that the mutated epitopes were expressed. This would yield comparable results as to what Sjoblom and Wood transcriptome sequencing would find in that both methods would identify peptides which were actually expressed in the tumor cell.
Neither Parmiani, Nielsen, Ley, Choi, Gnirke, Sjoblom, Wood nor Lennerz disclose identifying subject-specific peptides with neo-epitopes, wherein each neo-epitope binds to a HLA protein of the subject with an IC50 less than 150 nM according to a validated HLA-peptide-binding prediction algorithm, wherein each of the at least two cancer neoantigen peptides has a length of from 8-12 amino acids.
Johnston disclose a method for administering novopeptides having at least 8, 9 or 10 amino acids to cancer patients (page 6, lines 12-18). Johnston disclose that includes one or more point mutations in a nucleic acid sequence that differs from a non-cancerous reference sequence from the organism (page 6, line 21 to page 7, line 2). Johnston discloses that vaccine candidate novopeptides can be assessed for likely ability to be displayed by given HLA types using algorithms known to those having ordinary skill in the art (page 18, lines 1-3). Johnston further disclose that tumor specific novopeptides have a great advantage over self-tumor antigens as cancer vaccines since they avoid the problems of autoimmunity and systemic tolerance (page 37 lines 13-22). Johnson further disclose that in mouse models tumor specific novopeptides have been shown to generate high-avidity T cell responses more readily than self-tumor antigens (Id). Johnson disclose that testing in a melanoma mouse model confirms that novopeptides are effective therapeutic and prophylactic vaccines (page 8, lines 2-4).
One of ordinary skill in the art would have been motivated to apply Johnston’s disclosure of novopeptides having lengths of 8-10 amino acids to Parmiani, Nielsen, Ley, Choi, Gnirke, Wood, Lennerz’s method of identifying a plurality of nucleic acid sequences from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, that are expressed by the cancer cells and comprise a cancer specific mutation because both Parmiani and Johnston both disclose the advantages of administering novo-peptides to cancer peptides. In addition, both Nielsen and Johnston disclose using algorithms to determine the predicted IC50 values for several peptides binding with multiple HLA alleles.
Sette teaches utilization of quantitative assays to measure the binding of antigenic peptides to MHC class I molecules and disclose that binding affinities of peptides to class I molecules of 50 nM or less were preferable (Abstract; page 814, 2nd paragraph to page 818, 2nd paragraph). Sette disclose that an affinity threshold of approximately 500 nM determines the capacity of a peptide epitope to elicit a CTL response (Id). Sette disclosed that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule (Id). Sette disclose that their data have important practical implications from the point of view of peptide-based CTL vaccine development, because they illustrate how quantitative binding assays can be used to rapidly select peptide epitopes that have a high likelihood of being immunogenic for CTL responses (page 820, 1st column).
One of ordinary skill in the art would have been motivated to apply Sette’s disclosure of the importance of having epitopes that bind to MHC class I molecules with affinities of 50 nM or less to Parmiani, Nielsen, Ley, Choi, Gnirke, Sjoblom, Wood and Lennerz’s method of identifying a plurality of nucleic acid sequences from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, that are expressed by the cancer cells and comprise a cancer specific mutation because Sette disclose that epitopes that bind to MHC class I molecules with high affinities have a higher likelihood of being immunogenic for CTL responses.
It would have been prima facie obvious to combine Parmiani, Nielsen, Ley, Sjoblom, Wood and Lennerz’s method of identifying a plurality of nucleic acid sequences from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, that are expressed by the cancer cells and comprise a cancer specific mutation and administering a composition of the peptides with Sette’s disclosure of the importance of having epitopes that bind to MHC class I molecules with affinities of 50 nM or less and Johnston’s disclosure of novopeptides having lengths of 8-50 amino acids to have a method of identifying a plurality of nucleic acid sequences from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells and that do not include nucleic acid sequences from non-cancer cells of the subject, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, wherein each of the two or more different peptide sequences are expressed by the cancer cells and comprise a cancer specific mutation, predicting which epitopes of the two or more different peptide sequences form a complex with an expressed protein encoded by an HLA allele of the subject by a validated HLA-peptide-binding algorithm; selecting the plurality of epitopes predicted in (iv) based on the HLA peptide binding analysis, wherein at least
two of the epitopes of the plurality selected bind to a protein encoded by an HLA
allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm.
A person of ordinary skill in the art given the teachings of Parmiani, Nielsen, Sjoblom, Wood, Ley, Choi, Gnirke, Lennerz, Johnston and Sette would have been able to identify, predict and select cancer-specific peptides after sequencing the genomic or exomic nucleic acid from a tumor cell.
Neither Parmiani, Nielsen, Sjoblom, Wood, Ley, Choi, Gnirke, Lennerz, Johnston nor Sette disclose that the different cancer specific epitope binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
Kozhich disclose enhancement of immunogenicity by increasing the affinity of a peptide binding to its MHC molecule by amino acid substitutions of the native peptide (page 4146, 2nd column to page 4148, 1st column).
Baradin discloses that increasing the binding affinity to the MHC molecule often resulted in stronger immunogenicity (page 329, 2nd column). Baratin disclose amino acid substitutions that increase the binding affinity to the MHC molecule resulting in stronger immunogenicity (page 329, 2nd column to page 331, 2nd column).
One of ordinary skill in the art would have been motivated to apply Kozhich and Baratin’s disclosures that changes in the amino acid structure of a peptide may result in an increase the binding affinity to the MHC molecule resulting in stronger immunogenicity to Parmiani, Nielsen, Sjoblom, Wood, Ley, Choi, Gnirke, Lennerz, Johnston and Sette’s method of predicting and selecting a plurality of cancer-specific epitopes because Sette disclose that that binding affinities of peptides to class I molecules of 50 nM or less were better at generating T cell responses to the peptides while Kozhich and Baratin disclose methods for increasing the binding affinity of peptides to class I peptides. In addition, Kozhich, Baratin and Sette all disclose the importance of binding affinity of a peptide to an MHC molecule and the immunogenicity of that peptide. Thus, one of skill in the art would have understood that amino acid substitutions may increase the of binding affinity of cancer-specific epitope to class I peptides cancer specific epitope sequences and thus increase the cancer-specific epitope’s immunogenicity. Furthermore, one of skill in the art would have understood the benefits of having a cancer-specific epitope binding to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide. Given the importance of the binding affinity of a peptide to an MHC molecule to the immunogenicity of that peptide, it would have been obvious to select a cancer-specific epitope that binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
It would have been prima facie obvious to combine Parmiani, Nielsen, Sjoblom, Wood, Ley, Choi, Gnirke, Lennerz, Johnston and Sette’s method of predicting and selecting a plurality of cancer-specific epitopes with Kozhich and Baratin’s disclosures that changes in the amino acid structure of a peptide may result in an increase the binding affinity to the MHC molecule resulting in stronger immunogenicity to have a method of selecting a plurality of epitopes comprising obtaining a first biological sample comprising cancer cells from a subject, obtaining a second biological sample comprising non-cancer cells obtained from the same subject, isolating a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences from the cancer cells and sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, thereby obtaining a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences; and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, identifying cancer specific nucleic acid sequences based on comparison of the first plurality of nucleic acid sequences from cancer cells to the second plurality of nucleic acid sequences from non-cancer cells, wherein the cancer specific nucleic acid sequences are present in the first plurality of nucleic acid sequences but are not present in the second plurality of nucleic acid sequences, wherein the identified cancer specific nucleic acid sequences encode two or more different peptide sequences of two or more different proteins that are expressed by the cancer cells of the subject based on measured RNA levels, and wherein each of the two or more different peptide sequences of the two or more different proteins comprise an endogenous cancer specific mutation that is not present in the proteins expressed by the non-cancer cells from the subject, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject, and wherein each of the two or more different peptide sequences of the two or more different proteins binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide and selecting a plurality of epitopes predicted to bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150nM according to the validated HLA-peptide-binding prediction algorithm.
Claims 1, 8, 16-20 and 22 under 35 U.S.C. 103(a) as being unpatentable over Parmiani et al (J Immunol, 178:1975-1979, 2007, IDS, cited previously), Nielsen et al (PloS one 2:e796, 2007, IDS, cited previously), Sjoblom et al (Science, 314:268-274, 2006, cited previously), Wood et al (Science, 318:1108-1113, 2007, IDS, cited previously), Ley et al (Nature, 456:66-72, 2008, IDS, cited previously), Choi et al (PNAS, 106:19096-19101, 2009, IDS, cited previously) and Gnirke et al, Nature Biotechnology 27:182-189, 2009, IDS, cited previously) in view of Lennerz et al (PNAS, 102:16013-16018, 2005, IDS, cited previously) Johnston et al (WO 2007/101227, published 7 September 2007, IDS, cited previously), Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS, cited previously) and Kozhich et al (J Immunol 158:4145-4151, 1997) and Baratin et al (J Peptide Sci 8:327-334, 2002) in further view of Rammensee et al (US 2012/0082691, published 5 April 2012, effective filing date 14 December 2009, cited previously) and Chiang et al (US 20060008468 published 12 January 2006, IDS, cited previously).
Neither Parmiani, Nielsen, Sjoblom, Wood, Ley, Choi, Gnirke, Lennerz, Johnston, Sette, Kozhich nor Baratin disclose that the plurality of epitopes comprises 20 epitopes.
Rammensee disclose methods of identifying epitopes for making compositions of up to 20 cancer immunotherapeutic peptides (paragraphs 8, 73, 85-91, 143).
Chiang teaches an immunogenic composition capable of eliciting tumor specific T cell responses of four or more peptide after assaying the patient's tumor tissue for two or more tumor associated antigens (paragraph 13).
