DETAILED ACTION
Notice of Pre-AIA or 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 .
Claim Status
Claims 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 are pending and under examination.
Claims 1, 4-6, 8, 10, 14, 18, 20-21, 23, and 25 are amended.
Claims 1 and 5 are objected to.
Claims 1 and 14 are independent.
No claims are new or withdrawn.
Claims 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 are rejected.
Office Action Outline
Rejections applied
Abbreviations
X
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
X
102, 103
JE
Judicial Exception
X
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the10/28/2022 filing receipt, this application is a 371 of PCT/KR2021/000116, filed 01/06/2021. Additionally, this application claims priority to Korean application KR10-2020-0002260, filed 01/07/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. See paper entered 07/07/2022.
Drawings
The drawings are objected to as they fail to comply with 37 CFR 1.84(t) in that the drawings sheets lack numbering. The 13 drawing sheets filed 07/07/2022 should be labelled 1/13, 2/13, 3/13, ..., 13/13 because the sheets of drawings should be numbered in consecutive Arabic numerals, starting with 1. These numbers, if present, must be placed in the middle of the top of the sheet, but not in the margin. The numbers can be placed on the right-hand side if the drawing extends too close to the middle of the top edge of the usable surface. The drawing sheet numbering must be clear and larger than the numbers used as reference characters to avoid confusion. The number of each sheet should be shown by two Arabic numerals placed on either side of an oblique line, with the first being the sheet number and the second being the total number of sheets of drawings, with no other marking. See MPEP 608.02(v) and 37 CFR 1.84(t).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The abstract of the disclosure is objected to because of overall grammatical issues in the sentence "Specifically, provided are a method and system for screening neoantigens derived from a gene of which expression is essential for survival of a cancer cell and/or a is homogeneously expressed in all cells in cancer tissue as a diagnostic and/or therapeutic target, and uses of neoantigens." Possibly amending the abstract to recite, e.g., "Specifically, provided are a method and system for screening neoantigens derived from a gene, of which expression is essential for survival of a cancer cell and/or which expression is homogeneous in all cells in cancer tissue, and uses of the neoantigens as diagnostic and/or therapeutic targets" may overcome the objection. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The specification is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraphs [0075], [0097(twice)], [0124], and [0138]. 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.
The specification is further objected to for not complying with CFR 1.58(b) because Table 2 at [0136] and Table 3 at [0151] are illegible, in that the characters are blurry. 37 CFR 1.52(a)(1)(iv) requires all papers, other than drawings, that are submitted on paper or by facsimile transmission, and are to become a part of the permanent United States Patent and Trademark Office records in the file of a patent application must be plainly and legibly written. Additionally, 37 CFR 1.58(b) asserts tables must be presented in compliance with 37 CFR 1.52(a) and (b), and should have the lines and columns of data closely spaced to conserve space, consistent with a high degree of legibility. See MPEP § 608.01, 37 CFR 1.58(b), 1.52(a) and (b), and 1.125.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites "collecting neoantigens," which is interpreted as reading on embodiments including "selecting neoantigens" when considering specification [0023], as well as claim 8. Claim 14 recites a like term which is interpreted similarly.
Claim Objections
Claims 1 and 5 are objected to because of the following informalities:
In the "wherein the model for predicting" element of claim 1, the recitation of "causes cell apoptosis" should be amended to "causes cancer cell apoptosis."
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 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. Claims depending from rejected claims are rejected similarly, unless otherwise noted, and any amendments in response to the following rejections should be applied throughout the claims, as appropriate.
In claim 1, in the "obtaining neoantigens..." and later-recited similar instances, it is unclear whether the use of this verb causes the claim to read on physical or virtual obtaining or both. The specification at, for example, [21-23] does not clearly resolve the interpretation. The rejection may be overcome by clarifying which embodiments are within a BRI. For compact examination, virtual only is assumed, e.g. "obtaining" as in "identifying." The recited "collecting" similarly renders the claim indefinite. Claims 21 and 25 are similarly indefinite.
