DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 76-78, 80-84, 86-95, and 116-121 are pending and under examination.
35 USC § 112 rejections withdrawn
The rejections of claims 76-78, 80-84, 86-95 116 and 117-118 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement are withdrawn in view of Applicant’s amendment to the claims.
35 USC § 112 rejections maintained
The rejection of claims 119 and 121 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the applicant, regards as the invention are maintained.
The method of claim 76, wherein the method does not comprise demonstrating whether T cells in the population of T cells generated in ( c) are antigen-specific, wherein the method does not comprise demonstrating whether the at least five epitope sequences selected in (b) are immunogenic, or wherein the method does not comprise demonstrating whether the at least five epitope sequences selected in (b) bind to a protein encoded by an HLA allele of the subject.
It is not clear how comprise demonstrating whether T cells in the population of T cells generated in (c) would not be antigen-specific. A T cell by definition has a T cell receptor that is antigen-specific. It is also not clear how one would not demonstrate whether the five epitope sequences selected in (b) are immunogenic. Preparing a population of at least 1X108 autologous T cells comprising CD8+ T cells specific to at least five epitope sequences would necessarily demonstrate that at least one of the two epitopes was immunogenic. It is also not clear how the method for preparing the population of at least 1X106 to 1X1012 autologous T cells comprising CD8+ T cells specific to at two epitope sequences would not comprise demonstrating whether the five epitope sequences selected in (b) bind to a protein encoded by an HLA allele of the subject. Claim 119 seems to indicate that there would be many embodiments that would not be capable of preparing a population of at least 1X106 to 1X1012 autologous T cells comprising CD8+ T cells specific to at least five epitope sequences. However, in order to prepare a population of 1X106 to 1X1012 autologous T cells comprising CD8+ T cells would require an expansion of the autologous CD8+ T cells which would indicate that the CD8+ T cells are responding to an epitope which would necessarily mean that the CD8+ T cells are antigen-specific. Not knowing the exact epitope that the CD8+ T cells are responding to still does not demonstrate that the CD8+ T cells are not antigen-specific.
Applicant argues that the pending claims recite an exemplary process, an embodiment of which is highlighted in the application as filed and Figure 1 of Borgers et al. wherein a tumor and reference blood sample from each patient undergoes whole genome or exome sequencing, the tumor sample was also analyzed by RNA-seq, and
personalized neoantigens are predicted, rather than experimentally validated, or
"demonstrated".
In response, as discussed above, to prepare a population of 1X106 to 1X1012 autologous CD8+ T cells would require the expansion of the autologous CD8+ T cells to a specific epitope or epitopes which would necessarily demonstrate antigen-specific CD8+ T cells. The fact that it was not known beforehand whether the epitope was capable of inducing autologous CD8+ T cells to proliferate does not detract from the fact that the proliferating CD8+ T cells were recognizing a specific epitope, even if the sequence of the epitope was not known. Activated T cells would necessarily be antigen-specific T cell.
In addition, Fig. 1 of Borgers disclose personalized peptide manufacturing. Thus, the amino acid sequences of the peptides would be known. Not knowing the exact epitope that the CD8+ T cells are responding to still does not demonstrate that the CD8+ T cells are not antigen-specific. Proliferating CD8+ T cells would necessarily be antigen-specific.
The rejections of claims 119 and new claim 121 under 35 U.S.C. 112(a) as failing to comply with the written description requirement are maintained.
There is not support for the limitation “wherein the method does not comprise demonstrating whether T cells in the population of T cells generated in ( c) are antigen-specific, wherein the method does not comprise demonstrating whether the at least two epitope sequences selected in (b) are immunogenic, and wherein the method does not comprise determining whether the at least two epitope sequences selected in (b) bind to a protein encoded by an HLA allele of the subject”.
Applicant argues that as discussed above, the support provided in part IV of this response claim 119 can find explicit support in paragraph [0050] of the published application.
In response, as discussed above, to prepare a population of 1X106 to 1X1012 autologous CD8+ T cells would require the expansion of the autologous CD8+ T cells to a specific epitope or epitopes which would necessarily demonstrate antigen-specific CD8+ T cells. The fact that it was not known beforehand whether the epitope was capable of inducing autologous CD8+ T cells to proliferate does not detract from the fact that the proliferating CD8+ T cells were recognizing a specific epitope, even if the sequence of the epitope was not known. Activated T cells would necessarily be antigen-specific T cells.