One of skill in the art would have been motivated to apply Rammensee and Chiang’s immunogenic compositions comprising four or more peptides to Parmiani, Ley, Choi, Gnirke, Sjoblom, Wood, Johnston, Sette and Lennerz’s method of identifying and selecting a plurality of peptides from mutated nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, that are expressed by the cancer cells and comprise a cancer specific mutation because both Parmiani and Chiang disclose the advantages of administering subject-specific peptide to treat cancer, while Rammensee disclose the advantages of administering cancer specific peptides. It would have been prima facie obvious to combine Parmiani, Nielsen, Ley, Choi, Gnirke, Sjoblom, Wood, Johnston, Sette and Lennerz’s method of identifying and selecting a plurality of peptides identified from nucleic acid sequences from cancer cells of a subject that are unique to the cancer cells, wherein the identified plurality of nucleic acid sequences encode two or more different peptide sequences, that are expressed by the cancer cells and comprise a cancer specific mutation with Rammensee and Chiang’s immunogenic composition capable of eliciting tumor specific T cell responses to four or more peptides to have a method of selecting a plurality of epitopes comprising obtaining a first biological sample comprising cancer cells from a subject, obtaining a second biological sample comprising non-cancer cells obtained from the same subject, isolating a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences from the cancer cells and sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, thereby obtaining a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences; and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, identifying cancer specific nucleic acid sequences based on comparison of the first plurality of nucleic acid sequences from cancer cells to the second plurality of nucleic acid sequences from non-cancer cells, wherein the cancer specific nucleic acid sequences are present in the first plurality of nucleic acid sequences but are not present in the second plurality of nucleic acid sequences, wherein the identified cancer specific nucleic acid sequences encode two or more different peptide sequences of two or more different proteins that are expressed by the cancer cells of the subject based on measured RNA levels, and wherein each of the two or more different peptide sequences of the two or more different proteins comprise an endogenous cancer specific mutation that is not present in the proteins expressed by the non-cancer cells from the subject, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject, and wherein each of the two or more different peptide sequences of the two or more different proteins binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide and selecting a plurality of epitopes predicted to bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150nM according to the validated HLA-peptide-binding prediction algorithm, wherein the plurality of epitopes comprises 20 epitopes.
Applicant argues that according to the Rule 1.132 Declaration of Dr. Cornelis J.M. Melief submitted on October 11, 2022 during prosecution of the instant application, the approach taken by the '791 application was not the direction that the field was taking prior to 2010 and as noted by Dr. Melief, the '791 application takes an unbiased and
systematic approach to identify all unique passenger mutations for use as targets for a personalized vaccine by using an "unbiased whole genome approach to select mutations in any expressed part of the genome irrespective of which gene the mutations were in." According to Dr. Melief, the claimed method is personalized because: "(l) it is based on the mutations contained within the individual's cancer and therefore it is specific to an individual's cancer; and (2) it is based on the mutated peptides that are likely to be presented by the subject's individual HLA alleles." Applicant argues by
contrast, prior to the instant application, the field was focused on using mutated tumor associated antigens and antigens with driver mutations for vaccines which were shared across many patients, and so were 'off-the-shelf' products that could be extensively investigated using time consuming and laborious techniques such as competitive MHC binding assays prior to preparation. Applicant argues that as noted by Dr. Melief, the "cancer vaccines at the time generally exploited shared tumor antigens." Applicant argues that according to Dr. Melief, the claimed method provides a new and different approach to cancer vaccines. Applicant argues that unlike biased approaches outlined below in Section D. and E., the claimed methods identify and select epitopes with passenger mutations carrying somatic mutations arising in the cancer of the subject, and thus overcome the issues of central tolerance for over-expressed antigens. In particular, by comparative full genome sequencing of tumor and normal tissue from the same subject, the claimed methods identify and select epitopes with passenger mutations within any given tumor that can be utilized, significantly expanding the number of targetable neoantigens over and above those resulting from only driver mutations.
Applicant argues that Dr. Melief states that: "From my knowledge, the '791 application was the first attempt to systematically explore the approach to identify and target all mutation-derived neo-antigens in a single patient in a timely manner. Applicant argues that for at least the reasons below, Applicant submits the Office has failed to
establish a prima facie case of obviousness because one of ordinary skill in the art would have had no reason or motivation to modify the teachings of the references relied upon by the Office to arrive at the claimed invention and would not have found the outcome predictable.
Applicant further argues that previously submitted objective evidence of non-obviousness which must be considered by the Office. Applicant argues that one of ordinary skill in the art looking to develop methods for personalized cancer
approaches, i.e., identifying and selecting epitopes of two or more different peptide sequences of two or more different proteins comprising an endogenous cancer specific mutation, 1) would have had no reason or motivation to rely on and/or combine references related to identification of common cancer mutations/peptides to understand tumorigenesis or generate therapeutics for a population of patients, and 2) would not have found the outcome predictable, as these are completely distinct approaches in the field of cancer (see, at least Sections B. and C. below). As discussed below in Sections D., E., and F., even assuming arguendo one of ordinary skill in the art would have been motivated to combine the references, they would not have arrived at the presently
claimed invention. Additionally, Applicant argue that there was no reasonable expectation of generating the claimed methods without impermissible hindsight based upon the teachings of the instant application (see Section G. below). Further, as discussed in Section H., Applicant argues that the instant invention meets long felt, but unmet, need and addresses a problem that was previously not recognized in the art.
Applicant’s arguments have been considered but are not persuasive. Previously submitted objective evidence of non-obviousness had been previously considered and, as previously discussed, had been determined to be not sufficient to overcome the prima facie obviousness rejections. Parmiani discloses a method for identifying such neoantigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor (page 1977, 1st column). Parmiani did disclose that sequencing the genomic DNA from patients tumors would be a massive effort but that all the methods for this procedure were known. Thus, Parmiani discloses the blueprint for the present invention.
Whole genome, whole exome and whole transcriptome sequencing was known in the art (Sjoblom, Wood, Ley, Choi and Gnirke). Ley, Sjoblom, Wood disclose methods for generating cancer cell nucleic acids from a biological sample comprising cancer cells obtained from a solid tumor from the subject and generating non-cancer cell nucleic acids from a second biological sample comprising non-cancer cells obtained from the same subject. Algorithms for identifying peptides that have a high affinity for a particular MHC molecules were known in the art (Nielsen, Johnson and Sette). Furthermore, Wood disclose that most mutations were subject specific. Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm.
Given that most mutations are patient and tumor specific it would have been obvious to one of skill in the art to have used Parmiani’s recommendation that the ultimate strategy would be through whole genome sequencing of the patient’s tumor to predict and identify cancer and patient specific peptides which could be used to treat the patient. The blueprint for the present invention was known in the art, the methods for generating cancer cell nucleic acids from biological samples and sequencing the nucleic acids by whole genome, whole exome and whole transcriptome sequencing were known in the art and the methods for identifying and selecting subject and cancer cell-specific peptides using prediction algorithms were known in the art.
A.
Applicant argues that the Office fails to fully acknowledge the Fritsch and Melief Declarations and state why they are insufficient to overcome the rejection as required by the MPEP.17. Applicant argues that the Office simply restates the arguments presented by Applicant, asserts they are not persuasive, and continues to repeat the
rejections. Applicant argues that both Declarations directly address the cited references and submits evidence establishing recognition of a problem and success in solving the problem, a long, unmet need and recognition of the claimed invention. Applicant argues that the Office dismisses the evidence for not being commensurate in scope with the claims. It appears the Office is looking for a perfect or near perfect correspondence to establish a nexus, which is not required as set forth above. Applicant argues that the evidence presented in the Fritsch Declaration by expert opinion and cited references (i.e., Hachoen et al., Vonderheide et al., Joao Duarte, Ott et al., Adam Piore, etc.) each disclose methods or products including the claimed features of identifying and selecting epitopes utilizing the claimed methods as set forth throughout the Fritsch Declaration. Applicant argues that, the evidence presented in the Melief Declaration by expert opinion on the field of cancer vaccination prior to 2010 and the Applicant's recognition and success in solving a problem for personalized cancer vaccines utilizes the claimed
methods for identifying and selecting epitopes. Applicant argues that there is a nexus between the evidence submitted in the Fritsch and Melief Declarations and the claimed
invention, and that the Office consider and give weight to this evidence as required
Applicant’s arguments have been considered but are not persuasive. With regards to Applicant’s previous argument that as noted by Dr. Melief, prior to 2010, "the field was very much focused on shared tumor antigens as it just wasn't yet considered feasible to take the approach of the present application, that the importance of neo-antigens and their potential uses in cancer immunotherapy was not appreciated until 2015-2017, 5-7 years after the filing date of the '791 application. the '791 application was the first attempt to systematically explore the approach to identify and target all mutation-derived neo-antigens in a single patient in a timely manner, that "prior to the art recognizing this problem, the coinventors of this application recognized the problem and provided a solution-the instant invention, as previously noted, Parmiani discloses a method for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor (page 1977, 1st column). Thus, Parmiani discloses the blueprint for the present invention. Furthermore, Ley, Sjoblom, Wood disclose methods for generating cancer cell nucleic acids from a biological sample comprising cancer cells obtained from a solid tumor from the subject and generating non-cancer cell nucleic acids from a second biological sample comprising non-cancer cells obtained from the same subject; (ii) sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and (iii) identifying a plurality of cancer specific nucleic acid sequences from the first plurality of nucleic acid sequences that are specific to the cancer cells and that do not include nucleic acid sequences from the second plurality of nucleic acid sequences. Wood disclose that most mutations were subject specific. Parmiani, Johnston and Nielsen disclose (iv) predicting or measuring which epitopes of the two or more different peptide sequences form a complex with the one or more proteins encoded by the one or more HLA alleles of the same subject by a validated HLA-peptide binding prediction algorithm; and (v) selecting the plurality of epitopes predicted in (iv). Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm.
Thus, the blueprint for the present invention was known in the art, the methods for generating cancer cell nucleic acids from biological samples and sequencing the nucleic acids by whole genome and whole exome sequencing were known in the art and the methods for identifying and selecting subject and cancer cell-specific peptides using prediction algorithms were known in the art. Thus, the rationale for why the Declarations by Dr Melief and Dr Fritsch were considered to be insufficient to overcome the rejections as required by MPEP were properly disclosed.
