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 .
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 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.
Withdrawal of Objections and Rejections
Applicant's response, filed 12/19/2025, has been fully considered.
In view of the amendment and remarks from 12/19/2025, the specification objections, claim objections and the rejection of the following claims are withdrawn:
claims 56-68 and 83-85 under 35 USC § 112(b)
claims 30-31, 35-36, 42-46, 48, 51-64, 66, and 81-84 under 35 USC § 102
claims 38-41 and 49-50 under 35 USC § 103
The following rejections and/or objections are either maintained or newly applied for claims 30, 32-37, 39-68 and 81-85. They constitute the complete set applied to the instant application. Herein, "the previous Office action" refers to the Non-Final Rejection of 10/01/2025.
Status of the Claims
Claims 30, 32-37, 39-85 are pending.
Claims 69-80 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, as set forth in the Non-Final Office Action dated 10/01/2025.
Claims 1-29, 31 and 38 are cancelled.
Claims 30, 32-37, 39-68 and 81-85 are rejected.
Priority
This US Application 17/481,243 (09/21/2021) is a CON of 15/550,286 (08/10/2017) which is a 371 of PCT/EP16/52684 (02/09/2016) and claims priority from PCT/EP15/53021 (02/12/2015), as reflected in the filing receipt mailed on July. 16, 2025. The claims to the benefit of priority are acknowledged and the effective filing date of claims 30, 32-37, 39-68 and 81-85 is 02/12/2015.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/29/21; 01/05/24; 03/06/24; 05/20/24; 07/24/24; 03/03/25; 07/11/25; and 12/19/25 were considered by the examiner.
Claim Interpretation
Regarding “comparing the MHC class II binding scores of the corresponding modified peptide and the abundance scores for the corresponding modified protein”. It is interpreted that both the MHC class II binding scores and the abundance scores are aspects involved in predicting immunogenicity as per the instant specification (pg. 25 lines 25-31). Therefore any concepts reading on comparing immunogenicity predictions also reads on comparing MHC class II binding scores and the abundance scores predictions. Furthermore, an "abundance score" is being interpreted as a measurement for the level of expression of a peptide or modified peptide.
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 41 is 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. Dependent claims are rejected similarly, unless otherwise noted below. Any newly recited portions are necessitated by claim amendment. The following issues cause the respective claims to be rejected under 112(b) as indefinite:
In claim 41, the recited "the mutation site(s)" requires but lack antecedent basis, rendering their claims indefinite because there is no previous recitations of "mutation site(s)" in claim 30 or 32, from which claim 41 depends on. To overcome this rejection, the claim may be amended to depend on claim 40.
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 30, 32-37, 39-68 and 81-85 are rejected under 35 USC § 101 because the claimed inventions are directed to one or more Judicial Exceptions (JEs) without significantly more. Regarding JEs, "Claims directed to nothing more than abstract ideas..., 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)). Any newly recited portions are necessitated by claim amendment.
101 background
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
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 30, 32-37, 39-68 and 81-85), which falls within one of the categories of statutory subject matter. [Step 1: 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
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows:
• "a) ascertaining a score for binding of a modified peptide comprising a fragment of a modified protein to one or more MHC class II molecules (its "MHC class II binding score)" (independent claims 30 and 32);
• "b) ascertaining a score (an "abundance score") for the modified protein based on a score for level of expression of a protein to which the one or more amino acid modifications are associated and a score for variant allele frequency of the modified protein" (independent claims 30 and 32);
• "c) predicting immunogenicity of the one or more amino acid modification based on the MHC class II binding score of the modified peptide and the abundance score of the modified protein" (independent claim 30);
• "c) performing steps a) and b) for two or more different immunogenic amino acid modifications" (independent claim 32);
• "d) selecting and/or ranking the two or more different immunogenic amino acid modifications by comparing the MHC class II binding scores of the corresponding modified peptide and the abundance scores for the corresponding modified protein" (independent claim 32);
• "selecting and/or ranking the two or more different immunogenic amino acid modifications comprises a selection and/or ranking of peptides comprising the two or more different immunogenic amino acid modifications for their immunogenicity" (claim 33);
• "wherein comparing the MHC class II binding scores and the abundance scores comprises ranking the two or more different amino acid modifications by their MHC class II binding scores and removing amino acid modifications for which the corresponding modified protein has an expression or abundance score of less than a given threshold" (claim 34);
• "wherein the MHC class II binding score reflects a probability for binding of the modified peptide to the one or more MHC class II molecules" (claim 37);
• "wherein the abundance score is determined by multiplying the score for level of expression of the protein to which the one or more amino acid modifications are associated with the score for variant allele frequency of the modified protein" (claim 39);
• "wherein the score for variant allele frequency is determined from a sum of detected sequence reads covering mutation site(s) corresponding to the amino acid modification(s) and carrying the amino acid modification(s) divided by a sum of all detected sequence reads covering the mutation site(s)" (claim 40);
• "wherein the score for variant allele frequency is determined from a sum of mutated nucleotides detected at the mutation site(s) corresponding to the one or more amino acid modifications divided by a sum of all nucleotides detected at the mutation site(s)" (claim 41);
• "selecting the modified peptide(s) from the two or more different modified peptides comprising the same amino acid modification(s) having a probability or having the highest probability for binding to one or more MHC class II molecules" (claim 46);
• "wherein a highest score for binding to one or more MHC class II molecules of the two or more different modified peptides comprising the same amino acid modification(s) is assigned to the amino acid modification(s)" (claim 48);
• "further comprising a step of determining a score for level of expression (an "RNA expression score") of the RNA encoding the protein to which the one or more amino acid modifications are associated" (claim 49);
• "further comprising a step of determining a score for variant allele frequency (a "variant allele frequency score") for the modified protein" (claim 50);
• "identifying non-synonymous mutations in one or more protein-coding regions of a transcript corresponding to the modified protein" (claims 51-52);
• "b) predicting one or more immunogenic amino acid modifications or one or more immunogenic modified peptides" (claim 60);
• "predicting, ranking, and/or selecting one or more immunogenic amino acid modifications" (claim 80); and
• "b) predicting one or more immunogenic amino acid modifications in a protein comprising a tumor-associated neoantigen" (claim 84).