35 USC § 103 rejections maintained.
The rejections of claims 76-78, 80-82, 84, 86-95, and 116-121 under 35 U.S.C. 103 as being unpatentable over Parmiani et al (J Immunol, 178:1975-1979, 2007, IDS, cited previously), Lennerz et al (PNAS, 102:16013-16018, 2005, IDS, cited previously) Echchakir et al (Cancer Res 61:4078-4083, 2001) and Rivoltini et al (J Immunol, 154:2257-2265, 1995) in view of Ley et al (Nature, 456:66-72, 2008, IDS, cited previously), Choi et al (PNAS, 106:19096-19101, 2009), Gnirke et al, Nature Biotechnology 27:182-189, 2009), Sjoblom et al (Science, 314:268-274, 2006, IDS, cited previously), Wood et al (Science, 318:1108-1113, 2007, IDS, cited previously) Johnston et al (WO 2007/101227, published 7 September 2007, IDS, cited previously) and Leturcq et al (US 9,222,070, published December 29, 2015, filed July 24, 2007) in further view of, and Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS, cited previously), Kozhich et al (J Immunol 158:4145-4151, 1997, cited previously) and Baratin et al (J Peptide Sci 8:327-334, 2002, cited previously) are maintained.
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). tumors. Parmiani disclose 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 (Id). Parmiani disclose that many autologous T cells have been generated to mutated peptides (Table 1). As evidenced by Lennertz, Echchakir and Rivoltini, cited in Parmiani, some of these T cell were autologous cytotoxic CD8+ T cells. 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). 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 autologous CD8+ T cells with dendritic cells (page 16017, 1st column). Echchakir disclose CD8+ CTLs to a mutated actinin-4 generated from mononuclear cells from a melanoma patient (Abstract; page 4079-4081). Rivoltini disclose inducing autologous CD8+ CTLs to a mutated peptide (page 2258-2260)
Thus, Parmiani disclose the value in identifying cancer-specific mutations that may can be used to make neoantigens capable of inducing neoantigen-specific CTLs. Parmiani disclose that whole genome sequencing would be desirable to identify the complete set of mutations in a patient’s tumor. Both Parmiani and Lennertz disclose that the importance of T cell responses to mutated proteins in cancer.
Parmiani does not specifically disclose that whole genomic and whole exome sequencing was well known in the art.
Ley disclose the use of parallel sequencing to sequence the genomic DNA of patient’s tumor cells and patient’s normal cells 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).
Sjoblom disclose a high-throughput identification of somatic mutations in cancer (page 268, 3rd column). Sjoblom identified somatic mutations in transcritomes 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).
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 disclose that the mutations include single-base substitutions, substitutions with missense changes, alteration of splice sites and insertions, deletions or duplications (Id).
One of ordinary skill in the art would have been motivated to apply Ley, Choi and Gnirke’s methods for whole genomic or exome sequencing to Parmiani’s teaching for the identification of unique human tumor antigens and their use in tumor immunotherapy because 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. Furthermore, Parmiani discloses that the ultimate immunotherapeutic strategy for targeting cancer and subject-specific epitopes will involve sequencing the whole genome of each individual tumor followed by the selection of epitopes whose motifs are predicted to be presented by the HLA allele of the individual (page 1977, 1st paragraph, 2nd paragraph) while 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. Furthermore, one of ordinary skilled in the art would have been motivated to apply Sjoblom and Wood’s method of identifying cancer mutations using whole transcriptome analysis because transcriptome analysis involves only identifying mutations in transcribed genes. It would not be of any benefit to generate mutated peptides based on exome analysis when the exome is not transcribed. These peptides may induce immune responses but since there would be no protein with the mutation expressed on the cancer cell, the immune response would not function to inhibit tumor growth.
Neither Parmiani, Ley, Choi, Gnirke, Sjoblom nor Wood specifically disclose preparing more than 1 X 108 CD8+ CTLs to neoantigenic peptides.
Johnson 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). Johnston disclose contacting T cells with MHC-matched tumor cells comprising novopeptides (page 4, lines 16-21; Figure 9; page 12, lines 3-22; page 20, lines 13-18; page 87, lines 9-25). Johnson disclose CTLs activated against novopeptide 6-21, described above were able to kill MHC-matched tumor cells pulsed with 6-21 novopeptide, but not unpulsed SW480 tumor cells (page 4, lines 16-20; Figure 9).
Letureq disclose preparing 1X108 autologous cytotoxic CD8+ T cells recognizing tumor antigens to be administered to a subject with melanoma (column 3, lines 9 to 49).
One of ordinary skill in the art would have applied Johnson’s method for preparing CD8+ CTLs to neoantigenic peptides to Parmiani, Ley, Choi, Gnirke, Sjoblom and Wood’s method for the identification of unique human tumor antigens and their use in tumor immunotherapy using whole exome because Parmiani discloses that CD8+ CTLs have been generated to neoantigens. Both Parmiani and Johnston both disclose the advantages of administering novo-peptides to cancer peptides.
Furthermore, one of ordinary skill in the art would have looked to other references, such as Letureq, to determine how many CD8+ CTLs to be prepared. Parmiani, Echchakir, Rivoltini Letureq and Johnson all involve T cell responses to tumor antigens.
