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 .
Applicant's amendment and remarks, filed 9/11/25, are acknowledged.
Claims 1-2, 10, 17 have been amended.
Claims 1-3, 6-17, 19, 22-23 are pending.
Claims 6-8, 14-16, and 22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1-3, 9-13, 17, 19, and 23 are being acted upon.
In view of Applicant’s claim amendments, the previous grounds of rejection under 112(b) have been reformatted, and some additional grounds of rejection have been added, necessitated by the claim amendments.
The rejection under 35 U.S.C. 112(d) is withdrawn in view of Applicant’s claim amendments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 9-13, 17, 19, and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a step of stimulating T cells with candidate tumor MANA that comprise a peptide or a protein, however, determining and comparison steps refer only to MANA “peptides” or “the candidate peptide”, It is not clear what comparison should be made when the protein antigen embodiment is selected in the stimulating step.
Claim 1 is also indefinite in the step of determining frequencies of antigen specific Vb CDR3 clonotypes following “an in vitro expansion”. Does this refer to the stimulating expansion in the prior step? Additionally, the determining frequency step that recites comparing to “pre-stimulation to post-stimulation” in vitro with MANA peptides and expansion of MANA stimulated cultures, and also recites that MANA stimulated cultures is compared to expansion observed in T cell cultures without peptide and/or uncultured T cells. The two different comparison limitations is unclear. For example, does the second comparison further limit the first comparison step? Is the “pre-stimulation” the same as the cultures without peptide and/or uncultured T cells? The claim then recites an additional step of “determining a level of antigen specific T cell expansion” and comparing expansion to T cells in the absence of candidate peptide which is also unclear. Is this a different step than the expansion determined and compared in the prior step involving determining frequencies of CDR3 clonotypes and comparing expansion to expansion observed in cultures without peptide? The claim is generally unclear and indefinite.
In claim 10, it is not clear if how the liquid biopsy is to be used. Is it is intended to further limit the tumor sample? The scope of the claims cannot be established. Furthermore, Claim 10 is indefinite for the same reasons set forth above for claim 1, since the same limitations have been incorporated into claim 10. Additionally, claim 10 recites incorporating the candidate tumor MANA antigen into an immunogenic treatment compositions and administering “the immunotherapy”. It is unclear what is to be administered. Is it “the immunotherapy” the immunogenic treatment compositions of the prior step? Could “the immunotherapy” be a different MANA antigen than the one incorporated in the prior step or a completely different composition than the immunogenic treatment compostion? The scope of the claim is unclear and indefinite. Claims 11-13 are also indefinite, as they depend from claim 10 and recite further limitations regarding the immunotherapy, which is indefinite for the same reasons.
Claim 17 is indefinite for the same reasons as set forth above for claim 10 regarding the liquid biopsy and the limitations of claim 1 that have been incorporate into claim 17. Likewise, claim 17 recites incorporating the candidate tumor MANA antigen into an immunogenic treatment compositions and administering “the vaccine” which is indefinite for the same reasons set forth above. Claim 19 is also indefinite since it also recites “the vaccine” which is unclear for the same reasons.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 1-3, 9-13, 17, 19, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable US 9,115,402, in view of Jones, 2015, Klinger et al., 2013, US 2015/0275296 and Hackl, August 2016 (all of record).