The Declaration by Dr Fritsch primarily dissected each art reference and how each differed from the present invention. However, as previously discussed one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Applicant has not specifically pointed out which limitation is not present in the cited art nor why one of skill in the art would have not been motivated to combine the cited art.
Parmiani teaches the identification of unique human tumor antigens involving sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor.
Lennerz disclose contacting isolated T cells from the patient and cancer and subject specific epitopes ex vivo (page 16015, 2nd column to page 16016 2nd column). Lennerz disclose contacting CD8+ T cells with dendritic cells (page 16017, 1st column).
Ley, Sjoblom, Wood disclose methods for generating cancer cell nucleic acids from a biological sample comprising cancer cells obtained from a solid tumor from the subject and generating non-cancer cell nucleic acids from a second biological sample comprising non-cancer cells obtained from the same subject; (ii) sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and (iii) identifying a plurality of cancer specific nucleic acid sequences from the first
plurality of nucleic acid sequences that are specific to the cancer cells and that do not
include nucleic acid sequences from the second plurality of nucleic acid sequences.
Parmiani, Johnston and Nielsen disclose (iv) predicting or measuring which epitopes of the two or more different peptide sequences form a complex with the one or more proteins encoded by the one or more HLA alleles of the same subject by a validated HLA-peptide binding prediction algorithm; and (v) selecting the plurality of epitopes predicted in (iv),
Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm;
Parmiani, Nielsen, Johnston, Rammensee and Chiang disclosing making a plurality of peptide sequences.
Johnston discloses of novopeptides having lengths of 8-40 amino acids which overlap the 8-50 amino acid peptides in the present claims. Lee disclose generating CTLs to peptides presented on dendritic cells.
Thus, all the limitations of the present claims are present in the art and motivations to combine are described above. Applicant appears to argue why the art should not be combined or that some art teaches away from the present claims.
With regards to the unexpected results as discussed in the Fritsch Declaration, the unexpected results are based on results which primarily discloses the administration of pools of immunogenic neoantigenic peptides greater than 13 amino acids in length. Ott (2019) discloses that eight patients with melanoma were chosen based on their high mutation rate. Ott discloses that vaccines contained 13- 20 long peptides with lengths of 15-30 amino acids were grouped into 4 separate immunization pools. It is not clear from Ott (2019) how many of the peptides had an IC50 < 150nm. It is also not clear if multiple epitopes were identified and used in a single long peptide. The peptide pools were administered multiple times with poly-IC. In addition, Ott does not disclose that the two or more different peptide sequences of the two or more different proteins binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide. In addition, the claims are drawn to methods of selecting a plurality of epitopes not a method for administering the epitopes to a cancer patient. Thus, the unexpected results are not commensurate in scope to the present claims.
Similar to Ott (2019), Keskin discloses that vaccines contained up to 20 long peptides that were divided into pools of 3–5 peptides (designated as pools A–D). The vaccines were administered to 10 patients with glioblastoma following radiotherapy in a prime–boost schedule (Fig. 1a). Two patients were withdrawn because of an insufficient number of actionable neoepitopes or disease progression after radiotherapy.
Ott (2020) involved patients with melanoma, non-small cell lung cancer or bladder cancer with at least 50 non-synonymous point mutations and/or gene fusions. Ott (2020) states that the primary objective of the study was to evaluate the safety and tolerability of NEO-PV-01 in combination with nivolumab. Up to 20 neoantigenic peptides were divided into four pools and administered in multiple does along the nivolumab and poly-IC. It is not clear how many of the peptides of Keskin, Ott (2019) and Ott (2020) bind to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
The present claims are drawn to identifying, predicting and selecting at least two epitopes having a predicted IC50 binding affinity of less than 150nM to one or more proteins encoded by one or more HLA alleles of the same subject and binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide. Thus, the characteristics of the selected peptides from the claims are much broader than the pool of peptides used in the references discussed in Fritsch as examples of unexpected results. Furthermore, the present claims are drawn to selecting two or more peptides, not a method of administering the peptides to a cancer patient.
B.
Applicant argues that the claimed method is non-obvious in view of the cited references and state of the art prior to the filing of the instant application the field of cancer vaccination was generally focused on non-mutated proteins that were associated with cancer and were shared by many patients, such as over-expressed, tumor-associated antigens, or tumor-specific antigens. Applicant argues that prior to
2010, and still today, it was believed that therapies, such as vaccines, could be developed that could induce an immune response to these antigens in order to target cancers across multiple patients. The field of cancer biology was primarily concerned with what the functional changes were as the result of any given mutation and how this might influence the behavior of a cell. Applicant argues that the claimed method of the '791 application is an unbiased approach that is "personalized because it is based on mutations within a patient's tumor and predominantly unique to that patient's tumor, and is also based on identifying which of those mutations will be presented by the patient's
specific HLA class I molecules. Applicant argues that because of this personalized approach, Dr. Melief states: "I believe that the invention is the bringing together a variety of techniques in an innovative way and applying them to the field of cancer immunotherapy. As a result of this, for the first time, it is possible in a very efficient and rapid manner to identify neo-epitopes in an individual patient's cancer and match these to the patient's HLA class I types in a manner that would select for peptides that were likely to be immunogenic. In Dr. Melief's opinion, the "methodology of the '791 application enabled a whole range of new and individual cancer targets to be used in therapy as there was no longer a requirement for the target to be shared by other patients ... Most importantly, this could be done quickly, and within a timeframe that is of realistic benefit to a patient with rapidly advancing cancer. Applicant argues that Dr. Melief states that: "each of the individual steps in claim 1 are but one aspect of the entire methodology that the inventors have utilized in making it possible for the first
time in a systematic fashion to identify neo-epitopes with a high likelihood of immunogenicity, leading to a streamlined approach for providing a personalized vaccine in the required timely manner
Applicant’s arguments have been considered but are not persuasive. The idea of personalized cancer vaccines was well known in the art prior to the filing date of the ‘791 application. As disclosed in Johnston, peptides based on the frameshift mutations of a particular patient’s tumor have been demonstrated to be immunogenic. Prior to the filing date of the ‘791 application, Ley, Sjoblom and Wood disclose whole exome and whole transcriptome sequencing necessary to identify the specific mutations in a tumor from a cancer patient. Wood disclose that most of these cancer mutations were unique and not present in the tumors of other cancer patients. Thus, if one wanted to administer multiple neoantigenic epitopes it would have been necessary to identify patient specific mutations.
As previously discussed, it was known prior to Applicant’s filing date that neoantigens were more immunogenic than tumor antigens that were overexpressed. Parmiani, Johnston and Lennerz all disclosed the advantages of cancer cell neoantigens in inducing immune responses in cancer patients. Parmiani teaches the identification of unique human tumor antigens and their use in tumor immunotherapy. Parmiani discloses a method for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Ley, Choi, Gnirke, Sjoblom and Wood disclose whole genome, whole exome or whole transcriptome sequencing necessary to identify the specific mutations in a tumor from a cancer patient. It is noted that whole transcriptome sequencing would yield comparable results to whole exome sequencing followed by determining whether the peptides were expressed, as in the present claims. Sjoblom discloses that extraction of all protein-coding sequences from the consensus coding sequences genes (page 268, 3rd column). Sjoblom discloses that a total of 120,839 nonredundant exons and adjacent intronic sequences were obtained from 14,661 different transcripts in coding sequences genes. Thus, Sjoblom and Wood use transcriptome sequencing to identify cancer-specific mutations. It is noted that Ott also assessed the expression of mutated alleles by RNA sequencing of the tumour to determine that the mutated epitopes were expressed. This would yield comparable results as to what Sjoblom and Wood transcriptome sequencing would find in that both methods would identify peptides which were actually expressed in the tumor cell. Wood discloses that most of the identified mutations were unique to a particular patient. Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm. Thus, it would have been obvious to identify, predict and select at least two cancer-cell specific neoantigenic epitopes having a predicted IC50 binding affinity of less than 150nM to one or more proteins encoded by one or more HLA alleles of the same subject in order to make a personalized cancer vaccine. Given the patient-specific nature of most cancer cell mutations it would have been obvious to identify, predict and select patient and cancer specific peptides to be used in therapy.
C.
Applicant argues that one of ordinary skill in the art had no reason or motivation to combine references focused on common cancer mutations and understanding cancer pathogenesis to develop methods for selecting and identifying cancer- and patient-specific epitopes and would not have found the outcome predictable. Applicant argues that Parmiani does not teach or suggest a method of generating, sequencing, identifying, predicting, and selecting, wherein the cancer-specific peptides comprise the genus of cancer-specific peptides identified in the claimed method have in common the distinguishing identifying characteristics of 1) a cancer specific mutation, 2) the binding affinity identified by an HLA peptide-binding prediction algorithm, and 3) a predicted IC50 of less than 150nM, as required by independent claim 1. Applicant argues that the statements in Parmiani are mere proposals. Applicant argues that Parmiani is a review article, with no testing of its hypothetical approaches. After mentioning the possibility of
sequencing a genome for individual tumors-which it does in future tense using the verb "will," and in a hedged tone using "potentially", -Parmiani moves to explaining other approaches for the rest of the article, which approaches it presumably deems more attainable. Applicant argues that Parmiani states that the contemplated approach would "potentially include all the mutated Ags expressed by [the] tumor at the time of analysis". Applicant argues that the language used by Parmiani suggests that Parmiani had not settled on the detail of the approach, and thus these statements are speculative.
Applicant’s argument has been considered but is not persuasive. Parmiani teaches the identification of unique human tumor antigens involving sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Thus, Parmiani discloses the roadmap for
the active method steps of the present claims. In addition, as discussed above, the other method steps of generating, identifying, predicting and selecting cancer-specific peptides, as well as the listed parameters for the peptides, were known in the art. As discussed above, whole genome, whole exome and whole transcriptome sequencing of the nucleic acids from a patients tumor cell was known in the art. It was known in the art that most tumor mutations are patient-specific. Identifying peptides with high affinity to a patient’s MHC molecule using established algorithms was known in the art. It was also known in the art that peptides that bind to MHC class I molecules with an IC50 of less than 150nM according to the established algorithm were much more likely to be immunogenic than peptides with affinities of greater than 150 nM. It was known that mutated peptides that bind to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide were preferred. It is not known what problem was overcome as all the active method steps and parameters for the cancer-specific peptides were known in the art.