In the "obtaining neoantigens of a cancer patient" element of claim 1, it is unclear if the recited "sequencing data" in the recitation "based on sequencing data" is the same sequencing data as in the "obtaining sequencing data" element of claim 1. If the intention is to be the same sequencing data, then the element "obtaining neoantigens of a cancer patient" of claim 1 should be amended to "based on the sequencing data;" the claim will be interpreted as such.
In claim 1, the recited "the gene essential for cancer cell survival" (first recited in the element beginning "wherein the model") requires but lacks clear antecedent basis. If this recitation refers to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim element, this is not clear. This rejection might be overcome by for example amending to recite the article "a" instead of "the."
In an issue related to the lack of antecedent basis issue directly above, in claim 1, the relationship is unclear between the plural "genes essential for cancer cell survival" (recited in the element beginning with "identifying genes") and the singular "the gene essential for cancer cell survival" (recited in the claim 1 elements beginning "wherein the model," "wherein the obtaining," and "collecting neoantigens.") It is not clear which singular gene (of the plurality genes) is being referred to in "the gene essential for cancer cell survival." The issues extends to claims 4 and 6, which respectively recite "the identified gene essential for cancer cell survival" and "the gene essential for cancer cell survival."
Clarifying the distinction between the plural (genes essential for cancer cell survival) and the singular (gene essential for cancer cell survival) in claim 1 might help overcome the rejection.
In the "obtaining neoantigens of a cancer patient" element of claim 1, it is unclear in what way the "comparing a sequence of a cancer cell and a sequence of a normal cell, based on sequencing data obtained from the cancer patient" would be performed when/if the sequencing data has been obtained by single cell sequencing in the "obtaining sequencing data" element. Also unclear is if the sequence of a normal cell is obtained from sequencing data of a cancer patient.
In the element beginning with "wherein the model for predicting cell survival" of claim 1, the connection is unclear between the terms "expression" and "removal" in the recitation "... a gene of which expression reduction or removal causes...." It is unclear if removal refers to expression or not. The rejection might be overcome by possibly amending to recite, e.g., "... a gene of which expression reduction or removal of the gene causes..." as discussed in Specification [0085] and [0093]. Claim 14 (in the "to generate a model for predicting cell survival" element) is rejected similarly.
In a rejection somewhat similar to the issue directly above, in claim 4, the connection is unclear between the terms "expression level" and "removed" in the recitation "... when its expression level is decreased or removed;" it appears a term is missing. The rejection might be overcome by possibly amending to recite, e.g., "... when its expression level is decreased or the gene is removed;" as discussed in Specification [0085] and [0093].
In claim 9 the recited "the neoantigen" requires but lacks clear antecedent basis. If this recitation refers to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim element, this is not clear. This rejection might be overcome by for example amending "the neoantigen" to recite "the neoantigens"
In claim 10, the recited "the neoantigen" requires but lacks clear antecedent basis, and further the connection between the plural "the neoantigens" and the singular "the neoantigen" is unclear in the recitation "determining of binding affinity of the neoantigens to HLA of an antigen-presenting cell comprises obtaining prediction of the binding affinity by inputting a sequence of the neoantigen." It is not clear if the binding affinity is determined by the neoantigens or a neoantigen.
The recitations of "neoantigens" in claims 9, 10, and 13 are unclear as to if they are collected neoantigens or obtained neoantigens. Possibly amending the instances of "the neoantigens" in claims 9, 10, and 13 to "the collected neoantigens" would help overcome the rejection.
Claim 14 is rejected as directly reciting a machine and a process in the same claim. A claim to a machine, e.g. here a "system," cannot directly recite a process step such as the claim-14-recited "wherein the... processor executes..." It may suffice to add "configured to" before this process step so as to properly focus on claimed structure. However, regarding any software-embodied process steps, it should be clear that it is the stored instructions which are configured according to the recited process steps. MPEP 2173.05(p).II pertains regarding a claim directed to both product and process.