Dependent claims 35-36, 42-45, 47, 51, 54-55, and 82 recite further steps that limit the judicial exceptions in independent claims 1 and 6 and, as such, also are directed to those abstract ideas. For example, claim 35 further limits the modified protein to comprising a tumor-associated neoantigen of a patient; claim 36 further limits the tumor-associated neoantigen to being a peptide or protein comprising a tumor-specific amino acid modification; claim 42 further limits the two or more different amino acid modifications to being present in the same and/or in different modified proteins; claim 43 further limits step (a) in claim 30 to being performed on two or more different modified peptides, said two or more different modified peptides comprising the same amino acid modification(s); claims 44-45, 47, and 51 further limit the two or more different modified peptides; claim 54-55 further limit the mutations identified; and claim 82 further limits the protein to comprising a tumor-associated neoantigen of a patient
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation. Without further detail as to the methodology involved in "predicting amino acid immunogenicity based on the RNA expression score," under the BRI, one may simply, for example, use pen and paper to perform mathematical steps to evaluate whether an amino acid modification will be immunogenic. Further support for the mathematical techniques used in the claims is provided in the specification at pg. 77 lines 5-7, which describes mathematical algorithm used to combine good MHC class II binding with abundant expression data of the mRNA encoding the mutated epitope. Thus, the recited terms correspond 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). MPEP 2106.04(a)(2) pertains. The human mind is also sufficiently capable of select and rank amino acid modifications or modified peptides by comparing scores associated to each modification.
[Step 2A Prong One: claims 30, 32-37, 39-68 and 81-85: Yes ]
Step 2A, 1st prong, 1st Mayo/Alice question: natural product -- MPEP 2106.I and 2106.04
The instant claims recite a natural correlation by correlating the measurement of an amount of a protein naturally found in the body with the immunogenicity of an amino acid modification. (see MPEP 2106.04(b).I).
[Step 2A, 1st prong, law of nature: claims 30, 32-37, 39-68 and 81-85: 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 49-50, 53, 56, 60, 81-82, and 84 recite additional elements that are not abstract ideas:
• "employing a computer-based analytical process" (claims 30, 32, and 81);
• "wherein the RNA expression score is determined by measuring the level of expression of RNA encoding the protein" (claim 49);
• "wherein the score is determined by measuring the level of expression of RNA encoding the modified protein" (claim 50);
• "wherein amino acid modifications are identified by partially or completely sequencing the genome, exome, or transcriptome of one or more cells" (claim 53);
• "manufacturing a vaccine that delivers one or more peptides or polypeptides comprising the one or more amino acid modifications predicted as being immunogenic or more immunogenic, and/or one or more modified peptides predicted as being immunogenic or more immunogenic" (claim 56);
• "a) detecting a mutation corresponding to a non-synonymous amino acid modification by partial or complete sequencing of the genome, exome, or transcriptome of one or more cells from a subject" (claims 60 and 84);
• "c) manufacturing a vaccine comprising one or more peptides or polypeptides comprising the one or more immunogenic amino acid modifications predicted as being immunogenic or more immunogenic or comprising the one or more immunogenic modified peptides predicted as being immunogenic or more immunogenic, or a nucleic acid encoding the one or more peptides or polypeptides (claims 60 and 84); and
• "b) manufacturing a vaccine comprising a peptide or polypeptide comprising the one or more immunogenic amino acid modifications or modified peptides predicted as being immunogenic or more immunogenic, or a nucleic acid encoding the peptide or polypeptide" (claim 82).
Claims 57-58 recite further details about the vaccine manufactured. Claim 59 recites further details about the "step of manufacturing". Claim 61-64 recite further details about the one or more peptides or polypeptides. Claims 65-66 and 85 recite further details about the vaccine manufactured. Claims 67-68 recite further details about the nucleic acid encoding the one or more peptides or polypeptides.
Considerations under Step 2A, Prong Two
Claims directed to “measuring the level of expression of RNA encoding a protein” and “partial or complete sequencing of the genome, exome, or transcriptome of one or more cells” read on detecting genetic material in a patient sample, being an insignificant extra-solution activity since this limitation merely serve to gather data that is utilized as input for the judicial exception. See MPEP 2106.05(g) and MPEP 2106.04(d).
Claims directed to “manufacturing a vaccine” and the types of vaccine that are being manufactured read on a generic “apply it” step because the claim merely recites an idea of an outcome without any indication of how the judicial exception impacts or influences this step. The dependent claims describe details about how the vaccine is being manufactured; not providing clarification of how the judicial exception impacts the additional element of manufacturing the vaccine.
The recited "employing a computer-based analytical process" is interpreted as requiring the use of a computer. The use of a computer is broadly interpreted and not actually described in the claims or specification. 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.
Further steps directed to additional non-abstract elements of a computing device/computer do not describe any specific computational steps by which the "computer parts" perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions.
Claims directed to “predicting immunogenicity .. based on a score” with a “computer-based analytical process” are considered as using a computer to perform an abstract idea, which is not sufficient to integrate an abstract idea into a practical application (see MPEP 2106.05(f)); since steps that can be performed mentally and merely performing the mental process in a computer environment do not negate the fact that something that can be carried out in the human mind. See MPEP 2106.04(a)(2).III.C.
[Step 2A Prong Two: claims 30, 32-37, 39-68 and 81-85: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during examination that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
Claims 30, 32, and 81 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)).
Claims directed to “measuring the level of expression” of genetic material; “partial or complete sequencing of the genome, exome, or transcriptome of one or more cells” and “manufacturing a vaccine” recite steps known in the art as conventional (Kreiter et. al. “mRNA Vaccination and Personalized Cancer Therapy” Cancer Immunotherapy Meets Oncology: In Honor of Christoph Huber. Cham: Springer International Publishing pp89-95 (2014) pg. 95 Fig. 2).
As explained above, the instant claims 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)).
[Step 2B: claims 30, 32-37, 39-68 and 81-85: No]
Conclusion: Instant claims are directed to non-statutory subject matter
For the reasons above, 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 not clearly anything significantly more.
Response to applicant's remarks in regard to Claim Rejection 35 U.S.C. ~ 101
The Remarks of 12/19/2025 have been fully considered but are not persuasive for the reasons below:
It appears that pg. 15 para. 3 represents the only Applicant remarks specific to 101 and the instant claims (emphasis added):
As such, performing steps recited in claims 30 and 32 by employing a computer-based analytical process are not mental processes, but are concrete steps that require involvement of a computational algorithm-based process …. Given the sheer number of parameters associated with such predictive models, they are computationally intractable for a human operator to perform. …, claims 30 and 32 recite methods involving particular computer-based analytical processes that are integrated into practical applications of predicting, selecting and/or ranking immunogenic amino acid modifications. As such, reconsideration and withdrawal of the rejection are respectfully requested.