Applicant appears to be arguing that because Parmiani discloses that immunization of cancer patients with cancer-specific following genomic or exome sequencing would require a massive effort, it was non-obvious. However, as disclosed in Choi, Gnirke, Ley, Sjoblom and Wood whole genome, exome or transcriptome sequencing necessary to identify the specific mutations in a tumor from a cancer patient were known prior to the filing date of the ‘791 application. Furthermore, the claims only encompass sequencing and selecting at least two cancer-specific peptides from a subject. It is noted that the specification does not actually disclose the immunization of patients with the whole repertoire of autologous tumor cell Ags, only the identification of cancer-specific peptides using an algorithm and determining whether a small subset of the peptides were immunogenic in vitro.
In response to Applicant’s argument that one of ordinary skill in the art looking to develop personalized cancer approaches would not have had a reason or motivation to rely on disclosures focused on the academic approach of determining the role and function of a mutation in the pathogenesis of specific cancers, and would not have found the outcome predictable, as the problems to be solved are distinct, there is a vast amount of literature on peptide immunogenicity and how to determine the likelihood that a particular peptide would be immunogenic in patient with a specific MHC haplotype. Furthermore, the importance of cancer-specific peptides was known in the art. It is noted that the specification discloses that approximately 5% of the identified, predicted and selected peptides were immunogenic. Thus, the algorithm used by Applicant to identify, predict and select immunogenic cancer-specific peptides was clearly not very predictable. In addition, the claims are not drawn to methods for immunizing cancer patients with the identified, predicted and selected cancer-specific peptides.
In response to Applicant’s argument that According to Dr. Melief: "Parmiani does not however in my opinion disclose the method described and claimed in the '791 application but rather focuses on common or driver mutations, the specification discloses that driver genes represent promising tumor-specific antigens for inclusion in a vaccine (paragraph 196). Thus, even the inventors at the time the application was filed focused on driver mutations. Furthermore, Wood disclosures that most mutations were patient-specific.
In response to Applicant’s argument that Parmiani indicated "no vaccination or adoptive immunotherapy trials deliberately targeting molecularly characterized unique tumor Ags [antigens] have been conducted thus far, it is noted that the present claims are drawn to a method for identifying, predicting and selecting epitopes, not a method for administering the epitopes.
In response to Applicant’s argument that as noted in the Fritsch Declaration, "Parmiani fully admits that designing trials that preferentially boost the immune response targeting tumor-specific unique antigens 'represents a quite difficult task for solid human tumors, the present claims are drawn to methods for selecting cancer and patient specific peptides, not a method for administering cancer and patient specific peptides to a patient.
In response to Applicant’s arguments that it is necessary to understand what each individual reference teaches to determine whether one of ordinary skill in the art would have had a reason or motivation to combine the references in the manner asserted by the Office with a reasonable expectation of success, whole genome and whole exome sequencing, identifying mutations and selecting peptides that are likely to bind to a patient’s MHC molecule and induce an immune response were well known prior to the filing date of the application. One of ordinary skill in the art would have had a reasonable expectation of success to identify and select a plurality of patient and cancer-specific epitopes. Applicant has only pointed out which specific limitations were not present in a specific reference and has not sufficiently demonstrated a lack of motivation to combine the different references. Applicant has also not sufficiently demonstrated that specific references taught away from the present invention.
Applicant also argue that Parmiani discusses testing unique antigens to see whether they would be immunogenic by in vitro stimulation of patients PBMC or ex vivo assessment of the PBMC response of untreated or immunized patients. According to Dr. Melief, this is a "laborious and highly empirical approach and one that can be
contrasted with the approach taken in the '791 application, which avoids the need to directly determine immunogenicity in this way by requiring the antigens to have a threshold binding or prediction of binding to a class I HLA allele having an IC50 of <150 nM.
In response, the only way to know with certainty that a particular peptide was immunogenic is to test the peptide in an in vitro or in vivo assay, as Parmiani was proposing. It is noted that the specification discloses that approximately 5% of the identified, predicted and selected peptides were immunogenic. Thus, Parmiani’s standard for demonstrating that a peptide was immunogenic was much higher than Applicant’s standard. And as previously discussed it was well known in the art that a peptide was more likely to be immunogenic with binding to a class I HLA allele having an IC50 of <150 nM. But even with this high binding affinity to a class I HLA allele, the vast majority of those peptides would not be immunogenic in vivo, as Applicant has demonstrated in post-filing data using pools of 13- 20 peptides with lengths of 15-30 amino acids. And as previously discussed the present claims are drawn to methods for selecting cancer and patient specific peptides, not a method for administering cancer and patient specific peptides to a patient.
In response to Applicant’s argument that According to Dr. Melief: "Parmiani does not however in my opinion disclose the method described and claimed in the '791 application but rather focuses on common or driver mutations, the present specification discloses that the recurrent mutations (especially the most frequent ones: SF3B 1, TP53, MYD88 and ATM) are predicted to be driver mutations that are essential for tumor development or progression (paragraph 195). The Specification disclose that these driver genes represent promising tumor-specific antigens for inclusion in a vaccine (ID). Thus, at the time of filing Applicant thought that focus should be on driver mutations also. As stated previously, Parmiani discloses that the ultimate strategy for targeting such types of antigens will imply sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Parmiani did not specifically state that only driver mutations would be selected but the peptides would be selected on whether the mutated peptides have motifs that are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor.
In addition, Applicant argues that the Office's rationale for combining and modifying the cited references fail to consider each reference in their entirety. While the Office asserts one cannot show nonobviousness by attacking references individually where the references are based on combinations of references, it is necessary to understand what each individual reference teaches to determine whether one of
ordinary skill in the art would have had a reason or motivation to combine the references in the manner asserted by the Office with a reasonable expectation of success. As set forth in the MPEP,"[a] prior art reference must be considered in its entirety, i.e., as a whole. Applicant argues that the Office has failed to consider the cited references in their entirety and instead has oversimplified their teachings to reconstruct the presently claimed invention based on impermissible hindsight. Applicant argues that "[i]t is impermissible within the framework of section 103 to pick and choose from any one reference only so much of it as will support a given position, to the exclusion
of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art.
Applicant continues to argue that Nielsen, Sjoblom, Wood, Ley, Lennerz. Johnston, Sette, Rammensee, Chiang, Kozhich, and Baratin does not remedy the deficiencies in the teachings of Parmiani. Applicant argues that Nielsen describes the development of a bioinformatics method drawn from a database of known peptide-HLA-1 interactions, specifically 37,384 unique peptide interactions covering 24 HLA-A alleles and 18 HLA-B alleles. Applicant states that according to Dr. Melief, the invention of the '791 application does not lie in the specific techniques used but rather the combination of these techniques to enable a new way of treating cancer in a patient.
Applicant argues that Johnston discloses methods for identifying novopeptide candidates for vaccination against more than one tumor type in unrelated individuals by comparing sequences obtained from tumor and normal EST library databases. Applicant argues that these methods identify novopeptides contrary to the goal of the presently claimed invention, which is to identify and select cancer- and patient-specific epitope sequences.
Applicant argues that Sjobolm discloses methods for large scale analysis of breast and colorectal cancers to identify common mutations in a population of patients to "define the genetic landscape of two human cancer types." Applicant argues that while the Office asserts Sjoblom discloses comparison of nucleic acid sequences from cancer cells and non-cancer cells in the same subject to identify somatic mutations,
this is incorrect. Applicant argues that the sequences of cancer cells in Sjoblom is not whole genome sequencing as it is only around 14,000 genes. Applicant argues that the Discovery Screen section of Figure 1 of Sjoblom refers to amplification and sequencing of tumor DNA from 11 breast tumors, 11 colorectal tumors, and only 2 normal samples. Applicant argues that there is no disclosure that these 2 normal samples are patient matched to any of the 11 breast tumors or 11 colorectal tumors, or that these samples are subjected to whole genome or whole exome sequencing. Applicant argues that
it is clear from Sjoblom that only regions of patient-matched normal tissue are sequenced, and not the whole genome or whole exome as required by the claims.
Wood discloses analysis of 18,191 genes from breast and colorectal cancers to identify
mutations with a role in tumorigenesis. Applicant argues that similar to Sjoblom, this is not whole genome or exome sequencing, and the samples are not patient-matched as required by the claims.
Applicant also argues that Ley focuses on identifying somatic mutations that have a role in tumorigenesis of acute myeloid leukemia. Applicant argues that Ley states the importance of the identified mutations "will require functional validation studies in tissue culture cells and mouse models to assess their relevance. Applicant argues that each of Johnston, Sjoblom, Wood and Ley are focused on non-personalized
cancer approaches, i.e., identifying common cancer mutations to either understand the role of such mutations in tumorigenesis (Sjoblom, Wood and Ley) or to identify peptides that are not cancer- or patient-specific (Johnston). Applicant argues that as the disclosures of each of Johnston, Sjoblom, Wood and Ley are focused on non-personalized cancer approaches, one of ordinary skill in the art would have had no reason or motivation to combine these references in the manner asserted by the Office and would not have found the outcome predictable because
Applicant argues that they developed methods comprising identifying
and selecting cancer- and patient-specific epitope sequences comprising an endogenous cancer specific amino acid mutation, a distinct approach from the non-personalized cancer methods taught by the cited references. Applicant argues that one of ordinary skill in the art looking to develop personalized cancer approaches would not have had a reason or motivation to rely on disclosures focused on the academic approach of determining the role and function of a mutation in the pathogenesis of specific cancers and would not have found the outcome predictable as the problems to be solved are distinct.