The ‘402 patent teaches a method of identifying patient specific tumor specific mutated neoantigens (i.e. a MANA) of a human subject that serve as active vaccine composition which stimulate anti-tumor responses comprising performing sequencing to identify tumor specific somatic neoantigen mutations, identifying and selecting personal class I HLA-binding peptides using prediction algorithms (i.e. a predication pipeline) to empirically validate binding peptides, and detecting T cell responses of the subject to the peptides (see columns 1-2, 5, 7-8, and 36-37, and Figure 3, in particular). The ‘402 patent further teaches formulating the identified peptides as a vaccine composition and administering the peptides to the subject to treat a tumor (see columns 1-3, in particular). The ‘402 patent teaches using next generation sequencing to identify mutations using whole exome (i.e. exome data) of the tumor from each subject, and teaches identifying mutations by comparing matched tumor and normal non-tumor samples of each subject (see column 5, 7 and 37, and also the claims, in particular). The ‘402 patent teaches that the identified mutations should be those that are not identified in the normal non-tumor sample (see the claims and examples). The ‘402 patent also teaches that the mutation selection process involves evaluating the type of mutation, such as missense, frameshift, etc. (i.e. evaluating “self-similarity”). The ‘402 patent also teaches evaluating the gene expression in tumor cells and mRNA expression levels (see columns 5, 8, Fig. 2-3, and 7, in particular). The ‘402 patent teaches in order to further narrow down the mutant peptides, well established algorithms are used to predict peptides that bind the HLA class I alleles of each patient and selecting mutant peptides that bind with higher affinity (see column 1-2, 7-10, and Fig. 2). The ‘402 patent teaches that the prediction algorithms also include the requirement that the genes must be expressed in tumor cells (see, for example, columns 5, 8, Fig. 2-3 and 7). The ‘402 patent teaches identifying and selecting non-silent mutations, Id. The ‘402 patent also teaches using the algorithms o predict peptide sequences which are bound by the MHC molecules in the form of a peptide presenting complex (i.e. the algorithmics predict MHC antigen presentation, see column 9, particular). Thus, the method of the ‘402 patent takes next generating sequencing exome data from matched tumor and normal samples to identify candidate somatic mutation associated neoantigens, and assesses the data to evaluate “self-similarity”, gene expression, MHC presentation, and HLA class I binding using algorithms, i.e. a “prediction pipeline”. The ‘402 patent further teaches that said prediction steps are followed by testing whether the immune system can mount an effective immune response against the mutated tumor antigens (see column 10, in particular). The ‘402 patent teaches that testing of the peptides includes detecting T cell responses by evaluating induction of proliferation and expansion of T cells and functionally of the T cells, with the most efficient peptides being combined as a vaccine (see columns 26, in particular). The ‘402 patent exemplifies detecting the T cell response of the subject using predicted HLA binding mutated peptides, by culturing T cells from the subject with the peptides to expand the T cells and testing the T cells for reactivity against the peptide (see Example 4, column 38, in particular). The process also comprises culturing the T cells with and without the neoantigen peptide and determining that the neoantigen peptide has the ability to induce a T cell response in the patient if the expanded T cells are detected at a higher level that in the absence of the neoantigen peptide (see Fig. 10, in particular). The ‘402 patent teaches that the neoantigen vaccine can be administered in combination with anti-PD-1 antibodies (see column 29, in particular). The ‘402 patent teaches predicting binding to patient HLA-I alleles, and this would necessarily require determining patient HLA haplotype (see Fig. 6 and 11, in particular). The ‘402 patent teaches that the that the nucleic acids can be obtained from a tumor or body fluid, e.g. blood (i.e. a liquid biopsy, see column 14, in particular). The ‘402 patent teaches obtaining samples from blood and exemplifies the claimed method using samples collection from leukemia patients (i.e. patients with liquid tumors) that were purified using fluorescent activated cell soring using antibodies specific to tumor cells that express CD5 and CD19, i.e. performing or conducting a liquid biopsy to obtain tumor cells from the subject, see columns 14 and 37, in particular).
Although the ‘402 patent teaches next generation sequencing, it does not explicitly teach the specific parameters of the instant claims wherein (1) distinct paired reads contain the mutation in the tumor; (2) fraction of distinct paired reads containing a particular mutation in the tumor comprise at least 10% of the total distinct read pairs and (3) mismatched bases are not present in >1% of the reads in the matched normal sample nor databases of common germline variants derived from dbSNP and (4) position of the mutation is covered in both the tumor and normal sample. Likewise, although the ‘402 patent teaches a prediction pipeline or algorithm for evaluating neoepitope peptides, the ‘402 patent does not explicitly teach evaluating antigen processing.
Jones teaches a sequencing approach for cancer mutation discovery similar to the sequencing method of the ‘402 patent. Jones teaches the use of whole exome next generation sequencing to identify tumor specific somatic neoepitope alterations using tumor samples and matched normal samples from a patient (see abstract, pages 9-10, in particular). Jones teaches applying filters to exclude alignment and sequencing artifacts, such as unpaired reads, and that a mutation is identified only when distinct paired reads contained the mutation in the tumor, the number of distinct paired reads containing a particular mutation in the tumor was at least 10% of the exome read pairs, the mismatched based was not present in >1% of the reads in the matched normal sample as well as not present in a custom database of common germline variants derived from dbNSP, and that the position was covered in both the tumor and normal sample (see page 10). Jones explains that the process examines sequencing alignments of the tumor samples against a matched normal sample, while applying filters to exclude alignment and sequencing artifacts (see page 3 and 10, in particular).
