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 .
Status of the Claims
The claim set received 03 July 2025 has been entered into the application.
Claims 1 and 12 are amended.
Claims 13-19 are cancelled.
Claim 3 and 10 are previously canceled.
Claim(s) 1-2, 4-9, and 11-12 are pending.
Priority
This Application is a 371 of PCT/EP2019/081428 filed 15 November 2018.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP18206599.5, filed on 15 November 2018.
Election/Restriction
Upon review of the Applicants arguments and amendments received 25 July 2024 and the evidence of record, the individual groups and species would not provide an undue examination burden. Therefore, the restriction requirement and election of species requirement mailed 31 May 2024 have been withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 May 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
It is noted the articles are referenced at pages 59-62 of the specification.
Specification
The objection to the specification in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
The rejection of claim 1 because new matter under 35 U.S.C § 112(a) in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
The rejection of claims 13-19 because written description under 35 U.S.C § 112(a) in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
35 USC § 112(b)
The rejection of claim 1 step (e) under 35 U.S.C § 112(b) in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
The rejection of claims 13-19 under 35 U.S.C § 112(b) in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
Claim Rejections - 35 USC § 101
The instant rejection is maintained for reason for record in the Office Action mailed 20 May 2025 and modified in view of the amendments filed 03 July 2025.
The rejection of claims 13-19 under 35 U.S.C § 101 in the Office Action mailed 20 May 2025 is withdrawn in view of the amendments received 03 July 2025.
.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, 4-9, and 11-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1- Process, Machine, Manufacture or Composition
Claims 1-2, 4-9, and 11-12 are drawn to a method, so a process.
Step 2A Prong I - Identification of an Abstract Idea
comparing the sequencing of the tumor DNA and of the normal DNA to identify the mutations resulting in a change of the encoded amino acid sequence that is not present in the sample of non-cancerous cells of said individual
This step can be performed in the human mind by observing, comparing, and judging sequencing data of the tumor DNA and of the normal DNA to identify the mutations that are not present in the sample of non-cancerous cells of said individua and is therefore an abstract idea.
determining neoantigens in a sample of cancerous cells, wherein each neoantigen, comprises a coding sequence, comprises at least one of the identified mutations, and consists of 9 to 40 contiguous amino acids of the coding sequence in the sample of cancerous cells
This step can be performed in the human mind by observing, comparing, and evaluating the 9 to 40 contiguous amino acid coding sequence for mutations and is therefore an abstract idea. Here, it is noted the claimed step does not contain any physical or experimental procedures for determining neoantigens in a sample. As such, the determining step is broad and reads on a mental process of determining with the human mind.
b) determining for each neoantigen the mutation allele frequency of each of said mutations of step (a) within the coding sequence
This step can be performed in the human mind by organizing the determined neoantigen mutations of step (a) to determine a mutation allele frequency of the mutations within the coding sequences and is therefore an abstract idea. This step encompasses performing mathematical computations to determine a mutation allele frequency (i.e., mathematical/statistical relationship between mutations in a coding sequence and/or ratio) of mutations of the neoantigen and is therefore an abstract idea. Here, the determining is interpreted as an alternative to calculating a mutation allele frequency.
(c) determining the expression level of each coding sequence comprising at least one of said mutations, (i) in said sample of cancerous cells, or (ii) from an expression database of the same cancer type as the sample of cancerous cells
This step can be performed in the human mind by observing and evaluating coding sequence mutation data from step (i) a sample of cancerous cells or the expression database using the same cancer data as in previous step (i) (ii) for determining expression levels of the coding sequences and is therefore an abstract.
(d) predicting the MHC class I binding affinity of the neoantigens
This step can be performed in the human mind by following instructions for predicting MHC Class I binding affinity and is therefore an abstract idea.
wherein (I) the HLA class I alleles are determined from the sample of non-cancerous cells of said individual
This step can be performed in the human by observing and evaluating non-cancerous cells of said individual to determine HLA Class I alleles and is therefore an abstract idea.
(II) for each HLA class I allele determined in (I) the MHC class I binding affinity of each fragment consisting of 8 to 15 contiguous amino acids of the neoantigen is predicted, wherein each fragment is comprising at least one amino acid change caused by the mutation of step (a), and (III) the fragment with the highest MHC class I binding affinity determines the MHC class I binding affinity of the neoantigen
This step can be performed in the human mind by following instruction to predict MHC Class I binding affinity of the neoantigens by observing and evaluating (I) HLA Class I allele that are determined from non-cancerous cells of individuals, (II) the predicted MHC Class I binding affinity of the predicted neoantigen consisting of 8 to 15 contiguous amino acids and comprising as least one mutation from previous step (a) and the determined HLA Class I allele of previous step (I), and (III) the fragment with the highest MHC Class I binding affinity and is therefore an abstract idea.