In the "to generate a model" and "to identify a gene essential" elements of claim 14, there are respective recitations for "obtains neoantigens...of a cancer patient" and "obtain a neoantigen ...of a cancer patient." It is unclear if this is the same patient or not.
Claim 14 recites "comparing gene expression profile of a cancer patient and gene expression profile of a normal cell." It is unclear if the gene expression profile from the cancer patient is from a normal cell or a cancer cell. Possibly amending to "comparing gene expression profile of a cancer cell of a cancer patient and gene expression profile of a normal cell" would help to overcome the rejection.
In claim 25, the recited "the neoantigen load" requires but lacks clear antecedent basis. If this recitation refers to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim element, this is not clear. This rejection might be overcome by for example amending "the neoantigen load" to recite "a neoantigen load."
In claim 26, the recited "the obtained neoantigen load" lacks antecedent basis. If this recitation refers to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim element, this is not clear. This rejection might be overcome by for example amending "the obtained neoantigen load" to recite "the measured neoantigen load."
In claim 26, the relationship is unclear between "a neoantigen load" and "a control group" in the recitation "and a neoantigen load obtained from a control group consisting of cancer patients." It is not clear in what way a singular neoantigen load would be obtained from a plurality of cancer patients.
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 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04(a)). Note, the MPEP at 2106.04(a)(2) & 2106.04(b) further explains that abstract ideas and laws of nature are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
• certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people);
• mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information);
• laws of nature and natural phenomena are naturally occurring principles and/or relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1:
Claims 1-2, 4-6, 8-11, 13, 21, 23, and 25-26 are directed to a 101 process, here a method. Claims 14 and 16-20 are directed to a 101 machine or manufacture, here a system. As such, claims 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 are directed to a related method and system, which fall under categories of statutory subject matter. (See MPEP § 2106.03). (Step 1: Yes.)
Step 2A, Prong One:
The claims are found to recite abstract ideas in the form of mental processes and mathematical concepts, as well as a law of nature, as follows:
Mental processes and mathematical concepts:
Independent claim 1 recites a method for performing mental processes and mathematical concepts of:
• identifying genes essential for cancer cell survival using a model
• generating a model by learning a relationship between gene expression and apoptosis
• identifying a gene essential for cancer cell survival for which expression reduction or removal of the gene causes apoptosis
• obtaining neoantigens by comparing sequences of a cancer cell and a normal cell
• collecting (interpreted as selecting) neoantigens derived from the gene essential for cancer cell survival
Independent claim 14 recites a system for executing similar mental processes and mathematical concepts as recited in independent claim 1.
Dependent claims 2, 6, 8, 10, 17, 19-20, and 26 recite mental processes and mathematical concepts as follows:
• determining binding affinity (claim 2)
• determining if the identified gene is homogeneously expressed in cancer cells (claim 6)
• selecting nonsynonymous mutations (claim 8)
• obtaining prediction of the binding affinity of the neoantigens to HLA of an antigen presenting cell (APC) (claim 10)
• inputting a sequence of the neoantigen to a model (claim 10)
• generating the model by learning data regarding interaction between amino acids of a peptide and amino acids of an HLA which is MHC class I or II (claims 10 and 19)
• learn relationships between gene expression and apoptosis and between neoantigen and HLA of an APC (claim 17)
• preparing an anti-cancer vaccine (in part) by selecting a peptide sequence (claim 20)
• comparing neoantigen loads (claim 26)
Dependent claims furthering limiting the independent claims are as follows:
• claim 4 further limits the identified gene of claim 1
• claim 5 and 18 further limit what data the relationship is based on of claims 1 and 14
• claim 9 further limits the neoantigen of claim 1
• claim 11 further limits the APC of claim 10 to a macrophage, dendritic and/or B cell
• claims 13 and 16 further limit the neoantigen to having binding affinity when a CNN-MHC value is> 0.5 respectively of claims 10 and 14.