Neither Parmiani, Ley, Choi, Gnirke, Sjoblom, Woodnor Johnson disclose identifying tumor and subject-specific epitopes that are predicted to have an IC50 of less than 500 nM to a protein encoded by an HLA allele of the subject using an HLA peptide binding analysis program.
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 class 1 molecules are highly selective with regards to peptide size (page 818, 2nd paragraph) 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 500 nM or less to Parmiani, Ley, Choi, Gnirke, Sjoblom nor Wood and Johnson’s method of preparing T cells to tumor and subject specific epitopes because Sette disclose that epitopes that bind to MHC class I molecules with high affinities have a higher likelihood of being immunogenic for T cell responses.
Neither Parmiani, Ley, Choi, Gnirke, Sjoblom, Wood Johnson 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, Ley, Choi, Gnirke, Sjoblom, Wood, Johnson and Sette’s method of preparing T cells to tumor and subject 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 provide a cancer-specific epitope that binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
One ordinary skill in the art would have had a reason expectation of success in method of preparing a population of at least 1X108 autologous T cells comprising CD8+ T cells specific to at least two epitope sequences because preparing CD8+ T cells to specific neoantigenic peptides was well known in the art, whole genome and exome sequencing was known in the art and identifying peptides with mutations binding to a patient’s MHC with algorithms was known in the art. As discussed above, Letureq disclose preparing 1X109 autologous cytotoxic CD8+ T cells recognizing tumor antigens.
Both Ley and Sjoblom disclose sequencing both the patient’s tumor cells and the patient’s normal cells.
The rejections of claims 76-78, 80-84, 86-95, and 116-121 under 35 U.S.C. 103 as being unpatentable over Parmiani et al (J Immunol, 178:1975-1979, 2007, IDS, cited previously), Lennerz et al (PNAS, 102:16013-16018, 2005, IDS, cited previously), Echchakir et al (Cancer Res 61:4078-4083, 2001) and Rivoltini et al (J Immunol, 154:2257-2265, 1995) in view of Ley et al (Nature, 456:66-72, 2008, IDS, cited previously), Choi et al (PNAS, 106:19096-19101, 2009), Gnirke et al (Nature Biotechnology 27:182-189, 2009), Sjoblom et al (Science, 314:268-274, 2006, IDS, cited previously), Wood et al (Science, 318:1108-1113, 2007, IDS, cited previously) Johnston et al (WO 2007/101227, published 7 September 2007, IDS, cited previously), Leturcq et al (US 9,222,070, published December 29, 2015, filed July 24, 2007), Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS, cited previously), Kozhich et al (J Immunol 158:4145-4151, 1997, cited previously) and Baratin et al (J Peptide Sci 8:327-334, 2002, cited previously) in further view of Lee et al (Leuk Res, 32:1653-1660, 2008, cited previously) are maintained.
Neither Johnston nor Lennerz disclose that the T cells and APCs are present at a ratio of from 30: 1 to 300: 1.
Lee disclose stimulating T cells using allogeneic dendritic cells at effector cell:target cell ratios of 20:1 and 40:1 (Fig 4). Lee disclose generating CTLs to peptides presented on dendritic cells (section 3.4).
One of ordinary skill in the art would have been motivated to apply Lee’s effector cell:target cell ratios of 40:1 to Parmiani, Ley, Choi, Gnirke, Sjoblom, Wood, Johnson and Sette’s method of preparing T cells because Johnson, Lennerz and Lee all disclose contacting effector T cells with APCs presenting peptide epitopes in the context of the subject’s HLA alleles. It would have been prima facie obvious to combine Parmiani, Ley, Choi, Gnirke, Sjoblom, Wood, Johnson and Sette’s method of preparing T cells with Lee’s effector cell:target cell ratios of 40:1 to be able to optimize the cell:target cell ratio when preparing the T cells. MPEP 2144.05(II)(B) recites that there is a motivation to optimize result-effective variables.
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In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. The effector cell:target cell ratio would be considered to be a results effective variable.
One of ordinary skill in the art would have had a reasonable expectation of success because methods for inducing the activation of CD8+ CTLs with APCs were well known in the art.
Applicant argues that the according to the van Buren Declaration, he would not have thought that a population of at least 1 x 108 autologous T cells could be successfully generated ex vivo that exhibit killing of tumor cells by contacting a subject's T cells and APCs with the subject's cancer-specific neoepitopes selected based on a predicted IC50 to an MHC protein encoded by the HLA allele of the subject using a computer implemented HLA peptide binding analysis program. Van Buren states that he would have had no reasonable expectation of success that selecting such cancer-specific neoepitopes as having a predicted HLA-binding affinity IC50 of less than 500 nM for the respective cognate HLAs could lead to successful generation of both antigen specific CD8+ T cells and antigen specific CD4+ T cells starting with autologous T cells obtained from peripheral blood mononuclear cells (PBMCs) isolated from the subject. Van Buren states that he would have also had no reasonable expectation of success that the claimed method could lead to successful generation of antigen specific CD8+ T cells and antigen specific CD4+ T cells that kill tumor cells either in vitro or in vivo.