Applicant argues that the Office's prima facie case of obviousness fails at least because when considering the teachings of the cited references in their entirety, one of ordinary skill in the art looking to develop efficient methods for identifying and selecting cancer- and patient-specific epitope sequences comprising an endogenous cancer specific amino acid mutation would have had no reason or motivation to rely on and/or combine Johnston, Sjoblom, Wood, and Ley since the disclosures of these cited references are focused on a distinct problem: understanding common mutations in cancers to understand the pathogenesis of cancer and/or develop therapeutics targeting a cancer mutation suitable for a population of patients. Applicant argues that the ordinarily skilled artisan would not have found the outcome predictable in combining the references in the manner asserted by the Office at least because Parmiani emphasizes the challenges associated with personalized cancer approaches and none of Johnston, Sjoblom, Wood or Ley, alone or in combination, teach or suggest their methods,
related to a different and distinct problem, would be suitable for addressing the challenges reported by Parmiani.
Applicant argues that Dr Melief stated that the cited references do not provide the ordinarily skilled artisan with any reasonable expectation of successfully arriving at the claimed subject matter without the benefit of impermissible hindsight reconstruction afforded by the '791 application. Dr. Melief further states that the invention of the '791 application does not lie in the specific techniques used but rather the novel and unanticipated combination of these techniques to enable a new way of identifying patient specific neo-epitopes.
Applicant’s arguments have been considered but are not persuasive. As an initial note the claims are directed to methods of selecting cancer and patient-specific neoantigenic peptides, not methods of administering the peptides. In addition, as previously noted, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed above, there is ample motivation to combine the references independent of the inherent feature. Parmiani recites that the superior approach to identify and select cancer and patient specific mutations is to use whole genome sequencing to identify all the cancer and patient specific mutations. As Parmiani states this would be a massive effort but as previously discussed all the required methods for this effort were known in the art. Choi, Gnirke Ley, Sjoblom and Wood disclose whole genome, exome and transcriptome sequencing necessary to identify the specific mutations in a tumor from a cancer patient. Thus, whole genomic or exome sequencing necessary for the method disclosed in Parmiani for the immunization of cancer patients with cancer-specific peptides following genomic or exome sequencing were well known at the time of Applicant’s invention. Once the mutated sequences were identified all that would be required is to use known algorithms to identify and select the peptides that would have the highest affinities to the patients MHC molecules. Nielsen disclose using the NetMHCpan algorithm to determine the predicted IC50 values for several peptides binding with multiple HLA alleles. Johnston, Ley, Sjoblom and Wood all disclose methods for identifying mutations that are specific to a particular tumor in a cancer patient. Johnston discloses that vaccine candidate novopeptides can be assessed for likely ability to be displayed by given HLA types using algorithms known to those having ordinary skill in the art. Johnston further disclose the advantages of cancer- specific peptides. Sjoblom and Wood disclose that most mutations are specific to a particular patient. This supports Parmiani’s contention that whole genome sequencing of a particular patient’s tumor would be the ultimate strategy.
Sjoblom discloses that extraction of all protein-coding sequences from the consensus coding sequences genes (page 268, 3rd column). Sjoblom discloses that a total of 120,839 nonredundant exons and adjacent intronic sequences were obtained from 14,661 different transcripts in coding sequences genes (Id). Sjoblom discloses that these sequences were used to design primers for PCR amplification and sequencing of exons and adjacent splice sites. These sequences were used to design primers for PCR amplification and sequencing of exons and adjacent splice sites. Thus, Sjoblom and Wood use transcriptome sequencing to identify peptides with cancer-specific mutations that are expressed in the tumor cell. Wood discloses that most of the identified mutations were unique to a particular patient. It is noted that the specification does not actually disclose the immunization of patients with the whole repertoire of autologous tumor cell Ags, only the identification of cancer-specific peptides using an algorithm and determining whether a small subset of the peptides were immunogenic in vitro.
In addition, Parmiani discloses that the ultimate strategy for targeting such types of antigens will imply sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor.
Sjoblom identified somatic mutations in exomes from colorectal and breast cancer cell by comparing the nucleic acid sequences from the cancer cells in the subject to the nucleic acid sequences from non-cancer cells (page 268, 3rd column to page 269 3rd column). Sjoblom discloses controlling for polymorphisms which would be the reason why it would have been obvious to compare the nucleic acid sequences obtained by whole genome sequencing or whole exome sequencing of cancer cells from the subject to the nucleic acid sequences obtained by whole genome sequencing or whole exome sequencing of non-cancer cells from the subject. In support of this Wood disclose that any gene that was mutated in the tumor but not in normal tissue from the same patient was analyzed in additional tumors. (page 1108, 1st column). Parmiani disclose that the discussed unique tumor-specific antigens are not expressed by any normal tissue (page 1975, 2nd column). Thus, it would have been obvious to compare nucleic acid sequences obtained by whole exome sequencing of cancer cells from the subject to nucleic acid sequences obtained by whole exome sequencing of non-cancer cells from the subject.
In response to Dr. Melif’s statement that the cited references do not provide the ordinarily skilled artisan with any reasonable expectation of successfully arriving at the claimed subject matter without the benefit of impermissible hindsight reconstruction afforded by the '791 application, the field concerning the selection of peptides that are more likely to induce immune response has been well studied and documented. The parameters for the selection of peptides listed in the present claims were well known prior to the filing of the ‘791 application.
In response to Dr. Melief’s statement that the invention of the '791 application does not lie in the specific techniques used but rather the combination of these techniques to enable a new way of treating cancer in a patient, it is noted that the claims are directed to the selection of cancer and patient-specific peptides, not a method for treating a patient with the cancer and patient-specific peptides.
In addition, Applicant argues that Baratin and Kozhich fail to rectify the deficiencies of the combined references in rendering the instant claims obvious because Baratin and Kozhich each disclose strategies for generating artificial exogenous peptides by introducing amino acid mutations into a wild-type peptide to improve binding to MHC class I molecules. Applicant argues that one of ordinary skill in the art looking to identify and select at least two epitopes comprising an endogenous cancer specific amino acid mutation in a subject would have had no reason or motivation to rely on the teachings of Baratin and Kozhich, and certainly would not have found the outcome predictable, at least because the generation of artificial exogenous peptides is a distinct approach from the presently claimed methods.
In response, as discussed above, Baratin and Kozhich disclose that changes in the amino acid structure of a peptide may result in an increase the binding affinity to the MHC molecule resulting in stronger immunogenicity. Given that Sette discloses that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule, it would have been obvious to select cancer-specific peptides having a greater affinity to the HLA allele than the corresponding wild type peptide. It is noted that the specification discloses only one immunogenic cancer-specific epitope that has a binding affinity to an MHC molecule greater than the binding affinity of the wild type to an MHC molecule. Sette, Kozhich and Baratin all disclose that peptides with a predicted IC50 of less than 150nM were more likely to be immunogenic that peptides with a with a predicted IC50 of more than 150nM.
In response to Applicant’s argument that Baratin and Kozhich fail to rectify the deficiencies of the combined references in rendering the instant claims obvious because Baratin and Kozhich each disclose strategies for generating artificial exogenous peptides by introducing amino acid mutations into a wild-type peptide to improve binding to MHC class I molecules and that one of ordinary skill in the art would have had no reason or motivation to rely on the teachings of Baratin and Kozhich, because the generation of artificial exogenous peptides is a distinct approach from the
presently claimed methods, Baratin and Kozhich disclosures that changes in the amino acid structure of a peptide may result in an increase the binding affinity to the MHC molecule resulting in stronger immunogenicity
Parmiani states that the ultimate strategy for targeting cancer and patient specific would involve sequencing the entire genome of each individuals tumor followed by selection of mutated peptides whose motifs are predicted to be present by the HLA alleles of the patient bearing that particular tumor. The disclosures of Sjoblom and Wood demonstrating that most mutations are patient specific support this strategy. The disclosures of Sjoblom, Wood, Ley, Choi and Gnirke demonstrate that whole genome, whole exome and whole transcriptome sequencing was known in the art, indicating that Parmiani’s strategy was attainable. Johnston, Ley, Sjoblom and Wood all disclose methods for identifying mutations that are specific to a particular tumor in a cancer patient.To select mutated peptides whose motifs are predicted to be present by the HLA alleles of the patient bearing that particular tumor would require algorithms which were also known in the art. Nielsen disclose using the NetMHCpan algorithm to determine the predicted IC50 values for several peptides binding with multiple HLA alleles. Johnston discloses that vaccine candidate novopeptides can be assessed for likely ability to be displayed by given HLA types using algorithms known to those having ordinary skill in the art. Sette, Kozhich and Baratin all disclose parameters which may be used in the algorithms to select the neoantigenic peptides. Thus, one of ordinary skill in the art would have ample motivation to combine the references to have a method for identifying and selecting neoantigenic peptides following whole genome or whole exome sequencing of nucleic acids from the tumor of a cancer patient.
D.
Applicant argues that Parmiani, Johnston, Rammensee, and Chiang would not motivate a person of skill in the art to arrive at the instant invention. Applicant argues that Parmiani specifically teaches away from selecting peptides that are specific to the subject, but focuses on common/drivers that can be administered to multiple patients. Applicant argues that Parmiani's view is further supported by his summary on page 1977 beginning with "Implications for Immunotherapy' in which he lists the 4 potential mechanisms, for 'why unique Ags specific immunity may be clinically more effective'. Applicant argues that the fourth is described as: "resistance to host immunoselection being unique Ags essential to the maintenance of the neoplastic conditions." This is the definition of oncogene. Applicant argues that at the end of the paragraph, Parmiani reinforced his view by indicating mutation analysis performed for those genes belonging to signal pathways relevant to the disease; these are identified because they appear commonly in cancers.
In response as discussed previously, the specification discloses that the recurrent mutations (especially the most frequent ones: SF3B 1, TP53, MYD88 and ATM) are predicted to be driver mutations that are essential for tumor development or progression (paragraph 195). The Specification disclose that these driver genes represent promising tumor-specific antigens for inclusion in a vaccine (ID). Furthermore, the one described peptide described by structure having the characteristics (i-iv) is the peptide KVYEGVWKK, was already known in the art.