• claim 23 further limits the peptide sequence of claim 21 to having Kyte-Doolittle GRAVY < 0 and Instalndex < 40
Law of nature: Claims 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 recite a law of nature in the correlation between the naturally occurring genes and expressed neoantigens of those genes of a cancer patient.
Step 2A Prong One Summary: The claims recite mental processes and mathematical concepts as well as a law of nature. When considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in the claims (e.g., identifying genes; generating a model; obtaining neoantigens; collecting (selecting) neoantigens; etc.) are directed to processes that may be performed in the human mind, or with pen and paper, as there are no particular limitations recited in the claims which would prevent the mental processes from being performed in the human mind or with pen and paper. The claims recite inherent mathematical processes in e.g., generating a model; determining binding affinity; comparing neoantigen load; etc., while details of which are not explicitly shown, are discussed in the Specification, e.g., at [0076], [0091], [0107], [0129-0131], etc. Such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Additionally, a law of nature is recited in the claims in the correlation between the naturally occurring genes and expressed neoantigens of those genes of a cancer patient. Therefore, the claims recite elements that constitute a judicial exception in the form of an abstract idea(s) and law of nature. (Step 2A, Prong One: Yes.)
Step 2A, Prong Two:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions (abstract ideas in this instance) then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see MPEP § 2106.04(d)]. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
MPEP § 2106.04(d)(I) lists the following five example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) 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).
(2) 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).
(3) 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).
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c).
(5) 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).
The claims recite additional elements as follows:
Additional elements of data gathering steps: obtaining sequence data (an exome, a transcriptome, a single cell transcriptome, a peptidome, or an entire genome) (claim 1); the gene expression profile (claims 14 and 20); obtaining sequences (claim 21); and measuring the neoantigen load in a sample (claim 25). Data gathering steps are additional elements which perform functions of inputting, collecting, and outputting the data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology (see MPEP § 2106.04(d)(I)).
Additional elements of computer components: Claim 14 recites an additional element of a memory and processor. The claims require only generic computer components, which do not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP § 2106.04(d)(1) and MPEP § 2106.05(f)).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception 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) a treatment, (3) a particular machine, or (4) a transformation is clear in the record. For example, regarding the first consideration for improvement at MPEP 2106.04(d)(1), the record, including the Specification, does not yet clearly disclose an explanation of improvement over the previous state of the technology field, and the claims do not yet clearly result in such an improvement. (Step 2A, Prong Two: No).
Step 2B analysis:
Because the additional claim elements do not integrate the abstract idea or law of nature into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering, inputting, and outputting steps: The additional elements of obtaining sequence data (an exome, a transcriptome, a single cell transcriptome, a peptidome, or an entire genome) (claim 1); the gene expression profile (claims 14 and 20); obtaining sequences (claim 21); and measuring the neoantigen load in a sample (claim 25) do not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; determining the level of a biomarker in blood by any means; using polymerase chain reaction to amplify and detect DNA; detecting DNA or enzymes in a sample; analyzing DNA to provide sequence information or detect allelic variants; and amplifying and sequencing nucleic acid sequences, [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity. Additionally, the measuring neoantigen load is shown to be conventional by the following reference(s):
Schumacher (Current opinion in immunology, vol. 41, pp.98-103 (2016); cited on the attached Form PTO-892) presents a review on neoantigens in the cancer genome and discusses neoantigen load (p.98-99).
Additional elements of computer components: The additional elements of a memory and processor (claim 14) do not cause the claims to rise to the level of significantly more than the judicial exception, and as such do not provide an inventive concept; these are conventional computer components.
All limitations of claims 1-2, 4-6, 8-11, 13-14, 16-21, 23, and 25-26 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. (Step2B: NO.)
