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 .
Election/Restrictions
Applicant’s election of Group I, claims 1-39 and 43-50, in the reply filed on 9/24/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In this instant application, claims 42 and 51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/24/2025. Claims 1-39 and 43-50 are being examined on the merits.
Status of the Claims
Claims 1-39 and 43-50 are examined; claims 40-41 are cancelled; claims 42 and 51 are withdrawn.
Priority
This US Application 17/539,157 (11/30/2021) is a DIV of 14/787,110 (10/26/2015) which is a 371 of PCT/EP2014/001232 (05/07/2014) and claims priority of Foreign Application EP2013/001400 (05/10/2013), as reflected in the filing receipt mailed on April 13, 2022. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-39 and 43-50 is 05/10/2013.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/11/2022; 10/20/2022; 01/05/2024; 06/06/2024; 05/20/2024; 07/24/2024; 03/03/2025 and 09/24/2025 were considered by the examiner.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See disclosure page 27 line 14; page 73 line 23; page 84 line 12; page 87 line 5; and page 87 line 6. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
Claims 18-19 and 21-22 recite contingent limitations (MPEP 2111.04.II) because the peptide is identified as immunogenic ‘if’ the conditions in steps (i)-(iii) are met which causes the limitations to constitute non-requirements. Claims 20 and 49 depend on claim 18 which makes claims 20 and 49 non-requirements under the broadest reasonable interpretation of contingent limitations. Claim 23 depends on claim 21 which makes claim 23 a non-requirement under the broadest reasonable interpretation of contingent limitations.
Therefore, claims 18-23 and 49 are being interpreted as non-requirements under the broadest reasonable interpretation of contingent limitations. The applicant could adjust the claim language if this interpretation is not intended.
The recited “and optionally one or more non-cancerous cells” in claim 35 is interpreted as a optional limitation and therefore a limitation not required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-39 and 43-49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a) a first score for binding of a modified peptide to one or more MHC molecules, and b) a second score for binding of the corresponding parent peptide to the one or more MHC molecules, and/or c) a third score for binding of the modified peptide when present in a MHC- peptide complex to one or more T cell receptors” which is indefinite because it is unclear which score is an actual requirement. It is unclear if the first score AND the second score both requirements over the third score; or if the claim requires the first score OR the second score OR the third score. In the interest of compact prosecution the first interpretation is being applied wherein the first score AND the second score both requirements over the third score. The recited “a) a first score for binding of a modified peptide to one or more MHC molecules, and b) a second score for binding of the corresponding parent peptide to the one or more MHC molecules, and/or c) a third score for binding of the modified peptide when present in a MHC- peptide complex to one or more T cell receptors” is being interpreted as requiring one of the three scores introduced due to the “and/or” relationship. Thus, the first score will the score addressed in this examination.
Accordingly, claims 10-17 and 33 do not fit the case in which “the first score” is chosen - claim 1. Therefore, when the art already reads on the “first score” limitations it makes the “second” and “third” score limitations in claims 10-17 and 33 non-requirements.
Dependent claims 2-39 and 43-49 are similarly rejected because they are dependents claims and do not resolve the lack of clarity introduced.
Claim 6 recites “different MHC molecule types, in particular different MHC alleles” A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation (different MHC molecule types), and the claim also recites (in particular different MHC alleles) which is the narrower statement of the range/limitation. It is unclear which range is intended to be covered by the claim The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 5 and 33 recite “preferably” which is indefinite because it is unclear if the limitation is required by the claims.
Claim 34 recites “such as one or more cancer cells” which is indefinite because it recites exemplary claim language (see MPEP 2173.05(d)).
Claim 38 is indefinite because it recites a use claim (see MEP 2173.05(q)).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-39 and 43-49 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
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 1-39 and 43-49), 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))?
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)).
Mathematical concepts recited in instant claims 1, 8-10, 13-15, 18-19, 21-22, 32-33, 44 and 49 include the term “score”; which is a mathematical concepts. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one having ordinary skill in the art. Thus, the recited terms corresponds to verbal equivalents of mathematical concepts because they constitute actions executed by a group of mathematical steps in a form of a mathematical algorithm; thus mathematical concepts (MPEP 2106.04(a)(2)). A mathematical concept need not be expressed in mathematical symbols, because "words used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989).
