DETAILED ACTION
Notice of AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-17, 19-28, 31-34, 36-40, 42, and 44-46 are cancelled; claims 47-60 are new claims; claims 18, 29-30, 35, 41, 43, 47-60 are being examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 08/11/2025 is acknowledged. As listed above, claims are canceled by Applicant or withdrawn by the examiner as drawn to nonelected inventions pursuant to 37 CFR 1.142(b), and the remaining claims have been examined as listed above.
Priority
This US Application 17/414,480 (06/16/2021) is a 371 of PCT/US2019/066104 (12/12/2019) which claims priority from US Application 62/780,832 (12/17/2018) and US Application 62/820,042 (03/18/2019), as reflected in the filing receipt mailed on 10/09/2024. The claims to the benefit of priority are acknowledged; and the effective filing date of claims 18, 29-30, 35, 41, 43, 47-60 is 12/17/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/16/2021 and 01/24/2022 were considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
the term "neoantigens" is misspelled as "neoantigenes" [0007];
the term "spectrometry" is misspelled as "spectometry" [0020];
the term "immunogenic" is misspelled as "immunongenic" [0688];
the term "microcentrifuge" is misspelled as "microcentrigure" [0689];
the term "supernatant" is misspelled as "supernantant" [0689];
the term "calculated" is misspelled as "alculated" [0689];
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in [0450, 0462, 0753, 0760, 0764, 0775-0776], pg. 150 line 12, and pg. 309 lines 14 and 35. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Appropriate correction is required.
Claim interpretation
Claims 18 and 57 recite "a novel untranslated open reading frame" which is being interpreted as comprising ORFs in 5’ untranslated regions as per [0173] in the disclosure.
Claim Rejections - 35 USC § 112(b)
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.
Claim 29-30, 35, and 57-60 are rejected under 35 U.S.C. 112(b)as being indefinite for failing to particularly point out and distinctly claim the subject matter the invention.
The following issues cause the respective claims to be rejected under 112(b) as indefinite:
Claim 29 recites "determining by single cell sequencing the sequences", in which "the sequences" requires but lacks antecedent basis. There is no previous recitation of "sequences" in this independent claim.
In claim 29, "the subject" repeats the issue above (the previous "subject-specific" cannot provide antecedent basis).
In claim 29, "the identified subject-specific TCR pairs" " repeats the issue above.
Dependent claims 30 and 35 are similarly rejected because they depend from claim 29.
Claim 29 is missing a coordinating conjunction (i.e. "and/or" or one of the other) between the steps (c) and (d) for proper grammar . It's unclear whether all of the steps are required (e.g. conjunction is "and"), or whether only some of the steps are required (e.g. conjunction is "or"). The lack of specificity as to the relationship among the steps renders the claim indefinite.
In claim 57 recites "(b)... the Ribo-seq data..." which lacks antecedent basis.
Dependent claims 58-60 are similarly rejected because they depend from claim 57.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 18, 29-30, 35, 41, 43, 47-60 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
101 background
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Analysis of instant claims
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The instant claims are directed to a method (claims 18, 29-30, 35, 41, 43, 47-60), which falls within one of the categories of statutory subject matter.
[Step 1: claims 18, 29-30, 35, 41, 43, 47-60 – Yes].
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Background
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Analysis of instant claims
Mathematical concepts recited in instant claims 18 and 57, include the terms:
• "(b) conducting hierarchical ORF prediction on the Ribo-seq data " (claims 18 and 57);
Said term is being identified as mathematical concept. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one having ordinary skill in the art. In this instant disclosure, [0173 - Support Vector Machine classifiers] describes the claimed prediction analysis; which indicates the use of math. Thus, the recited terms corresponds to verbal equivalents of mathematical concepts because they constitute actions executed by a group of mathematical steps in a form of a mathematical algorithm; thus mathematical concepts (MPEP 2106.04(a)(2)). A mathematical concept need not be expressed in mathematical symbols, because "words used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989).