Hackl teaches that mutated proteins can be identified from next generation sequencing data of tumor tissue and matched normal samples through a two-step procedure that involves data pre-processing consisting of quality control, read preprocessing and mapping to identify somatic DNA mutations, and then software can be used to predict the effect on isoform and the effect at the protein level (See page 446 and Fig. 4, in particular). Hackl teach that protein level predictions involve evaluating neoantigen MHC binding affinity (See page 449, in particular). Hackl teach that in addition to prediction of neoantigen somatic mutations for MHC binding affinity, tools for predicting proteolytic cleavage (i.e. antigen processing) are available and can be integrated into neoantigen prediction pipelines to reduce false positives (see page 449 and 452 and Fig. 4, in particular). See Figure 4, where Hackl explains that identification of cancer neoantigens from next generation sequencing requires implementation of several computational tasks, including prediction of mutated peptides from whole exome sequencing data from matched tumor and normal samples, selection of expressed peptides of the tumor sample, HLA typing, prediction of peptide-MHC binding for specific HLA alleles. Figure 4 also explains the importance of antigen processing in generating peptides which are capable of binding MHC.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to apply the teachings of Jones to pre-process and filter the next generation sequencing data in the method of the ‘402 patent. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since Jones teaches that doing so can exclude alignment and sequencing artifacts. See also Hackl, which explains that neoepitope identification involves a two-step procedure that includes not only predictive algorithms regarding protein function, but also data pre-processing consisting of quality control, read preprocessing and mapping to identify somatic DNA mutations. Thus, the ordinary artisan would recognize the advantages of including the steps of Jones regarding paired reads in the sequencing method of the ‘402 publication to enhance mutation identification while excluding artifacts.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to apply the teachings of Hackl regarding predicting proteolytic cleavage, to the neoantigen prediction algorithm in the ‘402 patent. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since Hackl teaches that tools for predicting proteolytic cleavage (i.e. antigen processing) can be integrated into neoantigen prediction pipelines to reduce false positives.
Thus, together, the ‘402 publication, Jones, and Hackl teach all the steps of the claimed method except they do not explicitly teach the steps of “isolating DNA from the T cells” and “amplifying the TCR-beta CDR3 DNA”.
Klinger teaches that several tools have been developed to study the T cell responses of an individual, including detecting antigen specific T cells using functional assays like ELISPOT or proliferation assays to determine antigen specific T cells (see page 1, in particular). Klinger teaches, however, that these assays suffer from low sensitivity and variability, and that next-generation sequencing has recently emerged as a highly sensitive method for characterization of the immune repertoire (see page 1, in particular). Klinger teaches that in this method, individual clonotypes are identified based on the unique TCR rearrangements based on high throughput sequencing of the TCR repertoire which is accomplished by amplifying and sequencing regions of the V, D, J gene segments (i.e. CDR3 sequencing, see page 1, in particular). Klinger teaches performing the method by contacting a T cell sample with a peptide antigen to expand the T cells, followed by performing the sequencing method to identify clonotypes that respond to the antigen stimulation, as compared to a control without peptide stimulation (see page 5, in particular). Klinger teaches that the sequencing and immune assays represent a powerful high resolution approach for characterization of an immune response, and that the assays are applicable to many fields of medicine (see page 8, in particular). Klinger teach that the method may inform strategies for improved vaccine and immunotherapy protocols, and that the sequencing method could ultimately be the basis for diagnostic, prognostic and disease monitoring tools for immune mediated disorders (see page 8, in particular). Klinger teaches that current T cell immune assays are limited by their sensitivity and inability to discriminate the clonotypes that contribute to an immune response, and that the high throughput sequence based method is advantageous since it can identify individual clonotypes based on their unique TCR rearrangements, and that using a combined sequencing method with existing immune assays provides for qualitative antigen specific information and evaluation of individual clonotypes that contribute to an immune response with greater sensitivity and quantitative accuracy (see page 7, in particular). Klinger teach that the combined assay is robust and can efficiently identify antigen specific T cells (see page 8, in particular).