Mental processes, defined as concepts or steps practically performed in the human mind such as steps of observations, evaluations, judgments, analysis, opinions or organizing information include "ascertaining a score" (claims 1 and 13-14), “determining that tumor cells express the modified peptide” (claim 46); “determining that normal cells express the parent peptide” (claim 47); “ranking” (claim 49), “identifying nonsynonymous mutations in one or more protein-coding regions encoding” (claim 34) and “identifying from nucleic acid and/or peptide sequence data .. a plurality of modified peptides expressed in the tumor … identifying those modified peptides in which the substituted amino acid has sufficiently different physico-chemical properties from the parent amino acid such that the subject's TCR repertoire is able to detect the modified peptide; and selecting, …, from the plurality of modified peptides, as immunogenic to the subject's TCR repertoire at least one candidate modified peptide with respect to which” (claim 50). Under the BRI, the recited limitations are mental processes because a human mind is sufficiently capable of identifying information about peptides, evaluating a score; selecting and ranking data accordingly .
Dependent claims 7-15, 17-22, 32-33, 38-39 and 43-44 recite further details about “scores ascertained”; dependent claims 2-6, 16, 23-31, 36-37 and 48-49 recite further details about the “modified peptides” the “parent peptides” and the “MHC molecules” for which the score is ascertained; not reciting any additional non-abstract elements; all reciting further aspects of the information being analyzed, the manner in which that analysis is performed. Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas. The instant claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A Prong One: 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))?
Instant claims 1, 8 and 35 recite additional elements that are not abstract ideas: “receiving, by a computer-based analytical process, nucleic acid and/or peptide sequence data” (claim 1); “computer-based analytical process” (claim 1 and 8); and “sequencing a whole or partial genome or transcriptome” (claim 35).
Claims reciting “receiving sequence data” read on receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321. Dependent claim 45 recite further details about the type of data received reading on data gathering activities or the type of data being gathered.
Claims reciting “sequencing a whole or partial genome or transcriptome” 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 reciting “ascertaining on a score” by 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.
Hence, these are mere instructions to apply the abstract idea using a computer and insignificant extra-solution activity and therefore the claim does not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)). None of the dependent claims recite any additional non-abstract elements; they are all directed to further aspects of the information being analyzed, the manner in which that analysis is performed, or the mathematical operations performed on the information. [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of the 35 USC § 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05). Claim 81 recites 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 “receiving” data read on performing a standard computer task, which the courts have identified as a conventional computer function in Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362; OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015); and buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014).
Claims directed to “sequencing a whole or partial genome or transcriptome” (claim 35); recite steps known in the art as conventional (Li et. al. “Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines” Cancers 3(4):4191-4211 (2011) – pg. 4196 para. 1).
When the claims are considered as a whole, they do not integrate the abstract idea into a practical application; they do not confine the use of the abstract idea to a particular technology; they do not solve a problem rooted in or arising from the use of a particular technology; they do not improve a technology by allowing the technology to perform a function that it previously was not capable of performing; and they do not provide any limitations beyond generally linking the use of the abstract idea to a broad technological environment. See MPEP 2106.05(a) and 2106.05(h). [Step 2B: No]
Conclusion: Instant claims are directed to non-statutory subject matter
For these reasons, the claims in this instant application, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the abstract idea, so instant claims 1-39 and 43-49 are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-33, 38-39, 43-45 and 48-49 are rejected under 35 U.S.C. 103(a) as being unpatentable over DeGroot et. al. “Prediction of immunogenicity for therapeutic proteins: State of the art” Curr. Opin. Drug. Discov. Devel. 10(3):332-340 (2007) – referred to in the action as DeGroot.