It appears that these remarks address Step 2A, Prong Two – 3rd consideration regarding 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). With respect to "employing a computer-based analytical process" to apply the identified judicial exception of "predicting, selecting and/or ranking" (see Claim Rejections above), the computer-related elements are general purpose computer and do not rise to the level of significantly more than the judicial exception. The fact that the identified abstract idea relates to complex math (i.e. sheer number of parameters) does not negate the fact that the claims recite mathematical steps, even if it is complex. Additionally, even if it requires a long time, math is a process that can be done with a pen and paper and therefore, considered a mental step. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (Alice Corp., 573 U.S. at225-26, 110 USPQ2d at 1984; see MPEP 2106.05(A)). It is not yet clear what is the evidence that proves that the computer-based analytical process requires anything more than a general purpose computer.
Claim Rejections - 35 USC § 103
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.
A. Claims 30, 35-36, 39-64, 66, and 81-84 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen (KR-20130119845A) in view of Lanfear (“Association of Genetic Variation with Gene Expression and Protein Abundance within the Natriuretic Peptide Pathway” J Cardiovasc. Transl. Res. 6(5): 826–833 (2013)) as evidenced by Jenkins ("High‐throughput SNP genotyping." Comparative and Functional Genomics 3.1 (2002): 57-66 (2002)) as evidenced by Abdi ("Principal component analysis." Wiley interdisciplinary reviews: computational statistics 2(4):433-459 (2010)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 30 recites:
(a) ascertaining a score for binding of a modified peptide comprising a fragment of a modified protein to one or more MHC class II molecules (its "MHC class II binding score);
b) ascertaining a score (an "abundance score") for the modified protein based on a score for level of expression of a protein to which the one or more amino acid modifications are associated and a score for variant allele frequency of the modified protein; and
c) predicting immunogenicity of the one or more amino acid modification based on the MHC class II binding score of the modified peptide and the abundance score of the modified protein; wherein predicting immunogenicity of the one or more amino acid modifications comprises predicting whether the modified peptide comprising the one or more amino acid modifications will be immunogenic
• Hacohen teaches a method for generating tumor specific neoantigens via tumor genome sequencing to identify patient specific tumor mutations (pg. 9 col. 2 para. 3) by quantifying the binding of the candidate peptide to the HLA allele by confirming the expression of the mutated gene and applying a highly validated peptide-MHC binding prediction algorithm to generate a set of candidate immunogenic T cell epitopes based on non-silent mutations present in the tumor (pg. 42 col. 2 para. 5); wherein peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (i.e. step (a)) (pg. 13 col. 2 para. 4); wherein the tumor specific neoantigens is a modified polypeptide of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (pg. 23 col. 2 para. 3); wherein eight (47%) of the 17 predicted peptides resulting from missense mutations in patient 1 were associated with high binding affinity for the HLA allele (i.e. step (c)) (pg. 44 col. 2 para. 2).
• Hacohen does not teach step (b). However, Lanfear teaches associations of genetic sequence variation (i.e. comprising variant allele frequency) with gene expression (i.e. reading on protein expression since proteins are gene products) and protein abundance (pg. 1 para. 1); wherein statistical analysis was performed to quantify the correlation RNA and protein expression for each gene (i.e. quantifying protein expression reads on an abundance score) (pg. 3 para. 4); wherein SNP genotyping (i.e. step of determining a score for variant allele frequency) was performed to code gene variants (i.e. a score for variant allele frequency of the modified protein) (pg. 2 para. 4); wherein the ratio of target protein to total protein was reported and tested with genotyping (i.e. step (b)) (pg. 3 para. 3).
• It is known in the art that SNP genotyping among other alternatives comprises the investigation of SNP allele frequency variation as evidenced by Jenkins ("High‐throughput SNP genotyping." Comparative and Functional Genomics 3.1 (2002): 57-66 (2002)) in pg. 64 col. 1 para. 4; which reads on the argued "quantifying allele frequency via sequencing reads".
Claim 35 recites:
wherein the modified protein comprises a tumor- associated neoantigen of a patient
Claim 36 recites:
wherein the tumor-associated neoantigen is a peptide or protein comprising a tumor-specific amino acid modification
• Hacohen teaches a method for generating tumor specific neoantigens via tumor genome sequencing to identify patient specific tumor mutations (pg. 9 col. 2 para. 3); wherein the tumor specific neoantigens (i.e. tumor- associated neoantigen of a patient as in claim 35) is a modified polypeptide (i.e. tumor-specific amino acid modification as in claim 36) of various lengths (pg. 19 col. 2 para. 4).
Claim 39 recites:
wherein the abundance score is determined by multiplying the score for level of expression of the protein to which the one or more amino acid modifications are associated with the score for variant allele frequency of the modified protein
Claim 40 recites:
wherein the score for variant allele frequency is determined from a sum of detected sequence reads covering mutation site(s) corresponding to the amino acid modification(s) and carrying the amino acid modification(s) divided by a sum of all detected sequence reads covering the mutation site(s)
Claim 41 recites:
wherein the score for variant allele frequency is determined from a sum of mutated nucleotides detected at the mutation site(s) corresponding to the one or more amino acid modifications divided by a sum of all nucleotides detected at the mutation site(s)
• Hacohen does not teach the recitation above. However, Lanfear teaches associations of genetic sequence variation (i.e. comprising variant allele frequency as in claims 39-41) with gene expression (i.e. reading on protein expression since proteins are gene products as in claims 39-41) and protein abundance (pg. 1 para. 1); wherein statistical analysis was performed to quantify the correlation (i.e. mathematical manipulations involving multiplication as in claim 39) between RNA and protein expression for each gene (pg. 3 para. 4); wherein genotyping (i.e. step of determining a score for variant allele frequency as in claims 39-41) was performed to code gene variants (i.e. reading on amino acid modifications since proteins are gene products as in claims 39-41) (pg. 2 para. 4); wherein the ratio of target protein (i.e. protein containing the gene variant of interest) to total protein (i.e. divided by the sum of total modifications as in claims 40-41) was reported and tested with genotyping (i.e. detected sequence reads covering mutation site(s) corresponding to the amino acid modification(s) as in claim 40) (pg. 3 para. 3).
• It is known in the art that using principal component analysis (Abstract Lanfear) in statistical analysis to quantify the correlation between RNA and protein expression for each gene (pg. 3 para. 4 Lanfear) does involve mathematical manipulations that comprise the calculation of a composite score/quantification through multiplication as evidenced by Abdi ("Principal component analysis." Wiley interdisciplinary reviews: computational statistics 2(4):433-459 (2010)) in page 4 para. 2; wherein the components of a matrix are obtained by composite calculation involving multiple multiplying steps.
Claim 42 recites:
wherein two or more different amino acid modifications are present in the same and/or in different modified proteins
• Hacohen teaches tumor specific neoantigens being a modified polypeptide of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (i.e. two or more different amino acid modifications are present in the same and/or in different modified proteins) (pg. 23 col. 2 para. 3).