Therefore, the claims, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non patent-eligible 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
103 (1 of 3):
Claims 1-2, 4-6, 8-11, 13-14, and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Bulik-Sullivan (WO 2018/227030 A1; cited on the attached PTO Form 892) in view of Wang (EBioMedicine, vol. 50, pp.67-80 (2019); cited on the attached PTO Form 892).
Regarding the claim 1 and 14 element for obtaining sequencing data of a cancer patient, and comparing a sequence from a cancer sell and a normal cell, and collecting (interpreted as selecting) neoantigens, and the claim 20 element of a gene expression profile, Bulik-Sullivan discloses an optimized approach for identifying and selecting neoantigens for personalized cancer vaccines [0009]. Bulik-Sullivan shows exome, transcriptome, and/or whole genome tumor nucleotide sequencing data from tumor cells and normal cells of each patient are obtained. The tumor nucleotide sequencing data is used to obtain peptide sequences of each of a set of neoantigens identified by comparing the nucleotide sequencing data from the tumor cells and the nucleotide sequencing data from the normal cells. The peptide sequence of each neoantigen for the patient includes at least one alteration that makes it distinct from a corresponding wild-type parental peptide sequence identified from the normal cells of the patient [0010].
Regarding the claims 2, 14, and 17 elements for determining and modeling binding affinity of the neoantigens to HLA of an antigen-presenting cell, and the claim 11 element of the APC is a dendritic cell, macrophage, or B cell, Bulik-Sullivan shows a method for selecting neoantigens that have an increased likelihood of being capable of being presented to naïve T cells by professional antigen presenting cells (APCs) relative to unselected neoantigens based on the presentation model, optionally wherein the APC is a dendritic cell (DC) [00134]. Bulik-Sullivan shows measurements or predictions of binding affinity between a given MHC allele and a given peptide [00273].
Regarding the claim 8 element for non-synonymous mutations, and the claim 9 element of the neoantigen is specific to the cancer patient, Bulik-Sullivan shows a (neoantigen) vaccine can be compiled so that the selection, number and/or amount of neoantigens present in the composition is/are tissue, cancer, and/or patient-specific [00241]. Bulik-Sullivan shows number of non-synonymous mutations in each patient, and the proportion of sample patients that have the given number of non-synonymous mutations [00464]
Regarding the claims 10 and 19 element for predicting binding affinity of a peptide by learning data regarding interactions between amino acids of a peptide and of an HLA, the HLA being class I or II, the claims 13 and 16 element for CNN-MHC, and the claim 21 elements for preparing an anticancer vaccine comprising the neoantigen peptide sequences of 9-30 amino acids, Bulik-Sullivan shows the training data set may further include data associated with peptide-MHC binding affinity measurements for at least one of the isolated peptides [00116]. Bulik-Sullivan shows obtaining a tumor vaccine comprising the set of selected neoantigens [00143] and at least one of neoantigens in the set of selected neoantigens, when in polypeptide form, may include at least one of: a binding affinity with MHC with an IC50 value of less than l000nM, for MHC Class I polypeptides a length of 8-15, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, for MHC Class II polypeptides a length of 6-30, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids [00144]. Bulik-Sullivan shows convolutional neural networks (CNN) [00370], and each MHC allele is associated with a separate network model, and NNh(·) denotes the output(s) from a network model associated with MHC allele h [00371].
Bulik-Sullivan does not show the claims 1 and 14 elements for identifying genes essential for cancer cell survival using a model for predicting cell survival dependency generated by learning a relationship between gene expression and apoptosis, and identifying the gene essential for cancer cell survival as a gene for which expression reduction or removal of the gene causes cell apoptosis, the claim 4 element for apoptosis when expression is decreased or removed, the claim 5 element for cancer cell line data, and the claim 6 element for homogeneous expression. These elements are taught below by Wang.