Likewise, the ‘296 publication teaches a similar clonotype sequencing method that can be used to quantify the immunogenicity of an antigen (i.e. to functionally evaluating a candidate antigen, see paragraph 40, in particular).The ‘296 publication teaches that the method comprises incubating T cells with an antigen for a predetermined interval and allowing activation and proliferation (i.e. expansion) of the T cells, sequencing nucleic acids encoding a T cell receptor chain or a portion thereof from the T cells to provide clonotypes, and comparing said clonotypes to those obtained from T cells prior to antigen addition (i.e. in the absence of antigen), wherein antigen specific T cells are identified as present when the frequency of the clonotype increases as compared to the clonotype in the absence of antigen (see paragraphs 32- 38 and abstract, in particular). The ‘296 publication teaches a method can be used to identifying antigen specific T cells from a T cell sample from a cancer patient (i.e. autologous T cells) and contacting the T cells with a range of candidate protein antigens (see page 9, in particular). The ‘296 patent teaches tumor antigen proteins as the antigen and performing the method in a human (see paragraphs 60-61, in particular). The ‘296 publication teaches the clonotype is determined by isolating DNA from the T cells and amplifying the TCR beta variable regions, particularly the overlap region comprising the VDJ junction i.e. the CDR3 region, see page 15-16 and paragraph 131 and 134, in particular. Thus, the reference to determining clonotype in the method of the ‘296 publication above involves amplifying and sequencing TCR beta variable region, including the CDR3 region, as recited in the instant claims. In the method of the ‘296 publication, the frequency of the clonotype in the antigen stimulated and expanded T cells is compared to the frequency in T cells prior to antigen stimulation to determined that the clonotype has been expanded in the first population, but not the second population.. For example, see paragraph 124 of the ‘296 publication, wherein it is taught that the clonotypes were increased in the sample contacted and expanded with the antigen, wherein an identical T cell population that lacked the peptide, none of the clonotype was identified. In this instance, the identification of the clonotype is a measure of expansion of the clonotype in the T cells in response to the peptide antigen.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the CDR3 clonotype sequencing method of Klinger, and the ‘296 publication, as the functional T cells assay in the method of identifying neoantigen mutated tumor antigens in the method of the ‘402 patent, Hackl and Jones. The ordinary artisan would be motivated to do so, since Klinger teaches that incorporating clonotype CDR3 sequencing is advantageous, since is more sensitive than current T cell immune assays. Klinger also teaches that the assays allows discrimination of the clonotypes that contribute to an immune response since it can identify individual clonotypes and that using a combined sequencing method with existing immune assays provides for qualitative antigen specific information and evaluation of individual clonotypes that contribute to an immune response with great sensitivity and quantitative accuracy. The ordinary artisan would have a reasonable expectation of success since Klinger teaches that the combined assay is robust and can efficiently identify antigen specific T cells. Additionally, Klinger teaches that the sequencing assay represents a powerful high resolution approach for characterization of an immune response, and that the assays are applicable to many fields of medicine and may inform strategies for improved vaccine and immunotherapy protocols. Additionally, the ‘296 publication also teaches that the clonotype assay can be used to quantify the immunogenicity of an antigen. Thus, the ordinary artisan would recognize that the clonotype sequencing assays of the prior art, could be advantageously performed to further evaluate T cell responses in the method of the ’402 patent.
As noted above, the assay of Klinger and the ‘296 publication involve stimulating expansion of T cells, isolating DNA, amplification of CDR3, and comparing and determining antigen specific T cell clonotypes, as recited in the present claims in lines 6-17. Klinger teaches that the study used CMV as a model system to provide proof of principal, but also teaches that the methods articulated are applicable to many fields of medicine and may inform strategies for improved vaccines. Klinger also teach that the assay is robust and can efficiently identify antigen specific T cells. Furthermore, the ‘296 publication teaches a similar CDR3 clonotype assay as Klinger and teaches that it can be used to identify antigen specific T cells to an antigen of interest, in particular tumor or cancer antigens (see pages 11-12, in particular). Thus, the references provide motivation and reasonable expectation of success in using the assays as the functional assay in the method of the ‘402 patent.
In particular, the ‘402 patent teaches using proliferation or ELISPOT immune assay to detect antigen specific T cells. However, Klinger specifically teaches that the disclosed CDR3 clonotype assay is advantageous as compared to functional assays like ELISPOT which suffer from low sensitivity and variability. The ordinary artisan would be motivated to use the CDR3 clonotype assay in the method of the ‘402 patent to achieve the advantages specifically taught by Klinger, i.e. to provide qualitative antigen specific information and evaluation of individual clonotypes with greater sensitivity and quantitative accuracy by using an assay that is robust and efficient in identifying the presence of antigen specific T cells.
Applicant’s arguments filed 9/11/25 have been fully considered, but they are not persuasive.
Applicant argues that the claimed method evaluates antigen processing, MHC binding, self-similarity, and gene expression, while the ‘402 patent is restricted to only measuring peptide binding to HLA.