Claim 43 recites:
further comprising performing step a) on two or more different modified peptides, said two or more different modified peptides comprising the same amino acid modification(s)
• Hacohen teaches that two or more different peptides can be derived from the same polypeptide and have identical mutations (i.e. reading on two or more different modified peptides comprising the same amino acid modification(s)) (pg. 21 col. 2 para. 1).
Claim 44 recites:
wherein the two or more different modified peptides comprising the same amino acid modification(s) comprise different fragments of a modified protein, said different fragments comprising the same amino acid modification(s) present in the modified protein
• Hacohen teaches tumor specific neoantigens being a modified polypeptide of various lengths (pg. 19 col. 2 para. 4); wherein new antigen” refers to antigens resulting from tumor specific mutations in expressed proteins (i.e. same modifications as the modified protein) (pg. 15 col. 2 para. 2).
Claim 45 recites:
wherein the two or more different modified peptides comprising the same amino acid modification(s) comprise different potential MHC class II binding fragments of a modified protein, said fragments comprising the same amino acid modification(s) present in the modified protein
Claim 46 recites:
further comprising selecting the modified peptide(s) from the two or more different modified peptides comprising the same amino acid modification(s) having a probability or having the highest probability for binding to one or more MHC class II molecules
Claim 47 recites:
wherein the two or more different modified peptides comprising the same amino acid modification(s) differ in length and/or position of the amino acid modification(s)
• Hacohen teaches that peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (i.e. peptides of same modifications having different binding potentials due to different lengths as in claims 45 and 47) (pg. 13 col. 2 para. 4); that two or more different peptides can be derived from the same polypeptide and have identical mutations (i.e. the two or more different modified peptides comprising the same amino acid modification(s) as in claim 46) (pg. 21 col. 2 para. 1); wherein the peptide, polypeptide or analog may be modified by altering the order or composition of some residues (pg. 23 col. 2 para. 4) and increased binding affinity for MHC molecules may be achieved (i.e. reading on having a probability or having the highest probability for binding to one or more MHC class II molecules as in claim 46) (pg. 24 col. 2 para. 1); wherein peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (pg. 13 col. 2 para. 4).
Claim 48 recites:
wherein a highest score for binding to one or more MHC class II molecules of the two or more different modified peptides comprising the same amino acid modification(s) is assigned to the amino acid modification(s)
• Hacohen teaches that increased binding affinity for MHC molecules (i.e. comprising class I and class II MHC molecules) relative to the affinity of the parent peptide may be achieved by such substitutions (pg. 24 col. 2 para. 1); wherein peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (pg. 13 col. 2 para. 4).
Claim 49 recites:
further comprising a step of determining a score for level of expression (an "RNA expression score") of the RNA encoding the protein to which the one or more amino acid modifications are associated, wherein the RNA expression score is determined by measuring the level of expression of RNA encoding the protein
• Hacohen teaches that wild type peptides and modified peptides were tested in competitive binding assays to verify the HLA binding ability of all predicted peptides that passed RNA expression validation (i.e. step of determining a score for level of expression of the RNA encoding the protein to which the one or more amino acid modifications are associated) (pg. 44 col. 2 para. 3).
Claim 50 recites:
further comprising a step of determining a score for variant allele frequency (a "variant allele frequency score") for the modified protein, wherein the score is determined by measuring the level of expression of RNA encoding the modified protein
• Hacohen teaches the identification of peptides comprising previously identified tumor specific mutations (pg. 15 col. 2 para. 7); wherein genotyping analysis (i.e. step of determining a score for variant allele frequency) is a method used to identify DNA or RNA presence (pg. 16 col. 2 para. 2); wherein Fig. 7 shows a method for confirming RNA expression of a mutated gene (i.e. measuring the level of expression of RNA encoding the modified protein) (pg. 50 col. 2 para. 1).
Claim 51 recites:
wherein the modified peptide comprises a fragment of the modified protein, said fragment comprising the amino acid modification(s) present in the modified protein
• Hacohen teaches a method for identification of mutant polypeptides or fragments comprising a tumor specific mutation (pg. 19 col. 2 para. 4); wherein modified peptides were tested in competitive binding assays to verify the HLA binding ability of all predicted peptides that passed RNA expression validation (i.e. fragment comprising the amino acid modification(s) present in the modified protein) (pg. 44 col. 2 para. 3).
Claim 52 recites:
further comprising identifying non-synonymous mutations in one or more protein-coding regions of a transcript corresponding to the modified protein
• Hacohen teaches a method for identification of tumor specific neoepitopes wherein many different genetic changes that can alter amino acid sequences (i.e. non-synonymous mutations) and generate potential new T cell epitopes (pg. 42 col. 2 para. 5).
Claim 53 recites:
wherein amino acid modifications are identified by partially or completely sequencing the genome, exome, or transcriptome of one or more cells
• Hacohen teaches identifying DNA mutations using whole genome or whole exome sequencing of tumor samples versus matched germline samples from each patient (pg. 42 col. 2 para. 5).
Claim 54 recites:
wherein mutation(s) corresponding to the amino acid modification(s) are somatic mutation(s)
Claim 55 recites:
wherein said mutation(s) are cancer mutation(s)
• Hacohen teaches that suitable polypeptides from which neoantigenic peptides may be derived were found in databases that maintain comprehensive information on somatic mutations in human cancers (pg. 21 col. 2 para. 1).
Claim 56 recites:
further comprising a step of manufacturing a vaccine that delivers one or more peptides or polypeptides comprising the one or more amino acid modifications predicted as being immunogenic or more immunogenic, and/or one or more modified peptides predicted as being immunogenic or more immunogenic
• Hacohen teaches a method for manufacturing a vaccine composition comprising mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (i.e. predicted to be immunogenic) (pg. 27 col. 2 para. 2). wherein tumor specific neoantigens are modified polypeptides of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (pg. 23 col. 2 para. 3).
Claim 57 recites:
wherein the vaccine is a nucleic acid vaccine comprising a nucleic acid encoding the one or more peptides or polypeptides comprising the one or more amino acid modifications predicted as being immunogenic or more immunogenic, and/or one or more modified peptides predicted as being immunogenic or more immunogenic
• Hacohen teaches immunogenic compositions such as vaccine compositions capable of eliciting specific T cell responses (pg. 27 col. 2para. 2); wherein for treatment or immunization (i.e. vaccine), a nucleic acid encoding the described neoantigen peptide may be administered to a patient (pg. 36 col. 2 para. 2); wherein to generate a DNA sequence encoding an epitope (minigene) selected for expression in human cells, the amino acid sequence of the epitope is reversely translated (pg. 37 col. 2 para. 1).