and in addition to or alternatively to step (d)
This step can be performed in the human mind by following instructions to use step (d) in addition to or alternatively step (d) and is therefore an abstract idea.
d’) determining the HLA class II alleles in the sample of non-cancerous cells of said individual
This step can be performed in the human mind by following instructions to determine the HLA Class II alleles in non-cancerous cells of an individual and is therefore an abstract idea.
predicting the MHC class II binding affinity of the neoantigen
This step can be performed in the human mind by following instructions to predict MHC Call II binding affinity for the neoantigen and is therefore an abstract idea.
wherein for each HLA class II allele determined the MHC class II binding affinity for each fragment of 11 to 30 contiguous amino acids of the neoantigen is predicted, wherein each fragment is comprising at least one mutated amino acid generated by the mutation of step (a)
This step can be performed in the human mind by observing and evaluating the predicted MHC Class II binding affinity for the determined HLA Class II allele comprising 11 to 30 contiguous amino acid and at least one mutated amino acid of step (a) and is therefore an abstract idea.
the fragment with the highest MHC class II binding affinity determines the MHC class II binding affinity of the neoantigen
This step can be performed in the human mind by observing and evaluating the highest MHC Class II binding affinity to determine the binding affinity of the neoantigen and is therefore an abstract idea.
(e) ranking the neoantigens according to the values of mutations allele frequency, expression level, and binding affinity of MHC class I and/or MHC class II determined in steps (b), (c) (d) and/or (d') for each neoantigen from highest to lowest values, yielding a first, a second, a third, and/or fourth list of ranks
This step can be performed in the human mind because ranking values of frequency can be achieved as a mental process. This step encompasses performing mathematical operations (i.e., equalities and inequalities) for comparing highest and lowest values to yield a ranked list of numerical values and is therefore an abstract idea.
(f) calculating a rank sum from said first, second, third, and/or fourth list of ranks, wherein the rank sum is a weighted rank sum
This step can be performed in the human mind by organizing data to calculate a ranked sum. Here, summing data (i.e., weighted ranked values) is a process (i.e., adding ranked data together to yield a total value (sum)) that can be performed by the human mind and also reads on math (i.e., adding/totaling data). This step also describes the rank sum as a weighted rank sum.
the number of neoantigens determined in step (a) is added to the rank value of each neoantigen
This is can be performed in the human mind by organizing information of the neoantigens of previous step (a) by adding the rank value of each neoantigen and is therefore an abstract idea. This step encompasses performing mathematical operations of adding the rank value of each neoantigen and is therefore an abstract idea.
in the third list of ranks for which the prediction of MHC class I binding affinity of step (d) resulted in an IC50 value higher than 1000 nM
This is can be performed in the in human mind by organizing data of the third list of ranks of MHC Class I binding affinity of step (d) in a list with an IC50 value higher than 1000nM and is therefore an abstract idea.
in the fourth list of ranks for which the prediction of MHC class II binding affinity of step (d') resulted in an IC50 value higher than 1000 Nm
This is can be performed in the in human mind by organizing data of the fourth list of ranks of MHC Class II binding affinity of step (d’) in a list with an IC50 value higher than 1000nM and is therefore an abstract idea.
in case of step (c)(i) being performed by massively parallel transcriptome sequencing, the rank sum of step (f) is multiplied by a weighing factor (WF)
This step can be performed in the human mind by observing and evaluating whether massively parallel sequencing transcriptome sequencing has been performed for multiplying the rank sum of previous step (f) by a weighting factor and is therefore an abstract idea. This step encompasses performing mathematical operations of multiplication by multiplying the rank sum by a weight factor and is therefore an abstract idea.
Wherein the WF is 1, if the number of mapped transcriptome reads for the mutation is >0
This step can be performed in the human mind by observing and evaluating if the number of mapped transcriptomes reads for the mutation is > 0 to determine if the WF is 1 and is therefore an abstract idea. This step encompasses performing mathematical operation of equalities and inequalities and is therefore an abstract idea.
Wherein the WF is 2, if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is 0 and the transcripts-per-million (TPM) value is at least 0.5
This step can be performed in the human mind by observing and evaluating if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is 0 and the transcripts-per-million (TPM) value is at least 0.5 to determine if the WF is 2 and is therefore an abstract idea. This step encompasses performing mathematical operation of equalities and inequalities and is therefore an abstract idea.
Wherein the WF is 3, if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is >0 and the transcripts-per-million (TPM) value is at least 0.5
This step can be performed in the human mind by observing and evaluating if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is >0 and the transcripts-per-million (TPM) value is at least 0.5 to determine if the WF is 3 and is therefore an abstract idea. This step encompasses performing mathematical operation of equalities and inequalities and is therefore an abstract idea.