As noted above, the ‘402 patent also teaches that the mutation selection process involves evaluating the type of mutation, such as missense, frameshift, etc. (i.e. evaluating “self-similarity”). The ‘402 patent also specifically teaches evaluating gene expression in tumor cells and mRNA expression levels (see columns 5, 8, Fig. 2-3, and 7, in particular). The ‘402 patent specifically teaches the genes must be expressed in tumor cells (see, for example, columns 5, 8, Fig. 2-3 and 7). The ‘402 patent teaches identifying and selecting non-silent mutations, which also would fall within the scope of assessing gene expression. The ‘402 patent also teaches using the algorithms to predict peptide sequences which are bound by the MHC molecules in the form of a “peptide presenting complex”, i.e. the algorithmics predict MHC antigen presentation, see column 9, particular. Furthermore, the teaching of evaluating antigen processing is provided by Hackl.
Applicant argues that Hackl teach that pipelines that integrate several types of analysis have to be assembled ad hoc, and that standalone solutions are better suited. Applicant argues that previous algorithms may give a general list of possibilities, and that Applicant’s specification provides selection criteria that can be used to identify somatic mutations and antigen specific T cells that other methods cannot.
The claims do not exclude assembling standalone tools or using parallel analysis to provide a neoantigen prediction pipeline. The claims broadly encompass any pipeline, that merely “assesses” various parameters at a very high level of generality.
Applicant further argues that the amendments overcome the rejection and that Applicant’s invention is based on stimulating T cells in a 10-day culture system, wherein a differential expansion TCR analysis (TCRVb clonality) is performed in T cells cultures stimulated with MANA peptides as compared to that observed in T cell cultures without peptide and/or uncultured T cells.
The present claims recite no limitations regarding a 10 day culture, as argued by Applicant. Klinger and the ‘296 publication teach a clonotype analysis method within the scope of the instant claims. The references teach culturing T cells with peptide antigen to induce proliferation, sorting antigen specific T cells that have proliferated based on CFSE staining, isolating DNA from the sorted antigen specific T cells and amplifying and sequencing TCRb CDR3 to determine clonotype frequences. The references also teach comparing clonotypes observed in said antigen specific peptide stimulated, proliferated T cells to frequencies in T cell cultures without peptides or uncultured T cells (See page 5 and Fig. 1, in particular).
It is noted that the instant specification exemplifies performing the assay on bulk T cells from peptide stimulated cultures, and compares the results to, for example, those obtained by sorting for antigen specific T cells (using tetramers), which is the method taught by Klinger. It is suggested to amend the claims to limit them to CDR3 sequencing on bulk T cells from the culture as exemplified in the instant specification. This would exclude the assay taught by Klinger and the ‘296 publication, which does not use bulk T cells for CDR3 sequencing, but rather employs sorted, antigen specific T cells from the culture.
The following is a suggested amendment to claim 1 that would overcome the prior art, and additionally would clarify the claims to overcome the 112(b) rejections above.
In claim 1, replacing the steps that start with “stimulating expansion of autologous T cells” through the end of the claim with the following, would overcome the prior art and 112(b) rejections:
“culturing in order to stimulate expansion of the T cells;
isolating deoxyribonucleic acid (DNA) from bulk T cells from the culture;
amplifying and sequencing b (TCR-b) complementarity-determining region 3 (CDR3) DNA to determine frequencies of Vb CDR3 clonotypes in the bulk T cells;
comparing the frequencies of the Vb CDR3 clonotypes in the bulk T cells to Vb CDR3 clonality in T cells cultured in the absence of the candidate tumor MANA antigen and/or in uncultured T cells to identify antigen specific Vb CDR3 clonotypes;
determining that the candidate tumor MANA antigen has the ability to induce a T cell response if the frequency of antigen specific Vb CDR3 clonotypes identified in the bulk T cells is higher than the frequency in the T cells cultured in the absence of the candidate tumor MANA antigen and/or in uncultured T cells; and
incorporating the candidate tumor MANA antigen determined to have the ability to induce a T cell response into an immunogenic treatment composition.”
If desired, Applicant could also include a dependent claim to clarity that although the “bulk” T cell limitation would exclude the antigen specific sorting process in the prior art rejection, it would encompass sorting specific subtypes, such as CD8+ T cells, as exemplified in the instant specification. For example, “the method of claim 1, further comprising a step of sorting CD8+ T cells after culture and expansion of said autologous T cells with said candidate MANA antigen, and wherein the DNA is isolated from bulk CD8+ T cells from the culture”.
Claim 1-3, 9-13, 17, 19, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable US 9,115,402, in view of Jones, 2015, Klinger et al., 2013, US 2015/0275296 and US 10,563,266.