In response, it is noted that the claims are drawn to a method of preparing a population of at least 1X106 to 1X1012autologous T cells comprising activated T cells specific to at least five epitope sequences, but the specification but does not disclose any CD4+ T cells that kill tumor cells and the claims do recite any in vivo administration of the CD8+ T cells. In fact, Applicant specifically states that the claims are drawn to methods of preparing autologous T cells, which has been interpreted as not encompassing methods of administering autologous T cells. As discussed previously, the specification only disclose the amino acid structure of one cancer-specific epitope, KVYEGVWKK, that was capable of generating a T cell response that can be administered to a cancer patient. And that peptide was already known in the art. The specification does not identify even one example of a species of even five 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. Furthermore, the specification does not disclose the structure of any functional cancer-specific peptides have a length of greater than 15 amino acids that bind to a protein encoded by an HLA class I allele of the subject with a predicted IC50 of less than 500 nM or of less than 150 nM, and bind to a protein encoded by an HLA allele of the same subject with a stronger predicted or measured affinity than corresponding wild-type epitope.
In response to Applicant’s argument that there would be no reasonable expectation of success that selecting such cancer-specific neoepitopes as having a predicted HLA-binding affinity IC50 of less than 500 nM for the respective cognate HLAs could lead to successful generation of both antigen specific CD8+ T cells and antigen specific CD4+ T cells starting with autologous T cells obtained from peripheral blood mononuclear cells (PBMCs) isolated from the subject, making autologous CD8+ T cells to peptides ex vivo was well known in the art. Parmiani discloses that several T cells including CD8+ T cells were generated to neoantigenic peptides. Johnston discloses generating CD8+ T cells to neoantigenic peptides. Given that CD8+ T cells to neoantigens were already disclosed in Parmiani it is not clear why one of skill in the art would not have had a reasonable expectation of success in generating neoantigen specific CD8+ CTLs. Furthermore, the selection of cancer specific neoepitopes which could be used to induce CD8+ T cells to proliferate were known in the art and the selection of peptides having a HLA-binding affinity IC50 of less than 500 nM was known in the art. It is not clear why one of skill in the art would not have had a reasonable expectation of success in preparing a population of at least 1X106 to 1X1012autologous T cells comprising activated T cells specific to at least five neo-epitope sequences. One of ordinary skill in the art would have been incentive to create neoantigen specific CD8+ CTLs given that neoantigen specific CD8+ cells have been identified in vivo (Lennerz, Echchakir, Rivoltini).
A.
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 T cell epitopes for preparing autologous T cells with a reasonable expectation of success. Applicant argues that while the concept of personal cancer approaches existed at the time of the instant invention, Parmiani indicated "no vaccination or adoptive immunotherapy trials deliberately targeting molecularly characterized unique tumor Ags have been conducted thus far" and specified the only approach utilized regarding unique tumor antigens is "immunizing with the potentially whole repertoire of autologous tumor cell Ags ... by using irradiated, cytokine gene-transduced autologous tumor cells." Applicant argues that Parmiani stated this is because "construction of a tailored, personalized vaccine for each single patient based on unique Ags remains a difficult task. Parmiani indicated "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" for targeting tumor-specific unique antigens requires a "massive" effort. Applicant argues that Parmiani alone or in combination with the cited reference do not bridge the gap between generating cancer antigens and generating a population of T cells with precisely the cancer antigen composition that would be specific and effective for a patient and the cancer. Applicant argues that Parmiani fails to teach a method for identifying unique human tumor antigens, but instead emphasizes the challenges of developing such methods.
Dr. van Buuren agrees, stating in the Declaration:
Simply because novo-peptides and cancer-specific epitopes may have been thought to be important for generating cancer vaccines and that T cells may have been known to be a driver of immune responses to tumor, does not mean that contacting a cancer-specific epitope to T cells obtained from PBMCs of a subject ex vivo would generate an ex vivo population of autologous T cells comprising CD8+ and CD4+ T cells specific to the cancer-specific epitope that recognize autologous tumors and were capable of killing tumor cells.