Independent claim 1 recites “method for identifying one or more immunogenic peptides, the method comprising the steps of: receiving, by a computer-based analytical process, nucleic acid and/or peptide sequence data for a plurality of modified peptides, each modified peptide comprising one or more amino acid modifications at position(s), relative to a corresponding parent peptide; ascertaining, for each of the plurality of modified peptides, via the computer-based analytical process, each of: a) a first score for binding of a modified peptide to one or more MHC molecules, and b) a second score for binding of the corresponding parent peptide to the one or more MHC molecules, and/or c) a third score for binding of the modified peptide when present in a MHC- peptide complex to one or more T cell receptors, identifying, via a computer-based analytical process, from the plurality of modified peptides, at least one candidate modified peptide as immunogenic, by determining that, for the at least one candidate modified peptide: (i) the first score indicates binding to the one or more MHC molecules; (ii) the second score indicates binding to the one or more MHC molecules; and/or (iii) the third score indicates a probability of binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors”. Dependent claim 2 recites “wherein the modified peptides each comprise a fragment of a modified protein, said fragment comprising the amino acid modification(s) present in the protein”. Dependent claim 38 recites “which is used in the manufacture of a vaccine”. Dependent claim 39 recites “wherein the vaccine comprises modified peptide(s) identified as immunogenic by said method. Dependent claim 43 recites “wherein the one or more MHC molecules are MHC class II molecules”. Dependent claim 44 recites “wherein the first and the second scores are ascertained for binding to more than one MHC molecule, and the more than one MHC molecule comprises one or more MHC class I molecules and one or more MHC class II molecules”. Dependent claim 45 recites “wherein the subject is a human individual”.
De Groot teaches immunoinformatics analysis tools searching epitopes and immune-related molecules for vaccine design (i.e. peptide(s) identified as immunogenic used in the manufacture of a vaccine) (pg. 3 col. 2 para. 4) for humans (pg. 3 col. 2 para. 2); wherein protein derived T-cell epitopes binding to MHC can be predicted based on the presence or absence of specific amino acid side chains, determining how tightly an epitope binds to MHC (i.e. reading on the first score for binding to MHC molecule) (pg. 4 col. 1 para. 2); wherein a tool – OptiMatrix – (i.e. computer-based analytical process) iteratively substitutes all 20 amino acids in any given position of protein sequence (i.e. amino acid modifications in peptide sequences) and then re-analyzes the predicted immunogenicity of the sequence, following the change (pg. 7 col. 2 para. 3); wherein predictions can be made for MHC class I and MHC class II (pg. 4 Table 1); wherein immunogenicity is related to the strength of epitope binding to MHC molecules (i.e. reading on the first score indicating binding to the one or more MHC molecules) (pg. 4 col. 1 para. 1); wherein human epitope-driven vaccines have been produced and used in preclinical studies (pg. 7 col. 1 para. 3); anticipating claims 1-2, 38-39 and 43-45.
Dependent claim 3 recites “wherein the parent peptide has a germline amino acid at the position(s) corresponding to the position(s) of the amino acid modification(s) in the modified peptide”. DeGroot teaches an algorithm that measures the extent of 'human-ness' of strings of nonomer peptide frames, aiming to maximize the human-like sequence content by substitution of amino acids derived from human germline sequences of antibody framework and complementarity determining regions (pg. 7 col. 2 para. 4); anticipating claim 3.
Dependent claim 4 recites “wherein the parent peptide and the modified peptide are identical but for the amino acid modification(s)”. DeGroot teaches the measurement of both T-cell response to the whole wild-type therapeutic protein and T-cell response to epitopes derived (i.e. reading on fragments) from the wild-type therapeutic protein (i.e. reading on score for binding of a modified peptide to one or more MHC molecules and score for binding of the corresponding parent peptide to the one or more MHC molecules) (pg. 7 col. 1 para. 3); wherein a tool – OptiMatrix –iteratively (i.e. one by one – reading on the parent peptide and the modified peptide are identical but for the amino acid – the one being modified one at the time from the parent) substitutes all 20 amino acids in any given position of protein sequence (i.e. amino acid modifications in peptide sequences) and then re-analyzes the predicted immunogenicity of the sequence, following the change (pg. 7 col. 2 para. 3); anticipating claim 4.