Mental processes, defined as concepts or steps practically performed in the human mind such as steps of observations, evaluations, judgments, analysis, opinions or organizing information include:
• "(c) searching the nuORF database for matches with a MHC I immunopeptidome data set, wherein the matches between the nuORF database and the MCH I immunopeptidome dataset are identified as neoantigens" (claim 18);
• "selecting the TCR pairs that bind to the subject-specific neoepitopes" (claim 29);
• "(d) comparing the identified neoantigens to an annotated proteome database to identify a set of unannotated identified neoantigens from among the identified neoantigens" (claim 48);
• "(c) searching the nuORF database for predicted tumor nuORF matches with a MHC I immunopeptidome dataset, thereby identifying the matched predicted tumor nuORFs as tumor neoantigens" (claim 57); and
• "(d) comparing the identified tumor neoantigens to an annotated proteome database to identify a set of unannotated identified tumor neoantigens from among the identified tumor neoantigens" (claim 58).
Under the BRI, the recited limitations are mental processes because a human mind is sufficiently capable of evaluate data and search for matches, select data points, compare data to a database, and identify a neoantigen based on the comparison.
Dependent claim 43 recites further details about the "T-cell selection for the neoantigen identified"; dependent claims 47, and 60 recites further details about the "neoantigen selection"; dependent claims 52, and 54-56 recite further details about the "prediction" step; not reciting any additional non-abstract elements; all reciting further aspects of the information being analyzed, the manner in which that analysis is performed. Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas. The instant claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)).
Natural correlation recited in instant claims 18 and 57:
The instant claims recite a natural correlation by correlating the measurement of genetic material (i.e. dentification of codons and their corresponding open reading frames) naturally found in the body with the effect of open reading frame-deride neoantigen to bind subject-specific TCR pairs (see MPEP 2106.04(b).I).
[Step 2A Prong One: claims 18, 29-30, 35, 41, 43, 47-60 – Yes.]
Step 2A Prong One continued: natural product -- MPEP 2106.I and 2106.04
Preliminarily, at this 1st step of the analysis, elements of independent claims 18, 29 and 57 (and its dependent claims) are directed to natural products: at least, for example, the recited T cells and/or neoantigens. The claims read on embodiments in which claims 18 and/or 57 result in neoantigens which already are naturally occurring compounds. While the recited library antigens may not be found together in nature, Funk Brothers teaches that mixing individual elements does not necessarily render the composition markedly different from what occurs in nature.
[Step 2A Prong One continued: natural product: claims 18, 29 and 57: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Background
MPEP 2106.04(d).I lists the following example considerations for evaluating whether a judicial exception is integrated into a practical application:
An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Analysis of instant claims
Instant claims 18, 29, and 57 recite additional elements that are not abstract ideas:
• "(a) performing Ribosomal profiling (Ribo-seq) on a sample, thereby generating Ribo-seq dat" (claim 18);
• "(a) isolating from a sample of the subject a population comprising T cells" (claim 29);
• "(b) determining by single cell sequencing the sequences encoding the TCR pairs on individual cells in the population isolated in step (a)" (claim 29);
• "(c) transfecting or transducing T cell lines deficient in endogenous TCRs with the sequences encoding individual TCR pairs determined in step (b)" (claim 29); and
• "(d) using the T cell lines from step (c) to assay binding of the subject-specific TCR pairs to subject-specific neoepitopes" (claim 29).
• "(a) performing Ribosomal profiling (Ribo-seq) on a tumor sample and a non-tumor sample" (claim 57)
The steps regarding "performing Ribosomal profiling" and "single cell sequencing" (claims 18 and 29) are interpreted to require the use of a computer. The use of a computer is broadly interpreted and not actually described in the claims or specification. Under BRI, the computer nature of the drawings generated and disclosed methods [0173 and [0270] amounts to applying computer methods. Hence, the claims explicitly recite steps executed by computers and therefore can be described as computer functions or instructions to implement on a generic computer.