The ‘402 patent teaches a method of identifying patient specific tumor specific mutated neoantigens (i.e. a MANA) of a human subject that serve as active vaccine composition which stimulate anti-tumor responses comprising performing sequencing to identify tumor specific somatic neoantigen mutations, identifying and selecting personal class I HLA-binding peptides using prediction algorithms (i.e. a predication pipeline) to empirically validate binding peptides, and detecting T cell responses of the subject to the peptides (see columns 1-2, 5, 7-8, and 36-37, and Figure 3, in particular). The ‘402 patent further teaches formulating the identified peptides as a vaccine composition and administering the peptides to the subject to treat a tumor (see columns 1-3, in particular). The ‘402 patent teaches using next generation sequencing to identify mutations using whole exome (i.e. exome data) of the tumor from each subject, and teaches identifying mutations by comparing matched tumor and normal non-tumor samples of each subject (see column 5, 7 and 37, and also the claims, in particular). The ‘402 patent teaches that the identified mutations should be those that are not identified in the normal non-tumor sample (see the claims and examples). The ‘402 patent also teaches that the mutation selection process involves evaluating the type of mutation, such as missense, frameshift, etc. (i.e. evaluating “self-similarity”). The ‘402 patent also teaches evaluating the gene expression in tumor cells and mRNA expression levels (see columns 5, 8, Fig. 2-3, and 7, in particular). The ‘402 patent teaches in order to further narrow down the mutant peptides, well established algorithms are used to predict peptides that bind the HLA class I alleles of each patient and selecting mutant peptides that bind with higher affinity (see column 1-2, 7-10, and Fig. 2). The ‘402 patent teaches that the prediction algorithms also include the requirement that the genes must be expressed in tumor cells (see, for example, columns 5, 8, Fig. 2-3 and 7). The ‘402 patent teaches identifying and selecting non-silent mutations, Id. The ‘402 patent also teaches using the algorithms to predict peptide sequences which are bound by the MHC molecules in the form of a peptide presenting complex (i.e. the algorithmics predict MHC antigen presentation, see column 9, particular). Thus, the method of the ‘402 patent takes next generating sequencing exome data from matched tumor and normal samples to identify candidate somatic mutation associated neoantigens, and assesses the data to evaluate “self-similarity”, gene expression, MHC presentation, and HLA class I binding using algorithms, i.e. a “prediction pipeline”. The ‘402 patent further teaches that said prediction steps are followed by testing whether the immune system can mount an effective immune response against the mutated tumor antigens (see column 10, in particular). The ‘402 patent teaches that testing of the peptides includes detecting T cell responses by evaluating induction of proliferation and expansion of T cells and functionally of the T cells, with the most efficient peptides being combined as a vaccine (see columns 26, in particular). The ‘402 patent exemplifies detecting the T cell response of the subject using predicted HLA binding mutated peptides, by culturing T cells from the subject with the peptides to expand the T cells and testing the T cells for reactivity against the peptide (see Example 4, column 38, in particular). The process also comprises culturing the T cells with and without the neoantigen peptide and determining that the neoantigen peptide has the ability to induce a T cell response in the patient if the expanded T cells are detected at a higher level that in the absence of the neoantigen peptide (see Fig. 10, in particular). The ‘402 patent teaches that the neoantigen vaccine can be administered in combination with anti-PD-1 antibodies (see column 29, in particular). The ‘402 patent teaches predicting binding to patient HLA-I alleles, and this would necessarily require determining patient HLA haplotype (see Fig. 6 and 11, in particular). The ‘402 patent teaches that the that the nucleic acids can be obtained from a tumor or body fluid, e.g. blood (i.e. a liquid biopsy, see column 14, in particular). The ‘402 patent teaches obtaining samples from blood and exemplifies the claimed method using samples collection from leukemia patients (i.e. patients with liquid tumors) that were purified using fluorescent activated cell soring using antibodies specific to tumor cells that express CD5 and CD19, i.e. performing or conducting a liquid biopsy to obtain tumor cells from the subject, see columns 14 and 37, in particular).
Although the ‘402 patent teaches next generation sequencing, it does not explicitly teach the specific parameters of the instant claims wherein (1) distinct paired reads contain the mutation in the tumor; (2) fraction of distinct paired reads containing a particular mutation in the tumor comprise at least 10% of the total distinct read pairs and (3) mismatched bases are not present in >1% of the reads in the matched normal sample nor databases of common germline variants derived from dbSNP and (4) position of the mutation is covered in both the tumor and normal sample. Likewise, although the ‘402 patent teaches a prediction pipeline or algorithm for evaluating neoepitope peptides, the ‘402 patent does not explicitly teach evaluating antigen processing.
