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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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35 USC § 103(a) rejections withdrawn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cited previously) Kozhich et al (J Immunol 158:4145-4151, 1997) and Baratin et al (J Peptide Sci 8:327-334, 2002) are withdrawn to include references that demonstrate the use of whole genome sequencing prior to the filing date of the present application.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 unexpect