The steps regarding "isolating and transfecting cells" and "performing binding assays" read on data gathering activities; being an insignificant extra-solution activity since this limitation merely serve to gather data. See MPEP 2106.05(g) and MPEP 2106.04(d). Dependent claims 30, 35, 41, 50-51, and 59 recite further details about the subject-specific data being gathered.
Hence, these are mere instructions to apply the abstract idea using a computer and insignificant extra-solution activity and therefore the claims do not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)). None of the dependent claims recite any additional non-abstract elements; they are all directed to further aspects of the information being analyzed, the manner in which that analysis is performed, or the mathematical operations performed on the information.
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs).
In this Step 2A, Prong Two immediately above claim steps and/or elements were identified as part of one or more additional elements. Additional elements are further discussed in Step 2B below.
Here in Step 2A, Prong Two, no additional step or element clearly demonstrates integration of the JE(s) into a practical application.
At this point in examination it is not yet the case that any of the Step 2A, Prong Two considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of 1. an improvement, 2. treatment, 3. a particular machine or 4. a transformation is clear in the record.
For example, regarding the first consideration at MPEP 2106.04(d)(1), the record, including for example the specification, does not yet clearly disclose an explanation of improvement over the previous state of the technology field. The claims do not yet clearly result in such an improvement (e.g. specification: [0005]). [Step 2A Prong Two: claims 18, 29-30, 35, 41, 43, 47-60 - No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of the 35 USC § 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Claims 18 and 29 recite a computer or computer functions, interpreted as instructions to apply the abstract idea using a computer, where the computer does not impose meaningful limitations on the judicial exceptions; which can be performed without the use of a computer (MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
As explained above, the steps of "isolating, sequencing and transfecting cells" and "performing binding assays" constitute insignificant extra solution activity, and when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(g)). Hence, these elements, when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(d)).
It is known in the art that the use of experimental techniques such as ribosome profiling and T-cell sequencing and transfection to identify neoantigens is well-understood, routine and conventional (Pastor, Fernando, et al. "An RNA toolbox for cancer immunotherapy." Nature Reviews Drug Discovery 17(10):751-767 (2018)).
When the claims are considered as a whole, they do not integrate the abstract idea into a practical application; they do not confine the use of the abstract idea to a particular technology; they do not solve a problem rooted in or arising from the use of a particular technology; they do not improve a technology by allowing the technology to perform a function that it previously was not capable of performing; and they do not provide any limitations beyond generally linking the use of the abstract idea to a broad technological environment. See MPEP 2106.05(a) and 2106.05(h). [Step 2B: claims 18, 29-30, 35, 41, 43, 47-60 - No]
Conclusion: Instant claims are directed to non-statutory subject matter
For these reasons, the claims in this instant application, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the abstract idea, so instant claims 1-26 are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 18, 43, 47, 49-53, 55-57, and 59-60 are rejected under 35 U.S.C. 103(a) as being unpatentable over Olexiouk "Identification of small novel coding sequences, a proteogenomics endeavor." Proteogenomics 49-64 (2016) as evidenced by Lu "Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions." Clinical Cancer Research 20(13):3401-3410 (2014) in view of Ji "RibORF: Identifying genome‐wide translated open reading frames using ribosome profiling." Current protocols in molecular biology 124(1):e67 (2018), as cited on the attached Form PTO-892.