Jones teaches a sequencing approach for cancer mutation discovery similar to the sequencing method of the ‘402 patent. Jones teaches the use of whole exome next generation sequencing to identify tumor specific somatic neoepitope alterations using tumor samples and matched normal samples from a patient (see abstract, pages 9-10, in particular). Jones teaches applying filters to exclude alignment and sequencing artifacts, such as unpaired reads, and that a mutation is identified only when distinct paired reads contained the mutation in the tumor, the number of distinct paired reads containing a particular mutation in the tumor was at least 10% of the exome read pairs, the mismatched based was not present in >1% of the reads in the matched normal sample as well as not present in a custom database of common germline variants derived from dbNSP, and that the position was covered in both the tumor and normal sample (see page 10). Jones explains that the process examines sequencing alignments of the tumor samples against a matched normal sample, while applying filters to exclude alignment and sequencing artifacts (see page 3 and 10, in particular).
The ‘266 patent teaches a neoantigen prediction analysis method that can identify and prioritize mutation derived neoantigens of a patient for use in patient vaccines therapy (see column 1, in particular). The ‘266 patent teaches that existing strategies for identifying and prioritizing candidate neoantigens lack sensitivity and specificity, and that the invention provides for highly personalized efficacy for neoantigen identification for cancer immunotherapy (see columns 1-2, in particular). The ‘266 patent teaches that the prediction method comprises determining HLA-genotypes and binding affinity to HLA-I of neoantigen peptides, determining self-similarity and gene expression, and antigen processing (see the claims, columns 9-10, in particular). The ‘266 patent teaches performing sequencing from tumor samples, including blood (i.e. a liquid biopsy, see column 5, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to apply the teachings of Jones to pre-process and filter the next generation sequencing data in the method of the ‘402 patent. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since Jones teaches that doing so can exclude alignment and sequencing artifacts.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to apply the teachings of the ‘266 patent, to the prediction algorithm of the ‘402 patent. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘266 patent teaches that existing strategies for identifying and prioritizing candidate neoantigens lack sensitivity and specificity, and that the invention provides for highly personalized efficacy for neoantigen identification for cancer immunotherapy.
Thus, together, the ‘402 publication, Jones, and the ‘266 patent teach all the steps of the claimed method except they do not explicitly teach the steps of “isolating DNA from the T cells” and “amplifying the TCR-beta CDR3 DNA”.
Klinger teaches that several tools have been developed to study the T cell responses of an individual, including detecting antigen specific T cells using functional assays like ELISPOT or proliferation assays to determine antigen specific T cells (see page 1, in particular). Klinger teaches, however, that these assays suffer from low sensitivity and variability, and that next-generation sequencing has recently emerged as a highly sensitive method for characterization of the immune repertoire (see page 1, in particular). Klinger teaches that in this method, individual clonotypes are identified based on the unique TCR rearrangements based on high throughput sequencing of the TCR repertoire which is accomplished by amplifying and sequencing regions of the V, D, J gene segments (i.e. CDR3 sequencing, see page 1, in particular). Klinger teaches performing the method by contacting a T cell sample with a peptide antigen to expand the T cells, followed by performing the sequencing method to identify clonotypes that respond to the antigen stimulation, as compared to a control without peptide stimulation (see page 5, in particular). Klinger teaches that the sequencing and immune assays represent a powerful high resolution approach for characterization of an immune response, and that the assays are applicable to many fields of medicine (see page 8, in particular). Klinger teach that the method may inform strategies for improved vaccine and immunotherapy protocols, and that the sequencing method could ultimately be the basis for diagnostic, prognostic and disease monitoring tools for immune mediated disorders (see page 8, in particular). Klinger teaches that current T cell immune assays are limited by their sensitivity and inability to discriminate the clonotypes that contribute to an immune response, and that the high throughput sequence based method is advantageous since it can identify individual clonotypes based on their unique TCR rearrangements, and that using a combined sequencing method with existing immune assays provides for qualitative antigen specific information and evaluation of individual clonotypes that contribute to an immune response with greater sensitivity and quantitative accuracy (see page 7, in particular). Klinger teach that the combined assay is robust and can efficiently identify antigen specific T cells (see page 8, in particular).