Applicant continues to argue that each of Johnston, Rivoltini, Sjoblom, Wood, Leturcq and Ley disclose methods for identifying mutations common amongst a population of cancer patients, which are contrary to a personal approach. Applicant argues that each of Johnston, Rivoltini, Sjoblom, Wood, Leturcq and Ley are focused on non-personal cancer approaches, i.e., identifying common cancer mutations to either understand the role of such mutations in tumorigenesis (Sjoblom, Wood, Rivoltini, Leturcq and Ley) or to identify peptides that are not cancer- or patient-specific
Applicant argues that as the disclosures of each of Johnston, Rivoltini, Sjoblom, Wood, Leturcq and Ley are focused on non-personal 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 sought to develop 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-personal cancer methods taught by the cited references. Applicant argues that one of ordinary skill in the art looking to develop personal cancer approach 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’s arguments have been considered but are not persuasive. As previously discussed, 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). Sjoblom, Wood, and Ley all disclose that most cancer mutations are patient-specific leading one of skill in the art to conclude that an optimal cancer vaccine would require more than just known mutated peptides in order to optimize the preparation of a cancer vaccine or the preparation of an operative CD8+ CTL population. It is noted that the only two mutated peptides in the specification that were demonstrated to induce CTLs were neoantigenic peptides already known in the art to induce CTLs. Furthermore, only one of these identified peptides appeared to bind a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
The issue seems to be the source of the peptides. However, Parmiani discloses the possibility of whole genome sequencing to identify mutations which could be used to generate patient-specific neoantigenic peptides. As disclosed by Ley, Choi and Gnirke whole genome and exome sequencing was known in the art. Ley used whole genome sequencing to identify neoantigens. Sjoblom and Wood disclose whole transcriptome sequencing which would identify mutations in transcribed nucleic acids. Given that it would be important that the mutated nucleic acids were transcribed and mutated peptides generated by translation to use the neoantigenic peptides as potential treatments for cancer patients, whole transcriptome sequencing and identifying mutated RNA would bypass the necessary determination of whether a mutated peptide was generated from the mutated nucleic acid. Generating a vaccine based on mutated exome DNA that doesn’t result in the expression of a mutated peptide would not be a functional vaccine. This is supported by the specification. In Example 1 on a strategy to identify neoepitopes for vaccination the specification discloses that “we will confirm expression of mutated genes as RNA in CLL samples” (paragraph 175). Thus, Applicant’s own specification discloses the importance for the expression of the mutated peptide. It is not clear if whole exome sequencing followed by screening for expression of the mutated peptide would be superior to whole transcriptome sequencing. It appears that the results would be similar.
Once the genomic or exome nucleic acids were sequenced, the sequences would be entered into a computer with an algorithm that would generate patient-specific neoantigenic peptide candidates. Both Parmiani and Johnson disclose such algorithms. These peptides would be synthesized and used in a system to prepare neoantigen specific CD8+ CTLs. Thus, all the steps, whole exome sequencing, identifying neoantigenic peptides with known algorithms and preparing neoantigen specific CD8+ CTLs to the neoantigenic peptides were known in the art. Applicant has not specifically indicated why one would not have had a reasonable expectation of success in preparing patient-specific. neoantigen-specific CD8+ CTLs to the neoantigenic peptides.
It is noted that given what was known in the art and stated in the specification, one of skill in the art would not have had a reasonable expectation of success in preparing patient-specific. neoantigen-specific CD8+ CTLs to just five patient-specific neoantigenic peptides. As stated in the specification only 5-10% of peptides were capable of inducing a T cell response. So unless it was known prior to preparation of the CD8+ CTLs that one of the five peptides was immunogenic, most combinations of five neoantigenic peptides would not generate CD8+ CTLs. It is noted that both peptides, the E255K peptide and CML66 peptide used in Examples 5 and 6 to generate CD8+ CTLs were previously known to generate CD8+ CTLs. And only the E255K peptide was shown to binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
Applicant is correct that the art mostly discussed cancer vaccines were utilized based on common mutations found amongst a population of patients or administering autologous whole tumor lysates with the goal of inducing an anti-tumor immune response. Parmaini discloses that unique antigen-specific immunity are more clinically effective than shared antigens. Echchakir and Rivoltini disclose the generation of autologous CTLs recognizing mutated peptides not present in other cancer patients. Ley, Sjoblom and Woods disclose that most cancer mutations were patient specific. Thus, only using CTLs to shared mutations and not patient-specific neoantigens would not be an optimal strategy for treating cancer patients which is why Parmiani disclosed that the ultimate strategy for targeting neoantigens will imply sequencing the whole genome of each individual tumor followed by selection of mutated peptides whose motifs are predicted to be presented by the HLA alleles of the patient bearing that particular mutated tumor. Given that whole exome sequencing was conventional at the time the present invention was made, it would have been obvious to use whole exome sequencing to identify patient-specific mutations which could be used to generate patient-specific neoantigens.
It is noted that the specification does not demonstrate the preparation of at least at least 1X108 autologous T cells comprising CD8+ and CD4+ T cells specific to the cancer-specific epitope that recognize autologous tumors and were capable of killing tumor cells. Only CD8+ CTLs were generated, the number of CTLs was not specifically given and the two cancer-specific epitopes were already known in the art to generate CD8+ CTLs. Thus, the specification does not specifically demonstrate the preparation of CD8+ CTLs determined using neoantigenic peptide sequences from whole exome sequencing but demonstrated CD8+ CTLs were generated to known cancer neoantigens.