Claim 58 recites:
wherein the vaccine is a peptide or polypeptide vaccine comprising one or more peptides or polypeptides comprising the one or more amino acid modifications predicted as being immunogenic or more immunogenic, and/or one or more modified peptides predicted as being immunogenic or more immunogenic
• Hacohen teaches a method for manufacturing a vaccine composition comprising mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (i.e. predicted to be immunogenic) (pg. 27 col. 2 para. 2).; wherein tumor specific neoantigens are modified polypeptides of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (pg. 23 col. 2 para. 3).
Claim 59 recites:
wherein the step of manufacturing comprises in vitro transcription to generate an RNA encoding the one or more peptides or polypeptides comprising the one or more amino acid modifications predicted as being immunogenic or more immunogenic, and/or one or more modified peptides predicted as being immunogenic or more immunogenic
• Hacohen teaches a method for manufacturing a vaccine composition comprising mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (i.e. peptides presenting modifications and predicted to be immunogenic) (pg. 27 col. 2 para. 2); wherein a tumor specific neoantigen (CML66) is expressed by nuclear transfection of plasmid DNA or in vitro transcribed RNA (pg. 47 col. 2 para. 1).
Claim 60 recites:
a) detecting a mutation corresponding to a non-synonymous amino acid modification by partial or complete sequencing of the genome, exome, or transcriptome of one or more cells from a subject;
b) predicting one or more immunogenic amino acid modifications or one or more immunogenic modified peptides by the method of claim 30; and
c) manufacturing a vaccine comprising one or more peptides or polypeptides comprising the one or more immunogenic amino acid modifications predicted as being immunogenic or more immunogenic or comprising the one or more immunogenic modified peptides predicted as being immunogenic or more immunogenic, or a nucleic acid encoding the one or more peptides or polypeptides
• Hacohen teaches a method for identification of tumor specific neoepitopes wherein many different genetic changes that can alter amino acid sequences (i.e. non-synonymous mutations) and generate potential new T cell epitopes (pg. 42 col. 2 para. 5) by quantifying the binding of the candidate peptide to the HLA allele by confirming the expression of the mutated gene (i.e. step (b)) and applying a highly validated peptide-MHC binding prediction algorithm to generate a set of candidate immunogenic T cell epitopes based on non-silent mutations present in the tumor (pg. 42 col. 2 para. 5); wherein DNA mutations were identified by using whole genome or whole exome sequencing of tumor samples versus matched germline samples from each patient (i.e. step (a)) (pg. 42 col. 2 para. 5); wherein a method for manufacturing a vaccine composition comprises mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (i.e. step (c)) (pg. 27 col. 2 para. 2); wherein tumor specific neoantigens are modified polypeptides of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (pg. 23 col. 2 para. 3); wherein for treatment or immunization (i.e. vaccine), a nucleic acid encoding the described neoantigen peptide may be administered to a patient (pg. 36 col. 2 para. 2).
Claim 61 recites:
wherein the one or more peptides or polypeptides comprises one or more neo-epitopes or T-cell epitopes
Claim 62 recites:
wherein the one or more neo-epitopes or T-cell epitopes each comprises one or more tumor-specific amino acid modifications
• Hacohen teaches peptides and polypeptides modified to provide the desired properties such as the ability to induce CTL activity, capable of inducing T helper cell responses (pg. 25 col.2 para. 3); wherein tumor cells of patients with chronic lymphocytic leukemia and its many different genetic changes that can alter amino acid sequences generating potential new T cell epitopes (i.e. neo-epitopes or T-cell epitopes each comprises one or more tumor-specific amino acid modifications as in claims 61-62) (pg. 42 col. 2 para. 5).
Claim 63 recites:
wherein the one or more peptides or polypeptides further comprises one or more epitopes that do not comprise tumor-specific amino acid modifications
• Hacohen that wild type peptides (i.e. one or more peptides or polypeptides further comprises one or more epitopes that do not comprise tumor-specific amino acid modifications) and modified peptides were tested in competitive binding assays to verify the HLA binding ability of all predicted peptides that passed RNA expression validation (pg. 44 col. 2 para. 3).
Claim 64 recites:
wherein the one or more neo-epitopes or T-cell epitopes are separated by linkers
• Hacohen teaches peptides and polypeptides modified to provide the desired properties such as the ability to induce CTL activity, capable of inducing T helper cell responses (pg. 25 col.2 para. 3); which can be done by linking a sequence comprising one or more epitopes (i.e. reading on the use of linkers) capable of inducing T helper cell responses (pg. 25 col.2 para. 3).
Claim 66 recites:
wherein the vaccine provides MHC class I-presented epitopes that are capable of eliciting a CD8+ T cell response against cells expressing antigens from which the MHC class I-presented epitopes are derived
• Hacohen teaches CD8+ T cell response to mutated peptides confirmed by sequencing of chronic lymphocytic leukemia patient samples when testing validated HLA binding mutated peptides (pg. 44 col. 2 para. 3); described as candidate T cell epitopes capable of binding to the patient HLA allele and based on non-silent mutations present in the tumor (pg. 9 col. 2 para. 3).
Claim 81 recites:
employing a computer-based analytical process comprising predicting, ranking, and/or selecting one or more immunogenic amino acid modifications in a protein by the method claim 30
Claim 82 recites:
wherein the protein comprises a tumor-associated neoantigen of a patient
• Hacohen computer algorithms used to predict peptide sequences recognized by T cell receptors of T lymphocytes after binding by MHC molecules of class I or class II in the form of potential T cell epitopes (i.e. reading on the recited claim 81) (pg. 12 col. 2 para. 3); wherein the method was used to detecting a mutated antigen present in a tumor (i.e. tumor-associated neoantigen of a patient as in claim 82) but not in normal tissue (pg. 12 col. 2 para. 5).
Claim 83 recites:
a) performing the method of claim 82; and
b) manufacturing a vaccine comprising a peptide or polypeptide comprising the one or more immunogenic amino acid modifications or modified peptides predicted as being immunogenic or more immunogenic, or a nucleic acid encoding the peptide or polypeptide
• Hacohen teaches immunogenic compositions such as vaccine compositions capable of eliciting specific T cell responses (pg. 27 col. 2para. 2) by identifying tumor specific neoepitopes wherein many different genetic changes that can alter amino acid sequences and generate potential new T cell epitopes (pg. 42 col. 2 para. 5); wherein a method for manufacturing a vaccine composition comprises mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (pg. 27 col. 2 para. 2).