Independent claim 18 recites "a method for identifying neoantigens, comprising: (a) performing Ribosomal profiling (Ribo-seq) on a sample, thereby generating Ribo-seq dat" which Olexiouk teaches an integrative analyses of various types of omics data using ribosome profiling (Ribo-Seq) to contribute to cancer research and personalized medicine to humans (pg. v para. 3); wherein ribosome profiling is capable of capturing sample specific genomic variations, enabling focused neo-antigen identification (pg. 49 para. 1);
Independent claim 18 recites "(c) searching the nuORF database for matches with a MHC I immunopeptidome data set, wherein the matches between the nuORF database and the MCH I immunopeptidome dataset are identified as neoantigens" which Olexiouk teaches as a neoantigen identification workflow that includes tumor cells being sequenced to identify genomic variations specific in tumor cells, with a database is generated consisting of neo-antigen candidates, and in silico algorithms can be used to predict MHC antigen presentation, resulting in a more confident dataset (pg. 53 Fig. 4.1) by filtering the database of neo-antigen candidates (pg. 52 col. 2 para. 2) using a technique of library screening (pg. 3401 para. 4 Lu) and in-silico analysis identify candidate T-cell epitopes that were predicted to bind to the MHC class I molecules (pg. 3402 col. 1 para. 1 Lu) as evidenced by Lu.
Dependent claim 43 recites "a T cell specific for a neoantigen identified by the method of claim 18". Dependent claim 47 recites "a neoantigen library comprising neoantigens identified by the method of claim 18" which Olexiouk teaches as combining transcriptomics sequencing techniques (RNA-Seq) to identify mutated proteins absent in native cells with proteomics identification of major histocompatibility complex (MHC) presented antigens, identifying tumor specific genomic variation trough RNA-Seq, followed by in-silico filtering by algorithms to predict MHC antigen presentation and the construction of a database consisting of possible neoantigen (pg. 52 col. 2 para. 2); wherein all human cells present peptide antigens on MHC molecules, which interact with T-cell receptors (TCR), present on the plasma membrane of T-cells (i.e. reading on the identified MHC presented neoantigens binding to a specific T-cell) (pg. 52 col. 1 para. 2).
Dependent claim 49 recites "wherein the MHC I immunopeptidome dataset of step (c) is obtained using mass spectrometry" which Olexiouk teaches as MS -based proteomic studies comparing the obtained spectra against protein databases of known/predicted proteins, resulting in a high number of unidentified spectra used to map novel peptides absent from the used protein database (pg. 51 col. 2 para. 2).
Dependent claim 50 recites "wherein the sample is a subject-specific sample, a tissue- specific sample, a disorder-specific sample, or a disease-specific sample" which Olexiouk teaches as identifying patient-specific protein forms (i.e. comprising T-cell receptor pairs) and getting a better picture of molecular mechanisms of disease for precision and personalized medicine (pg. 21 para. 1).
Dependent claim 51 recites "wherein the tissue-specific sample is a cancer tissue sample" which Olexiouk teaches as variations obtained in a single cell in cancer research may result in tumorous behavior and where these variations are frequently distinct between different tumor types, capturing sample specific variations (pg. 60 col. 1 para. 2).
Independent claim 57 recites "a method for identifying neoantigens, comprising: (a) performing Ribosomal profiling (Ribo-seq) on a tumor sample and a non-tumor sample" which Olexiouk teaches an integrative analyses of various types of omics data using ribosome profiling (Ribo-Seq) to contribute to cancer research and personalized medicine to humans (pg. v para. 3); wherein ribosome profiling is capable of capturing sample specific genomic variations, enabling focused neo-antigen identification (pg. 49 para. 1); wherein a neoantigen identification workflow that includes tumor cells being sequenced to identify genomic variations specific in tumor cells, with a database is generated consisting of neo-antigen candidates, and in silico algorithms can be used to predict MHC antigen presentation, resulting in a more confident dataset (pg. 53 Fig. 4.1); wherein functional analysis of mutated genes were performed for tumor-derived cell lines (MCF7, Jurkat, and Huh7 cell lines) and non-tumor derived cell line (CCD18) (pg. 106 Fig. 7.7).