Likewise, the ‘296 publication teaches a similar clonotype sequencing method that can be used to quantify the immunogenicity of an antigen (i.e. to functionally evaluating a candidate antigen, see paragraph 40, in particular).The ‘296 publication teaches that the method comprises incubating T cells with an antigen for a predetermined interval and allowing activation and proliferation (i.e. expansion) of the T cells, sequencing nucleic acids encoding a T cell receptor chain or a portion thereof from the T cells to provide clonotypes, and comparing said clonotypes to those obtained from T cells prior to antigen addition (i.e. in the absence of antigen), wherein antigen specific T cells are identified as present when the frequency of the clonotype increases as compared to the clonotype in the absence of antigen (see paragraphs 32- 38 and abstract, in particular). The ‘296 publication teaches a method can be used to identifying antigen specific T cells from a T cell sample from a cancer patient (i.e. autologous T cells) and contacting the T cells with a range of candidate protein antigens (see page 9, in particular). The ‘296 patent teaches tumor antigen proteins as the antigen and performing the method in a human (see paragraphs 60-61, in particular). The ‘296 publication teaches the clonotype is determined by isolating DNA from the T cells and amplifying the TCR beta variable regions, particularly the overlap region comprising the VDJ junction i.e. the CDR3 region, see page 15-16 and paragraph 131 and 134, in particular. Thus, the reference to determining clonotype in the method of the ‘296 publication above involves amplifying and sequencing TCR beta variable region, including the CDR3 region, as recited in the instant claims. In the method of the ‘296 publication, the frequency of the clonotype in the antigen stimulated and expanded T cells is compared to the frequency in T cells prior to antigen stimulation to determined that the clonotype has been expanded in the first population, but not the second population., as recited in the comparing and determining steps of the instant claims. For example, see paragraph 124 of the ‘296 publication, wherein it is taught that the clonotypes were increased in the sample contacted and expanded with the antigen, wherein an identical T cell population that lacked the peptide, none of the clonotype was identified. In this instance, the identification of the clonotype is a measure of expansion of the clonotype in the T cells in response to the peptide antigen.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the CDR3 clonotype sequencing method of Klinger, and the ‘296 publication, as a functional T cells assay in the method of identifying neoantigen mutated tumor antigens in the method made obvious by the ‘402 patent, Jones, and the ‘266 patent. The ordinary artisan would be motivated to do so, since Klinger teaches that incorporating clonotype CDR3 sequencing is advantageous, since is more sensitive than current T cell immune assays. Klinger also teaches that the assays allows discrimination of the clonotypes that contribute to an immune response since it can identify individual clonotypes and that using a combined e sequencing method with existing immune assays provides for qualitative antigen specific information and evaluation of individual clonotypes that contribute to an immune response with great sensitivity and quantitative accuracy. The ordinary artisan would have a reasonable expectation of success since Klinger teaches that the combined assay is robust and can efficiently identify antigen specific T cells. Additionally, Klinger teaches that the sequencing assay represents a powerful high resolution approach for characterization of an immune response, and that the assays are applicable to many fields of medicine and may inform strategies for improved vaccine and immunotherapy protocols. Additionally, the ‘296 publication also teaches that the clonotype assay can be used to quantify the immunogenicity of an antigen. Thus, the ordinary artisan would recognize that the clonotype sequencing assays of the prior art, could be advantageously performed to further evaluate T cell responses in the method of the ’402 patent.
Applicant argues that that the claimed invention is nonobvious for the same reasons set forth above.
The claims stand rejected for the same reasons set forth above.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 9-13, 17, 19, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,563,266 in view of Jones, 2015, US 9,115,402, Klinger et al., 2013 (of record) and US 2015/0275296.
The ‘266 patent claims a method of prioritizing candidate neoantigens for a patient (i.e. a neoantigen prediction pipeline) comprising identifying one or more mutations in tumor nucleic acid sequences obtained from a patient sample but not in a non-tumor nucleic acid from the patient, and determining self-similarity, gene expression, HLA genotype, antigen processing and MHC binding affinity to rank candidate neoantigens and prioritize members according to likelihood of clinical significance, and using the prioritized candidate neoantigens for administering to the patient for treatment of cancer. Although the ‘266 patent does not explicitly claim that the neoantigens candidates are derived from exome data or from a liquid biopsy, that would be an obvious source of neoantigen data and tumor cells source based on the teachings of the ‘402 patent. Furthermore, the ordinary artisan would be motivated to further prioritize the neoantigen candidates based on functional T cell assays as made obvious by the ‘402 patent, Klinger, and the ‘296 publication for the same reasons set forth above. Additionally, it would be obvious to pre-process the sequencing data as taught by Jones for the same reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Applicant argues that that the claimed invention is nonobvious for the same reasons set forth above.
The claims stand rejected for the same reasons set forth above.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. S