Claim 84 recites:
a) detecting a mutation corresponding to a non-synonymous amino acid modification by partial or complete sequencing of the genome, exome, or transcriptome of one or more cells from a subject;
b) predicting one or more immunogenic amino acid modifications in a protein comprising a tumor-associated neoantigen by the method of claim 30; and
c) manufacturing a vaccine comprising a peptide or polypeptide comprising the one or more immunogenic amino acid modifications or modified peptides predicted as being immunogenic or more immunogenic, or a nucleic acid encoding the peptide or polypeptide
• Hacohen t teaches a method for identification of tumor specific neoepitopes wherein many different genetic changes that can alter amino acid sequences (i.e. non-synonymous mutations) and generate potential new T cell epitopes (pg. 42 col. 2 para. 5) by quantifying the binding of the candidate peptide to the HLA allele by confirming the expression of the mutated gene (i.e. step (b)) and applying a highly validated peptide-MHC binding prediction algorithm to generate a set of candidate immunogenic T cell epitopes based on non-silent mutations present in the tumor (pg. 42 col. 2 para. 5); wherein DNA mutations were identified by using whole genome or whole exome sequencing of tumor samples versus matched germline samples from each patient (i.e. step (a)) (pg. 42 col. 2 para. 5); wherein a method for manufacturing a vaccine composition comprises mutant peptides and mutant polypeptides corresponding to tumor specific neoantigens (i.e. step (c)) (pg. 27 col. 2 para. 2); wherein tumor specific neoantigens are modified polypeptides of various lengths (pg. 19 col. 2 para. 4); wherein polypeptides may have various substitutions (pg. 23 col. 2 para. 3); wherein for treatment or immunization (i.e. vaccine), a nucleic acid encoding the described neoantigen peptide may be administered to a patient (pg. 36 col. 2 para. 2).
Rationale for combining (MPEP §2142-2143)
Regarding claims 30, 35-36, 39-64, 66, and 81-84, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen in view of Lanfear because all references disclose methods for investigating immunogenicity predictions. The motivation would have been to establish the connection of sequence variants in certain genes to gene expression and or protein abundance (pg. 2 para. 2 Lanfear).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the immunogenic prediction methods of Hacohen to the methods by Lanfear because such a substitution is no more than the simple substitution of one known element for another. 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 immunogenicity predictions.
B. Claims 32-33 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen in view of Lanfear in view of DeGroot (“Prediction of immunogenicity for therapeutic proteins: State of the art” Curr. Opin. Drug. Discov. Devel. 10(3):332-340 (2007)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 32 recites:
(a) ascertaining a score for binding of a modified peptide comprising a fragment of a modified protein to one or more MHC class II molecules (its "MHC class II binding score");
b) ascertaining a score (an "abundance score") for the modified protein based on a score for level of expression of a protein to which the one or more amino acid modifications are associated and a score for variant allele frequency of the modified protein;
c) performing steps a) and b) for two or more different immunogenic amino acid modifications; and
d) selecting and/or ranking the two or more different immunogenic amino acid modifications by comparing the MHC class II binding scores of the corresponding modified peptide and the abundance scores for the corresponding modified protein
• Hacohen teaches a method for generating tumor specific neoantigens via tumor genome sequencing to identify patient specific tumor mutations (pg. 9 col. 2 para. 3) by quantifying the binding of the candidate peptide to the HLA allele by confirming the expression of the mutated gene and applying a highly validated peptide-MHC binding prediction algorithm to generate a set of candidate immunogenic T cell epitopes based on non-silent mutations present in the tumor (pg. 42 col. 2 para. 5); wherein peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (i.e. step (a)) (pg. 13 col. 2 para. 4); wherein 17 candidate peptide were investigate with the steps described (i.e. step (c)) (pg. 45 col. 2para. 1).
• Hacohen does not teach step (b). However, Lanfear teaches associations of genetic sequence variation (i.e. comprising variant allele frequency) with gene expression (i.e. reading on protein expression since proteins are gene products) and protein abundance (pg. 1 para. 1); wherein statistical analysis was performed to quantify the correlation RNA and protein expression for each gene (i.e. quantifying protein expression reads on an abundance score) (pg. 3 para. 4); wherein genotyping (i.e. step of determining a score for variant allele frequency) was performed to code gene variants (i.e. a score for variant allele frequency of the modified protein) (pg. 2 para. 4); wherein the ratio of target protein to total protein was reported and tested with genotyping (i.e. step (b)) (pg. 3 para. 3), wherein the described genetic statistical analysis is performed for multiple candidates (i.e. step (c)) (pg. 3 para. 4) .
• Hacohen does not teach step (d). However, De Groot teaches a sequence-based tool – EpiMatrix – that enables the evaluation (i.e. comprising a ranking step) of protein sequences for T-cell epitopes and comparisons across predictions (i.e. step (d)) for different HLA MHC alleles comprising MHC class I and MHC class II (pg. 5 col. 1 para. 1 and pg. 4 Table 1).
Claim 33 recites:
wherein selecting and/or ranking the two or more different immunogenic amino acid modifications comprises a selection and/or ranking of peptides comprising the two or more different immunogenic amino acid modifications for their immunogenicity
• Hacohen teaches a method for generating tumor specific neoantigens via tumor genome sequencing to identify patient specific tumor mutations (pg. 9 col. 2 para. 3); wherein polypeptides may have various substitutions (i.e. two or more different amino acid modifications) (pg. 23 col. 2 para. 3); wherein eight (47%) of the 17 predicted peptides resulting from missense mutations in patient 1 were associated with high binding affinity for the HLA allele (i.e. selecting and/or ranking the two or more different immunogenic amino acid modifications) (pg. 44 col. 2 para. 2)
Rationale for combining (MPEP §2142-2143)
Regarding claims 32-33, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen and Lanfear in view of DeGroot because all references disclose methods for investigating immunogenicity predictions. The motivation would have been to generated protein immunogenicity report for common protein-based therapeutics (pg. 5 Fig. 2 De Groot).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the immunogenicity prediction method of Hacohen and Lanfear to the methods by DeGroot because such a substitution is no more than the simple substitution of one known element for another. 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 immunogenicity predictions.
C. Claims 34 is rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen, Lanfear and DeGroot as applied to claim 32 above further in view of Muntel (“Abundance-based Classifier for the Prediction of Mass Spectrometric Peptide Detectability Upon Enrichment (PPA)” Mol. Cell Proteomics 14(2):430-40 (2014)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 34 recites:
wherein comparing the MHC class II binding scores and the abundance scores comprises ranking the two or more different amino acid modifications by their MHC class II binding scores and removing amino acid modifications for which the corresponding modified protein has an abundance score of less than a given threshold
• De Groot teaches a sequence-based tool – EpiMatrix – that enables the evaluation (i.e. comprising a ranking step) of protein sequences for T-cell epitopes and comparisons across predictions (i.e. comprising comparisons between any immunogenicity related predictions) for different HLA MHC alleles comprising MHC class I and MHC class II (pg. 5 col. 1 para. 1 and pg. 4 Table 1).