Wherein the WF is 4 if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is 0 and the transcripts-per-million (TPM) value is< 0.5
This step can be performed in the human mind by observing and evaluating if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is 0 and the transcripts-per-million (TPM) value is< 0.5 to determine if the WF is 4 and is therefore an abstract idea. This step encompasses performing mathematical operation of equalities and inequalities and is therefore an abstract idea.
Wherein the WF is 5 if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is >0 and the transcripts-per-million (TPM) value is < 0.5
This step can be performed in the human mind by observing and evaluating if the number of mapped transcriptome reads for the mutation is 0 and the number of mapped reads for the non-mutated sequence is >0 and the transcripts-per-million (TPM) value is < 0.5 to determine if the WF is 5 and is therefore an abstract idea. This step encompasses performing mathematical operation of equalities and inequalities and is therefore an abstract idea.
ordering the neoantigens by increasing weighted rank sum, yielding a ranked list of neoantigens
This step can be performed in the human mind by organizing information such as ordering neoantigens by weighted rank sum to yield a ranked list and is therefore an abstract idea. This step encompasses performing mathematical operations (i.e., inequalities and equalities) for ordering neoantigens by increasing ranked sum to yield a ranked list of neoantigens and is therefore an abstract idea.
(g) selecting 30-240 neoantigens from the ranked list obtained in previous step (f) starting with the lowest rank.
This step can be performed in the human by observing and evaluating the rank list of neoantigens obtained in previous step (f) to select 30-240 neoantigens starting with the lowest rank and is therefore an abstract idea.
Claims 2, 4-9, and 11-12 are further drawn to limitations that describe the abstract ideas of claim 1.
Step 2A Prong Two: Consideration of Practical Application
Claim 1 was amended to recite “step (h) constructing a personalized vaccine comprising at least one of the selected neoantigens of step (g).” Similarly, claim 12 was amended to recite “(v) constructing a personalized vector comprising the selected combination of neoantigens of step (iv).
The specification states “the invention as well relates to a method for constructing a vector or collection of vectors carrying the neoantigens for a personalized vaccine” [page 1 lines 4-5]. The specification discloses “the present invention provides a method for constructing a personalized vector encoding a combination of neoantigens according to the first aspect of the invention for use as a vaccine, comprising the steps of” [page 3-4] which leads to selecting the combination of neoantigens. The specification discloses “Responses were evaluated by using 2 peptide pools, each composed of 31 peptides encoded by the vaccine constructs (pool 1-31 neoantigens 1 to 31; pool 32-62 neoantigens 32to 62).” [page 5 lines 30-33] which describes using 2 peptide pools to evaluate immunogenicity. The specification discloses “The IC50 of a molecule can be determined experimentally in functional antagonistic assays by constructing a dose-response curve and examining the inhibitory effect of the examined molecule at different concentrations.” [page 11 lines 10-13]. The specification discloses “In a second aspect, the present invention provides a method for constructing a personalized vector encoding a combination of neoantigens according to the first aspect of the invention for use as a vaccine, comprising the steps of” [page 21-22] which does not provide physical construction steps for constructing a personalized vector but for selecting a combination of neoantigens. The specification discloses “These regions can therefore generate problems either during initial construction/synthesis of the vaccine expression cassette” [page 28-29 bottom page 28 to top of page 29]. The specification discloses “one TPA T-cell enhancer element was present at the N-terminus of each of the two 31 neoantigens constructs.” [page 57 lines 3-4]. The specification discloses “the order of the individual neoantigens in the poly-neoantigen encoded by the various constructs is shown” [page 57 table 9].
Here, with respect to claim 1 step (h) constructing a personalized vaccine comprising at least one of the selected neoantigens step and claim 12 step (v) constructing a personalized vector comprising the selected combination of neoantigens of claim 12 step (iv), the claimed steps do not integrate the recited judicial exception because the specification only discloses constructing methods that encompass selecting a combination of neoantigens for constructing personalized vector and does not disclose any physical steps and/or laboratory/clinical steps for synthesizing/constructing a personalized vaccine. The recited “constructing” reads on organizing information. As such, the recitation of the constructing steps of claims 1 and 12 attempt to cover any solution for constructing a personalized vaccine and constructing a personalized vector with no restriction on how the construction is accomplished and no description of the methods/techniques for constructing a personalized vaccine and/or constructing a personalized vector which does not integrate a judicial exception into a practical application or provide significantly more because this type of recitation is equivalent to the words "apply it". See MPEP 2106.05(f).