Independent claim 57 recites "(c) searching the nuORF database for predicted tumor nuORF matches with a MHC I immunopeptidome dataset, thereby identifying the matched predicted tumor nuORFs as tumor neoantigens"; dependent claim 59 recites "wherein the tumor sample and the non-tumor sample are obtained from a patient, thereby making the identified tumor neoantigens patient-specific tumor neoantigens"; dependent claim 60 recites tumor neoantigen library comprising tumor neoantigens identified by the method of claim 57" which Olexiouk teaches as a neoantigen identification workflow that includes tumor cells being sequenced to identify genomic variations specific in tumor cells, with a database is generated consisting of neo-antigen candidates, and in silico algorithms can be used to predict MHC antigen presentation, resulting in a more confident dataset (pg. 53 Fig. 4.1) by filtering the database of neo-antigen candidates (pg. 52 col. 2 para. 2) using a technique of library screening (pg. 3401 para. 4 Lu) and in-silico analysis identify candidate T-cell epitopes that were predicted to bind to the MHC class I molecules (pg. 3402 col. 1 para. 1 Lu) as evidenced by Lu.
Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02)
Regarding claims 18 and 57, Olexiouk does not teach "(b) conducting hierarchical ORF prediction on the Ribo-seq data generated in step (a), thereby generating a novel untranslated open reading frame (nuORF) database comprising predicted nuORFs" or "predicted tumor nuORFs".
Olexiouk teaches "generating a novel untranslated open reading frame (nuORF) database comprising predicted nuORFs" or "predicted tumor nuORFs" as ORFs in 5’ untranslated regions being identified with higher ribosome protected fragments intensity than the main canonical downstream translated ORF (pg. 55 col. 1 para. 1); wherein a database was created containing alterative translation initiation sites and their associated ORF identified by Ribo-Seq (pg. 55 col. 1 para. 1); wherein the identification of ribosome bound RNA's allows the creating of a custom search database (pg. 7 col. 2 para. 2); wherein a neoantigen identification workflow that includes tumor cells being sequenced to identify genomic variations specific in tumor cells, with a database is generated consisting of neo-antigen candidates, and in silico algorithms can be used to predict MHC antigen presentation, resulting in a more confident dataset (pg. 53 Fig. 4.1).
Furthermore, the "conducting hierarchical ORF prediction on the Ribo-seq data" is taught by Ji as a computational pipeline named RibORF to systematically identify translated open reading frames (pg. 1 para. 1); wherein predicted translated P-values representing the binary classification of candidate ORFs (i.e. hierarchical ORF prediction); wherein values can be smaller than 0 or be great than 1, with P values closer to 1 represents that the ORF is likely to be translated (i.e. the further away from 1 greater is the probability of finding untranslated ORFs); wherein users can select the cutoff P-value to define translated or untranslated ORFs (pg. 9 para. 2).
Regarding claim 52, Olexiouk does not teach "wherein conducting hierarchical ORF prediction comprises implementing a computational algorithm." Regarding claim 53, Olexiouk does not teach "wherein the computational algorithm is RibORF." However, Ji teaches claims 52-53 as a computational pipeline named RibORF to systematically identify translated open reading frames (pg. 1 para. 1).
Regarding claim 55, Olexiouk does not teach "wherein ORFs with a RibORF score greater than 0.7 are selected, ORFs having two reads and a RibORF score of 0.9 are selected, and/or ORFs having 250 reads and a RibORF score of 0.7 are selected." However, Ji teaches it as a computational pipeline named RibORF to systematically identify translated open reading frames (pg. 1 para. 1); wherein predicted translated P-values representing the binary classification of candidate ORFs (i.e. hierarchical ORF prediction); wherein values can be smaller than 0 or be great than 1, with P values closer to 1 represents that the ORF is likely to be translated (i.e. the further away from 1 greater is the probability of finding untranslated ORFs).