• Neither Hacohen or Lanfear or DeGroot teach “removing amino acid modifications for which the corresponding modified protein has an expression or abundance of less than a given threshold”. However, Muntel teaches a method for the quantification of relevant protein modifications (pg. 430 col. 2 para. 2) and prediction of protein enrichment needed to observe the peptide of interest (pg. 430 col. 1 para. 1); herein sequence coverage is defined as the number of detected peptides per protein (i.e. peptides carrying modifications) (pg. 431 col. 1 para. 1); wherein protein that was expressed at low amounts (7 fmol/µl) and presented low sequence coverage (<20%) were removed (i.e. removed amino acid modifications for which the corresponding modified protein has an expression or abundance of less than a given threshold).
Rationale for combining (MPEP §2142-2143)
Regarding claim 34, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen, Lanfear and DeGroot in view of Muntel because all references disclose methods investigating protein modifications. The motivation would have been to assess the detectability and the relevance of all peptides (pg. 430 col. 1 para. 1 Muntel).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the protein modification method of Hacohen, Lanfear and DeGroot to the methods by Muntel because such a substitution is no more than the simple substitution of one known element for another. 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 protein modifications.
D. Claims 37 is rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen and Lanfer as applied to claim 30 above further in view of Batalia (“Peptide Binding by Class I and Class II MHC Molecules” Peptide Science 43.4:281-302 (1997)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 37 recites:
wherein the MHC class I binding score reflects a probability for binding of the modified peptide to the one or more MHC class II molecules
• Neither Hacohen or Lanfear teach the limitation above. However, Batalia teaches that HLA-DR1 (a MHC class II allele) has a very similar structure to class I MHC; wherein the peptide binding cleft of class II MHC may be superimposed readily on the class I MHC peptide-binding cleft (i.e. wherein the MHC class I binding score reflects a probability for binding of the modified peptide to the one or more MHC class II molecules) (i.e. pg. 292 col. 2 para. 3);
Rationale for combining (MPEP §2142-2143)
Regarding claim 37, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen and Lanfear in view of Batalia because all references disclose methods for investigating immunogenicity predictions. The motivation would have been to take into consideration class I MHC and class II /MHC molecules and their similarity in domain organization, genomic structure, function and minor physical differences in terms of designing antigens (pg. 282 col. 1 para. 2 Batalia).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the immunogenicity prediction method of Hacohen and Lanfear to the methods by Batalia because such a substitution is no more than the simple substitution of one known element for another. 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 immunogenicity predictions
E. Claims 65 is rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen and Lanfer as applied to claims 30 and 60 above further in view of Xu (“CD4+ T-cell activation for immunotherapy of malignancies using Ii-Key/MHC class II epitope hybrid vaccines” Vaccine 30:2805– 2810 (2012)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 65 recites:
wherein the vaccine provides MHC class II-presented epitopes that are capable of eliciting a CD4+ helper T cell response against cells expressing antigens from which the MHC class II-presented epitopes are derived
• Neither Hacohen or Lanfear teach the limitation above. However, Xu teaches the use of MHC class II peptide epitopes incorporated into an hybrid Ii-Key/epitope technology to elicit CD4+ T-cell activation with specificity and increase vaccine potency (pg. 2809 col.1 para. 3).
Rationale for combining (MPEP §2142-2143)
Regarding claim 65, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen and Lanfer in view of Xu because all references disclose methods for investigating immunogenicity predictions. The motivation would have been to achieve a robust and specific CD4+ response and contribute to effective anticancer immunity (pg. 2809 col.2 para. 2 Xu).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the immunogenicity prediction method of Hacohen and Lanfer to the methods by Xu because such a substitution is no more than the simple substitution of one known element for another. 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 immunogenicity predictions.
F. Claims 67-68 and 85 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hacohen and Lanfer as applied to claims 30, 60, and 84 above further in view of Kreiter (“mRNA Vaccination and Personalized Cancer Therapy” Cancer Immunotherapy Meets Oncology: In Honor of Christoph Huber. Cham: Springer International Publishing pp89-95 (2014)), as cited on the 10/01/2025 Form PTO-892. Any newly recited portions are necessitated by claim amendment. Bullet points indicate the teachings of the instant features over the prior art. Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 67 recites:
wherein the nucleic acid is ribonucleic acid (RNA)
Claim 68 recites:
wherein the RNA has been modified to increase stability or expression.
Claim 85 recites:
wherein the vaccine comprises a synthetic mRNA vaccine encoding one or more neo-epitopes or T-cell epitopes
• Neither Hacohen or Lanfear teach the limitation above. However, Kreiter teaches the development of actively personalized mRNA-based cancer vaccines comprising mRNA-encoded mutated epitopes (i.e. as in claims 67 and 85) (pg. 95. col. 1 para. 2); wherein the stability and translation of the mRNA are controlled (i.e. reading on increasing or decreasing stability as in claim 68) by precisely regulated and complex mechanisms involving various pathways and molecules (pg. 90 col.1 para. 2).
Rationale for combining (MPEP §2142-2143)
Regarding claims 67-68 and 85, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Hacohen and Lanfer in view of Kreiter because all references disclose methods for investigating immunogenic neoepitopes. The motivation would have been to pursue the development, production, clinical testing, and commercialization of individualized mRNA vaccines (pg. 95. col. 1 para. 2 Kreiter).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the immunogenicity prediction method of Hacohen and Lanfer to the methods by Kreiter because such a substitution is no more than the simple substitution of one known element for another. 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 immunogenic neoepitopes.
Response to applicant's remarks in regard to Claim Rejection 35 U.S.C. ~ 102/103
The Remarks of 12/19/2025 have been fully considered but are not persuasive for the reasons below:
Applicant asserts in pg. 16 para. 1:
Applicants respectfully submit that Hacohen does not anticipate claim 30, at least because Hacohen's teachings do not pertain to ascertaining a score for binding of a modified peptide to MHC class II molecules…. netMHC (referred to as NetMHCpan in Nielsen) can be used only for assessment of binding to MHC class I
The rejection regarding Hacohen anticipating claim 30 has been withdrawn. However, for compact prosecution, the remarks regarding Hacohen not teaching "ascertaining a score for binding of a modified peptide to MHC class II molecules" will be addressed here. Hacohen teaches a method for generating tumor specific neoantigens via tumor genome sequencing to identify patient specific tumor mutations (pg. 9 col. 2 para. 3) by quantifying the binding of the candidate peptide to the HLA allele (i.e. reading on ascertaining a score) by confirming the expression of the mutated gene and applying a highly validated peptide-MHC binding prediction algorithm to generate a set of candidate immunogenic T cell epitopes based on non-silent mutations present in the tumor (pg. 42 col. 2 para. 5); wherein peptide fragments can form a complex with a protein of MHC class I or MHC class II by having a suitable length and suitable binding motif in its amino acid sequence (pg. 13 col. 2 para. 4). Therefore the argued recitation is taught by the prior art to Hacohen.