Furthermore, Parmiani does not teach away from selecting peptides other than those that are essential to the maintenance of the neoplastic conditions. MPEP 2143.01 (I)states that
The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
Parmiani does not disclose that unique antigens other than unique antigens essential to the maintenance of the neoplastic conditions may not be used to generate immunity to unique antigens. Furthermore, the specification disclose that these driver genes represent promising tumor-specific antigens for inclusion in a vaccine. Thus, Applicant’s own Specification advocates for the use of driver mutations in a cancer vaccine. The claims do not rule out the use of driver mutations for identifying and selecting a plurality of peptide sequences.
Applicant argues that a person of skill in the art would not look to Johnston and arrive at the instant claims because Johnston permits the selection of peptides that are expressed on non-cancerous cells. Applicant further argues that Johnston teaches selecting peptides that are not specific to the subject, but rather can be administered to multiple patients. Applicant argues that Johnston thereby discloses peptides that are to be for use in a population and no teaching or suggestion of making subject and cancer specific peptides. Applicant argues that Johnson states that "vaccination with a single novopeptide has been shown capable of conferring immunoprotection against more than one tumor types and in unrelated individuals"). Applicant argues that Johnston discloses peptides that are to be use in a population, and contains no teaching or suggestion of generating, sequencing, identifying, predicting, and selecting subject and cancer specific peptides
Applicant also argues that Johnston, states "Cross-protection with a single FS-novopeptide", further showing that Johnston is disclosing peptides that are to be used in a population. Applicant argues that Johnston states: "mutation ... that occurs in all tumors", further showing that Johnston is disclosing only peptides that are to be for use in a population. Applicant argues that Johnston provides no teaching or suggestion of subject specific peptides, and in fact, teaches away from the instant invention.
In addition, Applicant argues that in a Declaration by the inventor, Stephan A. Johnston, during the prosecution of US Patent No. 8,796,414 that issued from the Johnston patent publication cited by the Office in the present application, Johnston characterized the disclosure cited by the Office in the present application as a "disclosure ... to obtain expressed sequence tags (EST) corresponding to cancerous cells or tissues from a public EST database ... compare the EST sequences with corresponding genomic or other non-cancerous reference sequences." Applicant argues that Johnston himself acknowledges that there is no teaching or suggestion of sequencing tumor and non-tumor samples of the subject comprising subject specific peptides, as required by claim 1 and Johnston teaches away from the instant invention.
Applicant’s arguments have been considered but are not persuasive. As discussed above, Johnston disclose a method for administering novopeptides having at least 8 and no more than 40 amino acids to cancer patients. Johnston discloses that vaccine candidate novopeptides can be assessed for likely ability to be displayed by given HLA types using algorithms known to those having ordinary skill in the art. Novopeptides would include subject and cancer-specific peptides. Although Johnston did not specifically indicate that their novopeptides included mutations that have not been previously identified, Johnston does not does not criticize, discredit or discourage the identification, selection and making of subject and cancer-specific peptides. Furthermore, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).” “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).”
It is noted that the specification describes the amino acid structure of only one functional peptide, KVYEGVWKK (SEQ ID NO: 10), that has a cancer specific point mutation, a predicted IC50 of 150 nm or less. As previously stated, this peptide was already known in the art.
As previously discussed, Parmiani states that the ultimate strategy for targeting cancer and patient specific would involve sequencing the entire genome of each individuals tumor followed by selection of mutated peptides whose motifs are predicted to be present by the HLA alleles of the patient bearing that particular tumor.
In response to Applicant’s argument that Rammensee teaches away from the claimed invention, Rammensee does not criticize, discredit or discourage the identification and selection of subject and cancer-specific peptides. Silence does not constitute teaching away. Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005).
In response to Applicant’s argument that Chiang also teaches away from the pending claims by disclosing tumor associated antigens that can be found in non-cancerous cells, Chiang does not does not criticize, discredit or discourage the identification and selection of subject and cancer-specific peptides. Furthermore, silence does not constitute teaching away. Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005).
E.
Applicant also argues that there is no motivation to combine the references and
arrive at the amended claims with any reasonable expectation of success because the
combination of Parmiani, Johnston, Rammensee, and Chiang would render the
method of the amended claims inoperable. Applicant argues that the disclosure of Parmiani, focusing on common/drivers that can be administered to multiple patients, as well as the disclosures of Johnston, Rammensee, and Chiang, by teaching peptides comprising tumor associated antigens that may be found across a population of patients, would render the instant methods inoperable. Applicant argues that as the Fritsch Declaration states, "It is my opinion that after reading any of the cited references, either individually or in combination, one of skill in the art would not have reasonably expected to produce a method of generating, sequencing, identifying, predicting, and selecting that permits one to identify peptides that are specific to a patient with cancer comprising the features of (1)-(3). Applicant argues that even if Parmiani, Johnston, Rammensee, and Chiang were combined, they would render the instant methods inoperable by providing methods that identify and select antigens that can be applied universally to populations of patients.
Applicant further argues that a skilled artisan would have no reasonable expectation of success of arriving at the claimed methods because the disclosures of Johnston, Rammensee, and Chiang lack a teaching or suggestion of step ( c) of identifying a plurality of cancer specific nucleic acid sequences from the patient that are specific to the patient's cancer cells. Applicant argues that Identifying tumor associated antigens, rather than epitopes with cancer specific mutations would not allow an individual to carry out the remainder of the steps within claim 1, nor would it allow a person or ordinary skill in the art to successfully generate, sequence, identify, predict, and select the peptides comprising a cancer specific point mutation, and epitopes with the recited HLA binding affinity.
In addition, Applicant argues that a skilled artisan would have no reasonable expectation of success of arriving at the claimed methods because the disclosures of Johnston, Rammensee, and Chiang lack a teaching or suggestion of step (e). Applicant argues that there was no reasonable expectation of success that Johnston's cursory discussion of bioinformatic screening of candidate novopeptides for likely HLA compatibility would be applicable to the claimed method of selecting neoantigenic peptides comprising a cancer specific mutation and a specific cut-off value of HLA binding affinity. Applicant argues that it was not obvious or reasonably expected that a skilled artisan could successfully utilize validated HLA-peptide-binding prediction algorithms as a way to identify and select mutations that are subject- and tumor-specific, and thus unique to that patient.
Applicant’s arguments have been considered but are not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
As discussed previously Parmiani recited that that the ultimate strategy for targeting cancer and patient specific would involve sequencing the entire genome of each individuals tumor followed by selection of mutated peptides whose motifs are predicted to be present by the HLA alleles of the patient bearing that particular tumor. Whole exome, whole exome and whole transcriptome sequencing was known in the art. Once the sequences from a tumor were obtained the sequences from the tumor would be compared with the sequences from a normal control as discussed in Ley and Wood. The sequences comprising mutated nucleotides would be entered into a computer comprising an algorithm that would select peptides comprising mutations based on their ability to bind one of the MHC molecules from the patient’s with a high affinity. It is not clear why one of skill in the art would not have had a reasonable of success in selecting peptides with the claimed characteristics. All the steps were well-known and algorithms were available to be used to select the cancer and patient specific peptides at the time the application was filed.
Both Parmiani and Johnston disclose the identification and selection of subject and cancer-specific peptides. Wood disclose that there is a mixture of common mutations and unique mutations in tumors from cancer patients, but the majority of the mutations were patient-specific. The present claims do not differentiate between mutations that are common and those that are unique. In fact, the only structurally described functional peptide, KVYEGVWKK (SEQ ID NO: 10), that has a cancer specific point mutation and a predicted IC50 of 150 nm or less in the specification was already known in the art. Once a particle mutation in a tumor sample was identified, a person of skill in the art would be able to use algorithms as disclosed in Johnston, Parmiani and Nielsen to select peptides based on the HLA type of the cancer patient. As disclosed in Wood, there is a range of frequencies for specific mutations with patient-specific mutations the most observed. Neither Johnston nor Parmiani disclose that only peptides to frequent mutations will be selected.
As discussed previously, Parmiani did not require that the neoantigenic peptides were driver mutations. Furthermore, as discussed previously, the specification disclose that driver genes represent promising tumor-specific antigens for inclusion in a vaccine. Thus, Applicant’s own specification promotes the use of driver mutations in a cancer vaccine.
In response to Applicant’s argument that a person of ordinary skill in the art, looking to the disclosures of Johnston, Rammensee, and Chiang, would not be successful in the first steps of the claimed method, specifically, identifying a plurality of cancer specific nucleic acid sequences from the patient that are specific to the patient's cancer cells, it is not clear that based on Parmiani and Johnston and Wood, a person of ordinary skill in the art would not incorporate any peptide based on mutations found in the exome into a peptide composition. Neither Johnston nor Parmiani require that the neoantigenic peptides were already known in the art. Using algorithms such as the one described in Nielsen, nucleic acid sequences comprising mutations such as those described in Wood, one of skill in the art would have been able to identify and select subject and cancer-specific peptides that would be based on rare mutations as well as more frequent mutations. It appears from Wood that there is a range in the frequency of mutations in tumors.
Rammensee, and Chiang have been cited to describe parameters of the peptides to be made and administered. These parameters would be expected to be the same for neoantigenic peptides as well as non-neoantigenic peptides.
F.
Applicant argues that one of ordinary skill in the art combining the references in the manner asserted by the Office would not have arrived at the presently claimed invention. Applicant argues that as stated above, each of Johnston, Sjoblom, Wood and Ley are focused on identifying common cancer mutations, developing therapeutics to shared antigens universal to unrelated individuals, and/or understanding the pathogenesis of specific cancer types. Applicant argues that these references are contrary to developing personalized cancer approaches that identify and select cancer and patient-specific epitope sequences comprising an endogenous cancer specific amino acid mutation. Applicant argues that one of ordinary skill in the art combining these references, even in combination with Parmiani, would have arrived at methods for identifying mutations common amongst a shared population, not the presently claimed methods for selecting and identify cancer- and patient-specific epitope sequence.