Regarding claim 56, Olexiouk does not teach "wherein conducting hierarchical ORF prediction comprises: (i) determining trinucleotide codon periodicity; (ii) correcting offsets based on sequencing read length; (iii) combining sequencing reads; (iv) selecting for reads with NTG start codons; (v) selecting for reads with TAA/TGA/TAG stop codons; and/or (vi) annotating reads." However, Ji teaches it as output files generated by the algorithm containing fractions of reads in each nucleotide of codons (1st, 2nd, and 3rd) with 3-nt periodicity, with a high percentage of reads in 1st nucleotides of codons (pg. 6 para. 4).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 18, 43, 47, 49-53, 55-57, and 59-60, one of ordinary skill in the art would be motivated to apply the teachings by Ji to the method by Olexiouk because Ji teaches using ribosome profiling and computational tools for pervasive translation in putative ‘noncoding’ regions, such as 5 UTRs (untranslated regions) (pg. 1 para. 1 Ji). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for studying non-canonical translation events in biological functional roles.
Regarding the selection of score cutoffs in claim 55, MPEP 2144.05 “Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions (E9_R-01.2024)” affirms that one of ordinary skill in the art would be motivated to optimize a parameter when there is evidence in the record that the prior art recognized that. Thus the teachings by Ji would motivate one of ordinary skill in the art to modify the RibORF score cutoff to improve the quality of and optimize the data being identified by the method because Ji teaches that users can select the cutoff P-value to define translated or untranslated ORFs (pg. 9 para. 2).
Claim 41 is rejected under 35 U.S.C. 103(a) as being unpatentable over Olexiouk and Ji as applied to claim 18 above further in view of Hu "A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens." Blood, The Journal of the American Society of Hematology 132(18):1911-1921 (2018), as cited on the attached Form PTO-892.
Dependent claim 41 recites "further comprising identifying T cells obtained from the sample that are specific for one or more of the identified neoantigens."
Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02)
Regarding claim 41, neither Olexiouk nor Ji teaches the recited limitation. However, Hu teaches it as a system to identify viral antigen-specific TCRs (pg. 1911 para. 1).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 41, one of ordinary skill in the art would be motivated to apply the teachings by Hu to the method by Olexiouk and Ji because Hu teaches to select the identified subject-specific TCR pairs that bind specific neoepitopes to guide the design of effective T-cell-based immunotherapies (pg. 1911 para. 1 Hu). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigating neoantigens.
Claims 48 and 58 are rejected under 35 U.S.C. 103(a) as being unpatentable over Olexiouk and Ji as applied to claims 18 and 57 above further in view of Tang "neoantigenR: an annotation based pipeline for tumor neoantigen identification from sequencing data." bioRxiv 171843 (2017), as cited on the attached Form PTO-892.
Dependent claim 48 recites "further comprising step (d) comparing the identified neoantigens to an annotated proteome database to identify a set of unannotated identified neoantigens from among the identified neoantigens."
Dependent claim 58 recites "further comprising step (d) comparing the identified tumor neoantigens to an annotated proteome database to identify a set of unannotated identified tumor neoantigens from among the identified tumor neoantigens."
Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02)
Regarding claim 48, neither Olexiouk nor Ji teaches the recited limitation. However, Tang teaches it as a method that relies on canonical protein sequence database for neoepitope discovery; wherein after performing the NCBI protein search to remove annotated neoepitopes, unannotated and novel neoepitopes were used as candidates for subsequent neoantigen identification (pg. 7 para. 2).
Regarding claim 58, neither Olexiouk nor Ji teaches the recited limitation. However, Tang teaches it as a method that relies on canonical protein sequence database for neoepitope discovery; wherein after performing the NCBI protein search to remove annotated neoepitopes, unannotated and novel neoepitopes were used as candidates for subsequent neoantigen identification (pg. 7 para. 2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 48 and 58, one of ordinary skill in the art would be motivated to apply the teachings by Tang to the method by Olexiouk and Ji because Tang teaches a one-stop prediction of disease-specific alternative spliced neoepitopes that could be used to directly screen for neoantigens in the future allowing the evaluation of tumor-specific epitopes in a wide range of sequencing technologies (pg. 8 para. 2 Tang). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for neoantigen identification from sequencing data.
Claim 54 is rejected under 35 U.S.C. 103(a) as being unpatentable over Olexiouk and Ji as applied to claim 18 above further in view of Erhard "Improved Ribo-seq enables identification of cryptic translation events." Nature methods 15(5):363-366 (2018), as cited on the attached Form PTO-892.