In response to Applicant’s argument 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 personal 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, Parmiani discloses that identifying all the mutated nucleic acids from a tumor by whole genome sequencing would be a massive but not impossible effort. Parmini also disclose that identifying all the mutated nucleic acids from a tumor by whole genome sequencing would be the ultimate strategy. Furthermore, Parmini was published three years before the priority date of the present application. Next generation sequencing was rapidly advancing and the massive effort as disclosed in Parmini would be significantly less at the time of priority date of the present application. Furthermore, just because sequencing the entire genome of a patient’s tumor cells and normal cells would require a significant amount of effort does not make that effort non-obvious. As previously stated, whole genome and exome sequencing were conventional at the time of the invention, inputting the sequences into a computer and identifying prospective neoantigenic peptides using algorithms was routine at the time of the invention and generating CTLs to neoantigenic peptides ex vivo was routine. It would have been predictable to carry out the invention as claimed.
In response to Applicant’s argument that Parmiani alone or in combination with the cited reference do not bridge the gap between generating cancer antigens and generating a population of T cells with precisely the cancer antigen composition that would be specific and effective for a patient and the cancer, once peptides have been identified as binding to a patient’s MHC molecule with an affinity of less than 500 nM, as discussed above, it would have been straightforward to generate autologous CD8+ T cells to those peptides. As discussed previously, the specification only disclose the amino acid structure of one cancer-specific epitope, KVYEGVWKK, that was capable of generating a T cell response that can be administered to a cancer patient. And that peptide was already known in the art. The specification does not identify even one example of a species of even five 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. Furthermore, the specification does not disclose the structure of any functional cancer-specific peptides have a length of greater than 15 amino acids that bind to a protein encoded by an HLA class I allele of the subject with a predicted IC50 of less than 500 nM or of less than 150 nM, and bind to a protein encoded by an HLA allele of the same subject with a stronger predicted or measured affinity than corresponding wild-type epitope.
In response to Applicant’s argues that as the disclosures of each of Johnston, Rivoltini, Sjoblom, Wood, Leturcq and Ley are focused on non-personal 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, Johnston disclose preparing CD8+ cells to neoantigens, Rivoltini disclose that cancer-specific CD8+ T cells were present in cancer patients, Letureq disclose preparing 1X108 autologous cytotoxic CD8+ T cells recognizing tumor antigens while Sjoblom, Wood, and Ley all disclose that whole exome or transcriptome sequencing was known in the art. All have been discussed previously and the relevance of each to determination of obviousness of the present claims have been previously discussed. 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 novel subject and cancer-specific peptides.
Furthermore, neither Rivoltini, Sjoblom, Leturcq and Ley discredit or discourage the identification, selection and making of novel subject and cancer-specific peptides from whole exome sequencing. Wood disclosed that most cancer mutations were person-specific which would indicate the advantages of a personal cancer approach.
In response to Applicant’s argument 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, 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).
In response to Applicant’s argument that neither Wood nor Sjoblom, disclose whole genome or exome sequencing, and the samples are not patient-matched as required by the claims, Sjoblom identified somatic mutations in transcriptomes 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). Furthermore, if the cancer cells from the patient were not compared with the normal cells from a patient it would not be clear whether differences in nucleic acid sequences was the result of a mutation or a polymorphism unique to that patient. Making a CTL to a peptide comprising an amino acid change from a polymorphism would result in CTLs that attacked normal cells within the patient resulting in an autoimmune resposne.
B.
In addition, 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 personal 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 that 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.
Applicant’s arguments have been considered but is not persuasive. Sjoblom, Wood and Ley all disclose that the majority of mutations discovered using whole transcriptome sequencing were patient specific. Echchakir and Rivoltini disclose CD8+ T cells recognize unique peptide epitopes. There was ample evidence to suggest as disclosed in Parmiani that whole genome sequencing would be the ultimate strategy for targeting unique antigens. It is noted that Parmiani was published in 2007, just as whole genome and exome sequence techniques were being improved. As discussed above, Choi et al and Gnirke in 2009 disclosed techniques for whole exome sequencing. Given that the evidence indicated that most tumor antigen mutations were not widely shared between patients and given that whole genomic and exome sequencing were becoming standard, it would have been obvious to use Parmiani’s strategy for targeting all identified neoantigens. Once whole exome sequencing was performed on a patient’s tumor, one of ordinary skill in the art would use known algorithms to identify prospective neoantigenic peptides and determine whether the proteins comprising these neoantigenic peptides were expressed on the patient’s tumor cells. Preparing autologous CD8+ T cells to these neoantigenic peptides would be standard given the vast amount of previous work generating CD8+ CTLs to antigenic peptides.
With regards to Applicant’s arguments against Lennerz, as stated previously, 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 cancer-specific peptides using whole genome sequencing or whole exome sequencing.