Applicant argues that with regards to Lennerz, the Office has oversimplified these teachings. Applicant argues that while Lennerz is relied upon by the Office for disclosing the tumor response of a patient with cancer was primarily driven by T cells that recognize mutated tumor antigens, Lennerz as a whole teaches use of multispecific mixed lymphocyte-tumor cell cultures for identifying individual antigens. Applicant argues that Lennerz used a complicated and time-consuming screening program involving expressing cDNAs encoding HLA peptides along with cDNAs or fragments of cDNAs to identify that mutations in the genes were responsible for the recognition by T cells in an in vitro assay. Applicant notes the methods of the present claims identify epitope sequences that are cancer- and patient-specific by using whole genome or whole exome sequencing and select epitope sequences based on predicted HLA binding utilizing an HLA peptide binding analysis program implemented on a computer
system. Applicant argues that one of ordinary skill in the art looking to develop efficient methods for identifying and selecting cancer- and patient-specific epitope sequences for preparing autologous T cells would not have had a reason or motivation to rely on the teachings of Lennerz and would not have found the outcome predictable as such methods would take substantial time to implement.
In addition, Applicant argues that Nielsen fails to rectify the deficiencies of the cited references. Applicant argues that while Nielsen describes the development of a bioinformatics method for predicting peptide-HLA-1 interactions, one of ordinary skill in the art combining the methods of Nielsen in the manner asserted by the Office would not have arrived at the claimed invention. Applicant argues that as each of Johnston, Sjoblom, Wood, Ley, Rammensee and Chiang are focused on common cancer mutations/shared antigens, and Kozhich and Baratin disclose methods for generating artificial exogenous peptides modified for the purpose of enhancing or modulating immunogenicity, the skilled artisan would not have arrived at the claimed method comprising identifying and selecting cancer- and patient-specific epitopes of proteins comprising an endogenous cancer specific mutation
Applicant’s argument has been considered but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As previously discussed, all the limitations of the present claims and motivations to combine the different references have been discussed. The primary reference, Parmiani states that the ultimate strategy for targeting cancer and patient specific would involve sequencing the entire genome of each individuals tumor followed by selection of mutated peptides whose motifs are predicted to be present by the HLA alleles of the patient bearing that particular tumor. Wood discloses that most mutations were unique to that patient. Lennerz disclose that the tumor response of a patient with cancer was primarily driven by T cells that recognize mutated tumor antigens. Thus, Parmiani, Johnston and Lennerz all disclose that cancer-specific peptides may be used for the treatment of cancer patients. Parmiani disclosed general methods using whole genome sequence for identifying and selecting cancer- and patient-specific epitope sequences. Ley, Sjoblom and Wood disclose methods using whole exome sequencing for identifying mutations that are specific to a particular tumor in a cancer patient. Johnston discloses that vaccine candidate novopeptides can be assessed for likely ability to be displayed by given HLA types using algorithms. Given that Wood discloses that most mutations were unique to that patient along with Parmiani’s teaching methods for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor, it would have been obvious to develop personalized cancer approaches that identify and select cancer and patient-specific epitope sequences comprising an endogenous cancer specific amino acid mutations. It is not clear how Wood is focused on common cancer mutations/shared antigens given the Wood discloses that that most mutations were unique to that patient.
It is noted that a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). One would not have to look to Lennertz for methods for identifying cancer-specific peptides. Lennertz screening program involving expressing cDNAs encoding HLA peptides along with cDNAs or fragments of cDNAs to identify mutations does not detract from using the combined teachings of Parmiani, Johnston, Ley, Sjoblom and Wood for a method of identifying, predicting and selecting cancer-specific peptides using whole genome sequencing or whole exome sequencing. Given that Wood discloses that most mutations were unique to that patient along with Parmiani’s teaching methods for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor, it would have been obvious to develop personalized cancer approaches that identify and select cancer and patient-specific epitope sequences comprising an endogenous cancer specific amino acid mutations.
G.
Applicant argues that there was no reasonable expectation of generating the claimed methods without impermissible hindsight based upon the teachings of the '791 application. Applicant argues that as noted in by Dr. Melief, prior to 2010, "the field was very much focused on shared tumor antigens as it just wasn't yet considered feasible to take the approach of the present application. Applicant argues that as noted by Dr. Melief, the importance of neo-antigens and their potential uses in cancer immunotherapy was not appreciated until 2015-2017, 5-7 years after the filing date of the '791 application. Applicant argues that Dr. Melief states that from his knowledge, the '791 application was the first attempt to systematically explore the approach to identify and target all mutation-derived neo-antigens in a single patient in a timely manner.
In response, it is noted that Parmiani discloses a method for identifying such antigens that involves sequencing the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor (page 1977, 1st column). Thus, Parmiani discloses a blueprint for the present invention.
Furthermore, Sjoblom and Wood disclose methods for generating cancer cell nucleic acids from a biological sample comprising cancer cells obtained from a solid tumor from the subject and generating non-cancer cell nucleic acids from a second biological sample comprising non-cancer cells obtained from the same subject; sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and (iii) identifying a plurality of cancer specific nucleic acid sequences from the first plurality of nucleic acid sequences that are specific to the cancer cells and that do not include nucleic acid sequences from the second plurality of nucleic acid sequences. Wood disclose that most mutations were subject specific. Parmiani, Johnston and Nielsen disclose predicting which epitopes of the two or more different peptide sequences form a complex with the one or more proteins encoded by the one or more HLA alleles of the same subject by a validated HLA-peptide binding prediction algorithm; and selecting the plurality of epitopes. Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm.
Thus, the blueprint for the present invention was known in the art, the methods for generating cancer cell nucleic acids from biological samples and sequencing the nucleic acids by whole genome sequencing were known in the art and the methods for identifying and selecting subject and cancer cell-specific peptides using prediction algorithms were known in the art.
Furthermore, as discussed previously, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed above, all the limitations of the claims are present in the cited references and there is ample motivation to combine the references independent of the inherent feature.
H.
Applicant argues that the present invention involves recognition of a problem that had not previously been recognized and successfully addresses that problem, and has received recognition in the art. Applicant argues that as noted in Section B above, the field of cancer immunology struggled to bring to the clinic effective cancer vaccines. Applicant argues that the attempts to treat cancer by vaccination prior to and including 2010 had generally failed, with the exception of the use of a non-mutated tumor-associated antigen, prostate-specific acid phosphatase linked to GM-CSP, that remains the single FDA-approved cancer vaccine today. Applicant argues that according to Dr. Melief, the problem faced by the field was much larger than simply finding new cancer targets that may be useful in inducing a tumor-specific immune response. Therefore, a new approach to cancer vaccination was needed. Applicant argues that according to Dr. Melief, the '791 application successfully solved the problem by the development of a methodology, which doesn't comprise a single technique, but instead a collection of aspects that together allow for a personalized approach to treating a patient's cancer. Applicant argues that this personalized approach is unique to the patient's specific cancer and all of their unique HLA class I molecules. Applicant argues that for the first time this allowed vaccination to be focused on a much larger number of targets (patient specific neo-epitopes) that are potentially more immunogenic compared to tumor-associated antigens as they are new to the immune system and are not 'self' antigens and therefore less likely to be tolerated by the immune system.
Applicant further argues that according to Dr. Fritsch, "the instant invention addresses a problem of the two heterogeneities in tumor mutations." The instant invention is a paradigm shift, especially as it involves the identification and selection of subject- and tumor-specific peptides (neoantigens). Cancer shows an inter-tumoral heterogeneity, wherein each patient's tumor undergoes an independent evolutionary process from tumors of other patients; and, intra-tumoral heterogeneity, wherein each cell within a tumor of a patient has undergone an independent evolutionary process. Applicant argues that inter-tumoral heterogeneity (between patients) was recognized, while intratumoral heterogeneity was not. Applicant argues that prior to the priority date of May 14, 2010 of the present application, there was a long felt and unmet need to address the problem of tumor heterogeneity in order to develop cancer therapies which are subject- and tumor-specific to a subject's cancer cells. Applicant argues that despite
the cited art being available since 1994, well before the aforementioned priority date of the present application, no skilled artisan in the pertinent field provided a solution to the problem of tumor heterogeneity. Applicant argues that it was not until 16 years after the earliest publication date of the cited references, did the co-inventors of the present application recognize the problem and respond to the known intertumoral heterogeneity, while recognizing and responding to intra-tumoral heterogeneity as well. Applicant argues that the instant invention addresses the two heterogeneities in tumor mutations by providing a method that identifies and selects mutations that are subject- and tumor-specific and thus unique to that patient. Applicant argues that as previously discussed, the peptides to be used for a universal population, such as those of Parmiani, Johnston, Rammensee, and Chiang, directly teach away from the instant invention as they fail to recognize the problem of the two heterogeneities in tumor mutations, but instead target mutations that are universally found in a population
Applicant argues that the evidence presented in the Fritsch Declaration (i.e., Hachoen et al., Vonderheide et al., Joao Duarte, Ott et al., Adam Piore, etc.) each disclose methods or products including the claimed features of identifying and selecting at least two epitope sequences utilizing the claimed methods as set forth throughout the Fritsch Declaration. Applicant argues that the instant invention meets a long felt, but unmet need, as evidenced by the shortcomings of previous therapies, as well and addressing a problem that was previously not recognized in the art.