Applicant asserts in pg. 16 para. 2:
Additionally, independent claims 30 and 32 have been amended to recite, in part, "ascertaining a score (an "abundance score") for the modified protein based on a score for level of expression of a protein to which the one or more amino acid modifications are associated and a score for variant allele frequency of the modified protein". This feature was previously recited in dependent claim 38 (now canceled), which was not rejected as anticipated by Hacohen.
The combination of teachings by Hacohen and Lanfear addressed the argued recitation "ascertaining a score (an "abundance score") for the modified protein based on a score for level of expression of a protein to which the one or more amino acid modifications are associated and a score for variant allele frequency of the modified protein" (See Claim Rejections above). One would be motivated to combine the teachings by Hacohen and Lanfear to establish the connection of sequence variants in certain genes to gene expression and or protein abundance (pg. 2 para. 2 Lanfear) and because both arts describe teachings pertaining to the investigation of immunogenicity prediction. "The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law" See MPEP 2144.I Therefore the step argued above is well known in the art and thus accepted as a rational to combine the teachings in the prior art.
Applicant asserts in pg. 18 para. 2 to pg. 19 para. 1:
Applicants respectfully submit that the pending claims are not obvious over these references….Applicants respectfully submit that the Office Action has not established a prima facie case of obviousness, at least because the Office Action has not sufficiently established why one of ordinary skill in the art would have combined the cited references to arrive at the pending claims with any reasonable expectation of success … One of ordinary skill in the art would not have been led to such features
The detailed explanation of subject matter suggested by a prior art reference is entirely acceptable when establishing a rationale for obviousness: "to support the conclusion that the claimed invention is directed to obvious subject matter, either the references must expressly or impliedly suggest the claimed invention or the examiner must present a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references" (Ex parte Clapp, 227 USPQ 972 at 973 (BPAI 1985)); "Office personnel may also take into account 'the inferences and creative steps that a person of ordinary skill in the art would employ' (KSR v. Teleflex Inc., 82 USPQ2d 1385 at 1396 (SC 2007))" (MPEP 2141 § 11.C); "the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle" (MPEP 2144.02). The examiner's explanation of how the combination of teachings read over the claimed invention presents a convincing line of reasoning, takes into account and explains the inferences and creative steps by a person of ordinary skill in the art, and relies on logic and sound scientific principle. As described in the Claim Rejections above, one would be motivated to combine the described teachings by the prior art to arrive at the claimed invention.
Applicant asserts in pg. 19 para. 3:
Lanfear expressly cautions that their findings on genetic variation and expression are system-and tissue-specific, noting that … In fact, even in kidney tissue, while Lanfear discloses that "genetic variation may play a key role in determining protein abundance for NPRB .. . other genes tested did not show indications of genetic variation importantly affecting gene expression or protein abundance in kidney" (pg. 4, para. 4, emphasis added). Moreover, Lanfear reports a poor correlation between RNA and protein levels ("RNA and protein quantity correlated poorly with each other," Abstract). At least for these reasons, one of ordinary skill in the art would not have been led to present claims 30 or 32 (or dependent claims 39-41, 49, or 50) with any reasonable expectation of success
The detailed explanation of subject matter suggested that one would be motivated to apply the system-and tissue-specific teachings by Lanfear to predict how other genetic variations could impact immunogenicity to establish the connection of sequence variants in certain genes to gene expression and or protein abundance (pg. 2 para. 2 Lanfear). The fact that "Lanfear reports a poor correlation between RNA and protein levels" does not negate the fact that the teachings are present in the art and said teachings would motivated one of ordinary skill to arrive at the claimed invention. The same applies for all of the prior art. "It is well-established that a determination of obviousness based on teachings from multiple references does not require an actual, physical substitution of elements." In re Mouttet, 686 F.3d 1322, 1332, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
Applicant asserts in pg. 20 para. 1:
Regarding dependent claim 39, Lanfear does not teach or suggest that the "abundance score is determined by multiplying the score for level of expression of the protein to which the one or more amino acid modifications are associated with the score for variant allele frequency of the modified protein". Rather, Lanfear indicates an association between these two factors, which involves statistical modeling, e.g., linear regression, principal component analysis (Abstract), but it does not disclose the calculation of a composite score through multiplication
The teaching regarding the use of statistical analysis steps to quantify protein expression as described by Lanfear inherently teaches the calculation of a composite score/quantification through multiplication. It is known in the art that using principal component analysis (Abstract Lanfear) in statistical analysis to quantify the correlation between RNA and protein expression for each gene (pg. 3 para. 4 Lanfear) does involve mathematical manipulations that comprise the calculation of a composite score/quantification through multiplication as evidenced by Abdi ("Principal component analysis." Wiley interdisciplinary reviews: computational statistics 2(4):433-459 (2010)) in pg. 4 para. 2; wherein the components of a matrix are obtained by composite calculation involving multiple multiplying steps.
Applicant asserts in pg. 20 para. 2:
Lanfear does not teach or suggest such methods. Lanfear describes determining genetic variation (SNP status) through genotyping methods (p. 2, para. 4), rather than quantifying allele frequency via sequencing reads. Lanfear also assesses ratio of target protein to total protein (p. 3, para. 3). These are not, however, disclosures of the methods of claims 40 or 41
The teaching regarding the "determining genetic variation (SNP status) through genotyping" as described by Lanfear inherently teaches quantifying allele frequency via sequencing reads. It is known in the art that SNP genotyping among other alternatives comprises the investigation of SNP allele frequency variation as evidenced by Jenkins ("High‐throughput SNP genotyping." Comparative and Functional Genomics 3.1 (2002): 57-66 (2002)) in pg. 64 col. 1 para. 4; which reads on the argued "quantifying allele frequency via sequencing reads". Therefore, the prima facie case of obviousness has been established. MPEP 2141.III for "RATIONALES TO SUPPORT REJECTIONS UNDER 35 U.S.C. 103"; wherein "(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention". Furthermore, in this instant application, the amendments support existing claim rejections, in which the recited limitations are all addressed, see Claim Rejections above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/F.F.L./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685