Lennerz does disclose contacting isolated autologous T cells from the patient and cancer and subject specific epitopes ex vivo. Lennerz disclose contacting autologous CD8+ T cells with dendritic cells. Once a cancer-specific peptide was identified it would have been obvious to use the methods of Johnston and Lennerz to generate T cells that recognize the cancer-specific peptide in the context of the cancer patient’s MHC molecules.
In response to Applicant’s argument that Lee discloses generating allogeneic monocyte-derived dendritic cells pulsed with leukemic cell lysates, Lee disclose that using allogeneic and autologous dendritic cells to activate autologous T cells. Furthermore, Letureq disclose preparing 1X108 autologous cytotoxic CD8+ T cells recognizing tumor antigens to be administered to a subject with melanoma.
C.
Applicant also argues that post filing evidence demonstrates the population of T cell Prepared according to the claimed methods targets tumors. Borgers et al., published in Nature Medicine in May 2024, (submitted herewith as Exhibit C;
hereinafter "Borgers") discloses a first in human clinical trial using autologous T cells obtained from PBMCs isolated from the subjects with cancer that were generated according to the claimed methods. Applicant states that the data in Borgers demonstrate the proof of concept of this therapeutic approach Borges discloses an open label First in Human phase I clinical study to investigate safety and efficacy of a T cell therapy product made according to the claimed methods, of which the monotherapy arm tested two dose regimens, the first using 1x108 - 1x109 total cells; and the
second using 2x109 - 1x1010 total cells. Applicant argues that the van Buren Declaration describes the anti-tumor activity profile as showing "remarkable results." Applicant stated that of the nine patients treated, six had stable disease following treatment, including up to 36 weeks for one patient. In addition, four of these patients with stable disease showed tumor regression. Applicant states that a detailed analysis of the T cell parameters showed that both CD8+ T cells and CD4+ T cells contributed to the results observed. Applicant states that 14 of the 16 CD8+ responses were cytotoxic in response to target cells expressing the mutant neoantigen Applicant states that all T cell responses exerted multiple effector mechanisms. At least two functionalities (typically IFNy and CD107a) were detected in a large proportion of neoantigen-specific
CD8+ T cells, and most responses had a subset of T cells able to secrete both IFNy and TNF. Applicant states that most of the generated CD8+ T cell responses in the study surprisingly originated from the naive compartment and increased functional activity was observed for most of both pre-existing ( 4/7) and de novo (7 /9) responses that
were evaluated.
Applicant’s arguments have been considered but are not persuasive. First it is noted that the claims are drawn to preparing CD8+ cells to cancer and patient specific antigens not to a method for administering the CD8+ CTLs to cancer patients. Applicant argue that the present claims align with those in Vitiello (page 11, paragraph 2 of Applicant’s response of February 25, 2025) to argue that the written description rejection is improper. Applicant argues the instant claims are not directed to peptides with specific mutations, but to a method of preparing autologous T cells (Id). However, Borgers discloses that “For each patient, 40 short peptides (8–12 amino acids (aa), predicted to bind to MHC class I) and 20 long peptides (25 aa, predicted to bind to MHC class II or both I and II) were selected (page 882, 2nd column). Borgers disclose a polyclonal T cell product targeting multiple epitopes was generated by initiating six parallel culture vessels containing antigen-presenting cells (APCs), autologous T cells and up to 10 peptides per vessel to prime neoantigen-specific T cells. Thus, Borgers disclose the selection of specific peptides that had specific amino acid sequences. Given that Applicant is arguing that the instant claims are not directed to peptides with specific mutations, but to a method of preparing autologous T cells, it is not clear how relevant Borgers is to the present claims because Borgers is disclosing that peptides with specific mutations were being produced.
Furthermore, MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Borgers discloses that for each patient, 40 short peptides (8–12 amino acids (aa), predicted to bind to MHC class I) and 20 long peptides (25 aa, predicted to bind to MHC class II or both I and II) were selected (page 882, 2nd column). On average, 35 short and 13 long peptides were manufactured. Borgers discloses that a polyclonal T cell product targeting multiple epitopes was generated by initiating six parallel culture vessels containing antigen-presenting cells (APCs), autologous T cells and up to 10 peptides per vessel to prime neoantigen-specific T cells. Borgers states that to further expand already primed neoantigen-specific T cells and provide an additional opportunity to prime these cells, a second culture was initiated on day 12 and was used for restimulation of the first culture on day. Borgers states that all cultures were pooled and harvested on day 26. Thus, the procedures recited in Borgers are not commensurate in scope with the present claims which comprise the limitation “wherein the identified plurality of cancer-specific nucleic acid sequences encodes two or more different epitope sequences of two or more different proteins that are expressed by the cancer cells. It is noted that only two 9mer neoantigenic peptides were found to generate CD8+ CTL in the specification, and both these peptides were known in the art. In addition, only one of these peptides appeared to binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide. It is further noted that, as discussed above, Applicant argued that the instant claims are not directed to peptides with specific mutations, but to a method of preparing autologous T cells to in response to rejections for lack of written description rejection. However, Borgers produces peptides having a defined amino acid structure which would put them in possession of peptides with specific mutations. This appears to be in conflict with Applicant’s argument that the claims are not directed to peptides with specific mutations. The claims also do not recite any polyclonal T cell product targeting multiple epitopes. The specification does not disclose any polyepitope peptides.