The additional element of sequencing of claim 1 step (a) and using massively parallel sequencing (MPS) of claims 2 and 9 does not integrate the recited judicial exception into a practical application because using sequencing technologies to produce nucleic acid sequence data is deemed an extra-solution activity of data gathering. See MPEP 2106.05(g).
The recited additional element of using samples of cancerous and non-cancerous cells of claims 2 does not integrate the recited judicial exception into a practical application because the cancer and non-cancerous cells are used as a source of nucleic acid that is subsequently analyzed by the abstract ideas. See MPEP 2106.05(g).
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses 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.
Step 2B - Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
The additional element of using sequencing of claim 1 step (a) and using massively parallel sequencing (MPS) of claims 2 and 9 does not add more than the recited judicial exception because using sequencing technologies to produce nucleic acid sequence data is deem a well-known and conventional extra-solution activity. See MPEP 2106.05(d)(II) and 2106.05(g).
The recited additional element of using samples of cancerous and non-cancerous cells of claims 1-2 does not add significantly more than the recited judicial exception because using cells as a source of nucleic acid is well-known and conventional.
In conclusion and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant’s arguments, filed 03 July 2025, have been fully considered but the rejections are maintained. Therefore, the rejection has not been withdrawn.
The Applicant states “the claims have been amended to define that step a) comprises sequencing of tumor DNA and normal DNA of an individual and comparing the resulting sequencing data to individuate the mutations that result in a change in the encoded amino acid sequence in the tumor cells of the individual. It is clear from the application, as filed (at least on p. 14 11. 4-7, and p. 25 11. 12-21 shown below), that the claimed method for selecting cancer neoantigens for use in a personalized vaccine, includes such DNA sequencing experiments to generate the candidate cancer neoantigens” [remarks, page 9]. The Applicant points to the specification (p. 14 11. 4-7) and (p. 25 11. 12-21) for clarification. The Applicant states “In addition, the recited method may comprise determining the expression level of each coding sequence comprising at least one of said mutations (step (c) of claim 1). Therefore, the claimed method comprises at least the technical steps of sequencing DNA and optionally analyzing the expression level of each coding sequence. “[remarks, page 9].
In response, the sequencing additional element of claim 1 step (a) is utilized for gathering sequencing data from cancerous and non-cancerous cells for subsequent comparison to identify mutations. The additional element of nucleic acid sequencing is an extra-solution activity for obtaining sequencing data for identifying mutations between cancer and non-cancerous samples. Here, it is known that DNA sequencing merely produces nucleic acid data, and it is known that DNA sequence does not generate candidate neoantigens but generates data related to neoantigens. Here, the specification, (p. 14 11. 4-7) and (p. 25 11. 12-21), does not disclose methods or techniques for constructing personalized vaccine and/or a personalized vector but discloses support for using massively parallel sequencing to generate nucleic acid data that is subsequently analyzed for identifying genetic mutations (i.e., data analysis). With respect to claim 1 determining expression levels, it is noted in Step 2A Prong II of the 101 analyses above, the claimed step is drawn to abstract idea. It is noted the claims require determining expression levels using data from a database(s) and not from clinical/laboratory steps. Therefore, claim 1 is not patent eligible under 35 U.S.C §101.
The Applicant states “that amended claim 12 is directed to a method of constructing a personalized vector encoding a combination of neoantigens, which is a 'method of manufacture', and comprises the technical steps of DNA sequencing and optionally expression analysis according to claim 1.” [remarks, page 9].
In response, and as described in Step 2A Prong II of the 101 analyses above, constructing a personalized vector of claim 12 step (v) was found to be equivalent to the words "apply it" because, in light of the specification, constructing a personalized vector only encompasses selecting a combination of neoantigens for a constructing personalized vector and does not encompass any physical steps and/or laboratory/clinical steps for synthesizing/constructing a personalized vector that can utilized as a vaccine. Consequently, the constructing steps do not construct a practical application (i.e., a method of manufacture) of constructing a personalized vaccine and/or a personalized vector.
Furthermore, using DNA sequencing is an extra-solution activity that does not integrate the recited judicial exception into a practical application and does not add more than the recited judicial exception because it is utilized to obtain nucleic acid data that is subsequently analyzed by the abstract ideas. With respect to claim 1 determining expression levels, it is noted in Step 2A Prong II of the 101 analyses above, the claimed step “determining expression level of coding sequence comprising at least one of said mutations from (claim 1 step (c))” is drawn to abstract ideas.
Therefore, the claims are not patent eligible under 35 U.S.C § 101.
Conclusion
Claims 1-2, 4-9, and 11-12 are rejected.
No claims are allowed.
Finality
Applicant's This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH C PULLIAM whose telephone number is (571)272-8696. The examiner can normally be reached 0730-1700 M-F.
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/J.C.P./ Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635