Applicant’s arguments have been considered but are not persuasive. As an initial note, the claims are directed to a method for selecting two or more epitopes not a method for administering a vaccine comprising the epitopes. In addition, personalized approaches to treating a patient's cancer were well known, from developing vaccines for overexpressed tumor antigens to completely novel epitopes in patients with tumors having frameshift mutations. As discussed in Parmiani the promise of cancer-specific and patient specific peptides neoantigens for the use in cancer vaccines was already known at the time the ‘791 application was filed. Lennerz disclose that the tumor response of a patient with cancer was primarily driven by T cells that recognize mutated tumor antigens. Parmiani teaches the identification of unique human tumor antigens and their use in tumor immunotherapy. Parmiani discloses a method for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Sjoblom and Wood use whole transcriptome sequencing to identify cancer and patient-specific mutations, while Wood discloses that most of the identified mutations were unique to a particular patient. Ley, Choi and Gnirke disclose whole genome sequencing. Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm. Thus, the claimed invention, selecting a plurality of epitopes, comprising obtaining a first biological sample comprising cancer cells from a subject, obtaining a second biological sample comprising non-cancer cells obtained from the same subject, isolating a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences from the cancer cells and sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, thereby obtaining a first plurality of nucleic acid sequences comprising cancer cell nucleic acid sequences; and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and isolating a second plurality of nucleic acid sequences comprising non-cancer cell nucleic acid sequences from the non-cancer cells and sequencing the non-cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, identifying cancer specific nucleic acid sequences based on comparison of the first plurality of nucleic acid sequences from cancer cells to the second plurality of nucleic acid sequences from non-cancer cells, wherein the cancer specific nucleic acid sequences are present in the first plurality of nucleic acid sequences but are not present in the second plurality of nucleic acid sequences, wherein the identified cancer specific nucleic acid sequences encode two or more different peptide sequences of two or more different proteins that are expressed by the cancer cells of the subject based on measured RNA levels, and wherein each of the two or more different peptide sequences of the two or more different proteins comprise an endogenous cancer specific mutation that is not present in the proteins expressed by the non-cancer cells from the subject, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject, and wherein each of the two or more different peptide sequences of the two or more different proteins binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide and selecting a plurality of epitopes predicted to bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150nM according to the validated HLA-peptide-binding prediction algorithm was obvious in view of the art.
In addition, Applicant is arguing unexpected results based on the administration of the cancer and patient specific neoantigen, not on the selection of the neoantigens. Furthermore, the unexpected results Applicant is discussing primarily discloses the administration of pools of greater than 10 neoantigenic peptides having greater than 13 amino acids in length. It is not clear how many of these peptides in Ott (2019) or Ott (2020) have the claim limitation “wherein each cancer-specific peptide comprising the at least two epitope sequences binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide”.
MPEP 716.02(c) I recites that “Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention”. MPEP 716.01D recites “The ultimate determination of patentability must be based on consideration of the entire record, by a preponderance of evidence, with due consideration to the persuasiveness of any arguments and any secondary evidence”.
As discussed previously, the art discloses all the limitations of the present claims. Parmiani teaches the identification of unique human tumor antigens involving sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Ley, Sjoblom and Wood disclose whole exome sequencing necessary to identify the specific mutations in a tumor from a cancer patient. Johnston and Lennerz to generate T cells that recognize the cancer-specific peptide in the context of the cancer patient’s MHC molecules.
The specification does not identify even one example of a species of two epitope sequences that bind to a protein encoded by an HLA class I allele of the subject with a predicted IC50 of less than 500 nM, and bind to the protein encoded by an HLA class I allele of the subject with a predicted IC50 according to the validated HLA-peptide-binding prediction algorithm that is lower than a predicted IC50 according to the validated HLA-peptide-binding prediction algorithm of the corresponding wild type peptide to the protein encoded by the HLA class I allele of the subject that were capable of generating a population of T cells.
Based on the weight of the prior art it has been deemed that treatment protocol for the clinical studies is essential for the determination of unexpected results provided by the Applicant. Ott (2019) discloses that eight patients with melanoma were chosen based on their high mutation rate. Ott discloses that vaccines contained 13- 20 long peptides with lengths of 15-30 amino acids were grouped into 4 separate immunization pools. It is not clear from Ott (2019) how many of the peptides had an IC50 < 150nm. It is also not clear if multiple epitopes were identified and used in a single long peptide. The peptide pools were administered multiple times with poly-IC.
Similar to Ott (2019), Keskin discloses that vaccines contained up to 20 long peptides that were divided into pools of 3–5 peptides (designated as pools A–D). The vaccines were administered to 10 patients with glioblastoma following radiotherapy in a prime–boost schedule (Fig. 1a). Two patients were withdrawn because of an insufficient number of actionable neoepitopes or disease progression after radiotherapy.
Ott (2020) involved patients with melanoma, non-small cell lung cancer or bladder cancer with at least 50 non-synonymous point mutations and/or gene fusions. Ott (2020) states that the primary objective of the study was to evaluate the safety and tolerability of NEO-PV-01 in combination with nivolumab. Up to 20 neoantigenic peptides were divided into four pools and administered in multiple does along the nivolumab and poly-IC.
Thus, the treatment protocols that Applicant provided as examples of unexpected results are considerably more narrow than the present claims. Furthermore, it is not clear how many if any of the administered peptides in Ott and Keskin bind to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide. Thus, the unexpected results described by Applicants are not commensurate in scope with the breadth of the claims as currently presented, especially in view that the present claims are drawn to selection of two or more neoantigenic epitopes, not the administration of 10 or more peptides having amino acid sequences greater than 15.
In response to Applicant’s arguments concerning the research publications, most of the them appear to reference the Ott publications. However, as discussed previously, the claims as presently drawn are not commensurate in scope with the results in Ott (2019) and Ott (2020). Furthermore, as previously discussed, the claims are directed towards selecting neoantigenic peptides not a method for administering the neoantigenic peptides
With regards to Applicant’s previous arguments that as noted by Dr. Melief, prior to 2010, "the field was very much focused on shared tumor antigens as it just wasn't yet considered feasible to take the approach of the present application, that the importance of neo-antigens and their potential uses in cancer immunotherapy was not appreciated until 2015-2017, 5-7 years after the filing date of the '791 application that to Dr. Melief knowledge, the '791 application was the first attempt to systematically explore the approach to identify and target all mutation-derived neo-antigens in a single patient in a timely manner, it is noted that Parmiani discloses a method for identifying such antigens that involves sequencing of the whole genome of each individual tumor followed by the selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor (page 1977, 1st column). Thus, Parmiani discloses a blueprint for the present invention.
Furthermore, Sjoblom and Wood disclose methods for generating cancer cell nucleic acids from a biological sample comprising cancer cells obtained from a solid tumor from the subject and generating non-cancer cell nucleic acids from a second biological sample comprising non-cancer cells obtained from the same subject; (ii) sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing and (iii) identifying a plurality of cancer specific nucleic acid sequences from the first plurality of nucleic acid sequences that are specific to the cancer cells and that do not include nucleic acid sequences from the second plurality of nucleic acid sequences. Wood disclose that most mutations were subject specific. Parmiani, Johnston and Nielsen disclose (iv) predicting or measuring which epitopes of the two or more different peptide sequences form a complex with the one or more proteins encoded by the one or more HLA alleles of the same subject by a validated HLA-peptide binding prediction algorithm; and (v) selecting the plurality of epitopes predicted in (iv). Sette and Nielsen disclose epitopes that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150 nM according to the validated HLA-peptide-binding prediction algorithm.
Thus, the blueprint for the present invention was known in the art, the methods for generating cancer cell nucleic acids from biological samples and sequencing the nucleic acids by whole genome sequencing were known in the art and the methods for identifying and selecting subject and cancer cell-specific peptides using prediction algorithms were known in the art.
Both Sjoblom and Wood use transcriptome sequencing to identify cancer-specific mutations, while Wood discloses that most of the identified mutations were unique to a particular patient. It is noted that in Ott expression for mutated nucleic acids were assessed for expression following whole exome sequencing. Thus, the sequencing methods of Ott resemble the whole transcriptome sequencing of Sjoblom and Wood.
In response to Applicant’s argument that that inter-tumoral heterogeneity (between patients) was recognized, while intra-tumoral heterogeneity was not, it is not clear how the present claims would differentiate between inter-tumoral heterogeneity and intra-tumoral heterogeneity, it does not appear that the present claims differentiate inter-tumoral heterogeneity and intra-tumoral heterogeneity. The claims are drawn to a method for selecting a plurality of epitopes, comprising generating cancer cell nucleic acids from a first biological sample comprising cancer cells, sequencing the cancer cell nucleic acids by whole genome sequencing or whole exome sequencing, identifying cancer specific nucleic acid sequences based on comparison of the first plurality of nucleic acid sequences from cancer cells to the second plurality of nucleic acid sequences from non-cancer cells, wherein the cancer specific nucleic acid sequences are present in the first plurality of nucleic acid sequences but are not present in the second plurality of nucleic acid sequences, wherein the identified cancer specific nucleic acid sequences encode two or more different peptide sequences of two or more different proteins that are expressed by the cancer cells, and wherein each of the two or more different peptide sequences of the two or more different proteins comprise an endogenous cancer specific mutation that is not present in the proteins expressed by the non-cancer cells from the subject, predicting epitopes of the two or more different peptide sequences that form a complex with one or more proteins encoded by one or more HLA alleles of the same subject by a validated HLA-peptide-binding prediction algorithm, wherein predicting comprises predicting binding affinities of the epitopes to the one or more proteins encoded by the one or more HLA alleles of the same subject, and wherein each of the two or more different peptide sequences of the two or more different proteins binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide; and selecting a plurality of epitopes predicted in (d) that bind to a protein encoded by an HLA allele of the same subject with a predicted IC50 of less than 150nM according to the validated HLA-peptide-binding prediction algorithm. The claims do not differentiate between inter-tumoral heterogeneity and intra-tumoral heterogeneity. Furthermore, by identifying mutations in the genomic nucleic acid of a tumor from a subject one would identify mutations with inter-tumoral heterogeneity as well as intra-tumoral heterogeneity.
Furthermore, the premise of intra-tumoral heterogeneity was well known at the time the ‘791 application was filed. Both Sjoblom and Wood use transcriptome sequencing to identify cancer-specific mutations, while Wood discloses that most of the identified mutations were unique to a particular patient.
Summary
Claims 1, 8, 16-20 and 22 stand rejected.
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646
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