Dependent claim 54 recites " wherein the computational algorithm is PRICE."
Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02)
Regarding claim 54, neither Olexiouk nor Ji teaches the recited limitation. However, Erhard teaches as PRICE - a computational method that models experimental noise to enable researchers to accurately resolve overlapping short open reading frames and noncanonical translation initiation and predict short open reading frames-derived peptides efficiently enter the MHC I presentation pathway (pg. 363 col. 1 para. 1).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 54, one of ordinary skill in the art would be motivated to apply the teachings by Erhard to the method by Olexiouk and Ji because Erhard probabilistic inference of codon activities by an EM algorithm (PRICE) to model the stochastic processes involved in Ribo-seq (pg. 363 col. 2 para. 3 Erhard). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for analyzing Ribo-seq data.
Claims 29-30, and 35 are rejected under 35 U.S.C. 103(a) as being unpatentable over De Simone "Single cell T cell receptor sequencing: techniques and future challenges." Frontiers in Immunology 9:1638 (2018) in view of Hu, as cited on the attached Form PTO-892.
Independent claim 29 recites "a method of identifying subject-specific T cell receptor (TCR) pairs suitable for subject-specific cancer therapy, the method comprising: (a) isolating from a sample of the subject a population comprising T cells; (b) determining by single cell sequencing the sequences encoding the TCR pairs on individual cells in the population isolated in step (a)" which De Simone teaches as the assembling of full-length TCR sequences from single cell RNA-seq data allowing for alpha and beta chain sequence pairing and for the integration of clonality information with the whole transcriptome of a single T cell (pg. 5 col. 1 para. 1); wherein said technology is able to identify the T cell repertoire in cancer cases (pg. 3 col. 2 para. 2); wherein single cell RNA-seq technologies differ in the cell isolation methods, cDNA synthesis and amplification, and in the library preparation steps (pg. 3 col. 2 para. 3).
Dependent claim 35 recites "wherein the sample is a subject-specific sample, a tissue-specific sample, or a disorder-specific sample, or a disease- specific sample" which De Simone teaches as T cell repertoire investigation concluding that Treg cells do not present clonal enrichment in the tumor suggesting recruitment from the periphery while CD8+ T cells are clonally enriched suggesting clonal activation and expansion inside the tumor (pg. 5 col. 2 para. 1).
Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02)
Regarding claim 29, De Simone does not teach "(c) transfecting or transducing T cell lines deficient in endogenous TCRs with the sequences encoding individual TCR pairs determined in step (b); and d) using the T cell lines from step (c) to assay binding of the subject-specific TCR pairs to subject-specific neoepitopes and selecting the TCR pairs that bind to the subject-specific neoepitopes, the selected TCR pairs comprising the identified subject-specific TCR pairs" which Hu teaches as a system to identify viral antigen-specific TCRs and to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs (pg. 1911 para. 1); wherein the method cloned and expressed the 6 most dominant TCRs from each donor and transduced them into reporter cells (pg. 1915 col. 2 para. 2); wherein neoantigen-specific TCR sequences are identified for a newly characterized neoantigen via binding assay that identified binding affinity of IC50=106.5 nM (pg. 1918 Fig. 5B).
Regarding claim 30, De Simone does not teach "wherein the subject-specific neoepitopes are expressed on HLA molecules on a cell" which Hu teaches as potential epitopes arising from indel mutations to HLA class I (pg. 1913 col. 2 para. 2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 28, one of ordinary skill in the art would be motivated to apply the teachings by Hu to the method by De Simone because Hu teaches to select the identified subject-specific TCR pairs that bind specific neoepitopes to guide the design of effective T-cell-based immunotherapies (pg. 1911 para. 1 Hu). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigating neoantigens based on sequencing data.
Conclusion
No claims are allowed.
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/F.F.L./Examiner, Art Unit 1685
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686