Applicant also states that a detailed analysis of the T cell parameters showed that both CD8+ T cells and CD4+ T cells contributed to the results observed. However, the present claims only recite preparing a population of autologous CD8+ T cells. The specification does not disclose the administration of both CD8+ T cells and CD4+ T cells. Although as van Buuren states that CD8+ T cells were generated, the CD8+ T cells were not generated by only a combination of two separate neoantigenic peptides. Furthermore, generation of CD8+ CTLs with at least ten peptides would be an expected
result. In addition, it does not appear as if each cancer-specific peptide described in Bolger comprises epitope sequences that bind to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide.
Thus, the unexpected results are not commensurate in scope with the present claims. In addition, as Applicant argues, the claims are drawn to a method of preparing CD8+ CTLs, not a method of administering the CD8+ CTLs. It appears as if the unexpected results in Borgers discussed by Applicant were the results of the administration of the CD8+ T cells and CD4+ T cells. Also, the results in Borgers was demonstrated for melanoma patients. The claims are not drawn to the administration of CD8+ T cells to any cancer.
D.
Applicant states that during the prosecution of the instant application, Applicant has submitted the following objective evidence to address the Office's alleged prima facie case of obviousness: (a) Rule 1.132 Declaration of Dr. Edward Fritsch (submitted June 2, 2022; "Fritsch Declaration") and (b) Velez SITC 2021 (submitted June 2, 2022). Applicant argues that the Fritsch Declaration provided expert opinion regarding the
cited references along with evidence of long, unmet need and recognition of the claimed invention. Velez SITC 2021 was submitted as demonstrating unexcepted and surprising results. Applicant argues that the Velez SITC 2021 Poster utilized the claimed methods to prepare T cells to generate adoptive T cell cancer immunotherapies that can potentially be used to treat patients with metastatic ovarian cancer (OVC). The Velez SITC 2021 Poster presented serves to further support and confirm the teachings disclosed in the present application as filed. Applicant argues that as the Office has failed to acknowledge the Fritsch Declaration and Velez SITC 2021 and state why it is insufficient to overcome the present rejections
In response, it is noted that the arguments in Fritsch Declaration were addressed in the previous three Office Actions. The most relevant arguments were reiterated in Applicant’s responses to the previous Office Actions and were subsequently addressed in the Office Actions. The Fritch Declaration was referred to at least 33 times in the past three Office Actions. Applicant has not pointed to any substantiative argument presented in the Fritsch Declaration that was not addressed in an Office Action. Arguments on why each of the cited references would not have resulted in a prima facie case of obviousness have been addressed. Arguments on why particular references teach away from the claimed invention have been addressed. Arguments on why one of skill in the art would not have been motivated to combine the different references have been addressed.
Unlike what Applicant has argued the Velez SITC 2021 Poster was previous considered. As discussed previously, in the Velez SITC 2021 Poster, the authors showed that "both the peptide and RNA processes induced multiple CD8+ and CD4+ T cell responses with similar frequencies compared to the process performed previously in melanoma patients. However, Velez appear to discloses the administration of pools of immunogenic neoantigenic peptides greater than 13 amino acids in length. The present claims are drawn to contacting cancer-specific peptides comprising the at least two epitope sequences selected in (b ), or nucleic acid sequences encoding cancer-specific peptides comprising the at least two epitope sequences selected in (b), to antigen presenting cells (APCs) expressing the protein encoded by the HLA allele of the subject in the presence of T cells obtained from the subject ex vivo, wherein each cancer-specific peptide comprising the two or more different epitope sequences binds to a protein encoded by the HLA allele with a greater affinity than the corresponding wild type peptide, thereby generating a population of T cells comprising cytotoxic T cells (CTLs) CD8+ T cells specific to the at least two epitope sequences selected in (b). Thus, the methods used in Velez were much narrower than the claimed method. It is not clear from Velez how many if any cancer-specific peptides had a greater affinity than the corresponding wild type peptide for binding to a protein encoded by the HLA allele.
NEW REJECTIONS:
Claim Rejections - 35 USC § 112
Claims 76-78, 80-84, 86-95, and 116-121 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
There is not support in the specification as filed for the limitation “cancer-specific nucleic acid sequences encodes five or more different epitope sequences of three or more different proteins that are expressed by the cancer cells”.
Summary
Claims 76-78, 80-84, 86-95, and 116-121 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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