Regarding the claims 1 and 14 elements for identifying genes essential for cancer cell survival using a model for predicting cell survival dependency generated by learning a relationship between gene expression and apoptosis, and identifying the gene essential for cancer cell survival as a gene for which expression reduction or removal of the gene causes cell apoptosis, the claim 4 element for apoptosis when expression is decreased or removed, the claims 5 and 18 element for cancer cell line data, and the claim 6 element for homogeneous expression, Wang shows a study using systematic comparison for CRISPR- and shRNA-based gene essentiality profiles across a larger collection of cancer cell lines, and development of a computational approach called combined gene essentiality score (CES) that provides an effective data integration strategy to allow improved estimation of cancer dependency maps (p.68, col.2, ¶ 3). Wang shows GAPDH is a constitutively expressed gene that encodes the enzyme for regulating cell energy metabolism, the inhibition of which leads to apoptosis (p.72, bridging cols.1-2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the neoantigen screening method of Bulik-Sullivan and the identification of essential cancer genes of Wang to come to a method for neoantigen discovery of essential cancer genes. This is because Wang states to improve the estimation of true essentiality, a computational approach was developed called combined gene essentiality score (Wang p.68), and that probing genetic dependencies of cancer cells can improve the understanding of tumor development and progression, while Bulik-Sullivan presents a high accuracy neoantigen discovery method. One would have had a reasonable expectation of success in modifying Bulik-Sullivan with Wang, because Bulik-Sullivan and Wang are generally drawn to related teaching concerning neoantigens, and one of ordinary skill in the art would have understood how to and would have been motivated to apply the teaching of Wang to the related teachings of Bulik-Sullivan, and as such, the combination would have been obvious.
103 (2 of 3):
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Bulik-Sullivan in view of Wang as applied to claims 1-2, 4-6, 8-11, 13-14, and 16-21 above, and in further view of Parvizpour (BioImpacts: BI, vol. 9(1), pp.45-56 (2019); cited on the attached PTO Form 892).
Neither Bulik-Sullivan or Wang, alone or in combination, show a peptide sequence with Kyte-Doolittle GRAVY< 0 and Instalndex < 40 of claim 23.
Regarding the claim 23 element of a peptide sequence with Kyte-Doolittle GRAVY< 0 and Instalndex < 40, Parvizpour shows a vaccine peptide targeting cancer antigens with an instability index (i.e., InstaIndex) of 35.89, indicating stability of the protein; and the grand average of hydropathicity (GRAVY) was found to be -0.062 (p.49, col.2, ¶ 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of screening neoantigens and preparing anti-cancer vaccines of Bulik-Sullivan and Wang with the InstaIndex and GRAVY scoring of Parvizpour, because the InstaIndex and GRAVY values provide useful information regarding peptide stability and hydrophobicity.
103 (3 of 3):
Claims 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Bulik-Sullivan in view of Wang as applied to claims 1-2, 4-6, 8-11, 13-14, and 16-21 above, and in further view of Matsushita (Cancer immunology research, vol. 4(5), pp.463-471 (2016); cited on the attached PTO Form 892).
Neither Bulik-Sullivan or Wang, alone or in combination, show a neoantigen load (claim 25) nor comparing the neoantigen load and neoantigen loads from a group with confirmed treatment prognosis (claim 26).
Regarding the claim 25 element of a neoantigen load, and the claim 26 element for a neoantigen load from group with confirmed treatment prognosis, Matsushita shows a study which includes using neoepitope load (i.e., neoantigen load) in determining prognosis in clear cell renal cell carcinoma (ccRCC) patients. Matsushita shows findings that ccRCC patients with a high potential neoepitope load and higher-than-median HLA or b2M expression tended to have a better prognosis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of screening neoantigens and preparing anti-cancer vaccines of Bulik-Sullivan and Wang with the use of neoantigen loads of Matsushita, because Matsushita demonstrates that neoantigen load, antigen presentation machinery, and immune signatures in the tumor do influence the prognosis of patients with ccRCC (p.470, col.2).
Conclusion
No claims area allowed.
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/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686
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