Dependent claim 5 recites “wherein the parent peptide and the modified peptide are each 8 to 15, preferably 8 to 12, amino acids in length”. De Groot teaches tool named OptiMatrix identifies critical residues that contribute most to MHC binding affinity across multiple nonomer peptide frames and multiple HLA MHC alleles and averages the contribution of each amino acid to binding across nonomer peptide binding frames and HLA MHC alleles (pg. 7 col. 2 para. 3); anticipating claim 5.
Dependent claim 6 recites “wherein the one or more MHC molecules each comprise different MHC molecule types, in particular different MHC alleles”. Dependent claim 7 recites “wherein the one or more MHC molecules are each MHC class I molecules and/or MHC class II molecules”. DeGroot teaches immunogenicity predictions made for a number of MHC class I and MHC class II molecules (pg. 4 Table 1); anticipating claims 6-7.
Dependent claim 8 recites “wherein the first score and/or the second score are ascertained by a computer-based analytical process comprising a sequence comparison with a database of MHC-binding motifs”. De Groot teaches a tool – EpiMatrix – a matrix-based algorithm for T-cell epitope mapping that enables the evaluation of protein sequences for T-cell epitopes and comparisons across for different HLA MHC alleles comprising MHC class I and MHC class II (pg. 5 col. 1 para. 1 and pg. 4 Table 1); wherein prediction matrices were used for eight MHC class II alleles that are representative of more than 98% of human populations (i.e. reading on sequence comparison with a database of MHC-binding motifs) (pg. 5 col. 1 para. 2); anticipating claim 8.
Dependent claim 9 recites “wherein the first score that indicates binding to the one or more MHC molecules satisfies a first pre-determined threshold for binding to the one or more MHC molecules”. DeGroot teaches that EpiMatrix compared each relevant tested protein by summing the total number of EpiMatrix scores for each protein that was above an accepted cutoff for immunogenicity (epitope score > 1.67) (i.e. a first pre-determined threshold for binding to the one or more MHC molecules); anticipating claim 9
Dependent claim 24 recites “wherein the plurality of modified peptides comprises two or more different modified peptides, said two or more different modified peptides comprising the same modification(s)”. Dependent claim 25 recites “wherein the two or more different modified peptides comprising the same modification(s) comprise different fragments of a modified protein, said different fragments comprising the same modification(s) present in the protein”. DeGroot teaches a tool – OptiMatrix – that iteratively substitutes all 20 amino acids in any given position of protein sequence and then re-analyzes the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (i.e. there are cases in which the same amino acid can be substituted at the same position at different iterations) (pg. 7 col. 2 para. 3); wherein OptiMatrix identifies critical residues that contribute most to MHC binding affinity across multiple nonomer peptide frames (i.e. different modified fragments) and multiple HLA MHC alleles, and averages the contribution of each amino acid to binding across nonomer peptide binding frames and HLA MHC alleles (pg. 7 col. 2 para. 3); anticipating claims 24-25.
Dependent claim 26 recites “wherein the two or more different modified peptides comprising the same modification(s) comprise all potential MHC binding fragments of a modified protein, said fragments comprising the same modification(s) present in the protein:. DeGroot teaches the measurement of both T-cell response to the whole wild-type therapeutic protein and T-cell response to the epitopes derived from the wild-type therapeutic protein (i.e. reading on all potential MHC binding fragments) (pg. 7 col. 1 para. 3); anticipating claim 26.
Dependent claim 27 recites “further comprising selecting a modified peptide from the two or more different modified peptides that has a higher probability or that has the highest probability for binding to one or more MHC molecules”. DeGroot teaches a tool – OptiMatrix – that iteratively substitutes all 20 amino acids in any given position of protein sequence and then re-analyzes the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (pg. 7 col. 2 para. 3); wherein OptiMatrix identifies critical residues that contribute most to MHC binding affinity across multiple nonomer peptide frames and multiple HLA MHC alleles and averages the contribution of each amino acid to binding across nonomer peptide binding frames and HLA MHC alleles (i.e. identifying sequences with higher probability of binding to MHC molecules since the residues with most contribution are identified and contribution to binding is averaged for the sequence) (pg. 7 col. 2 para. 3); anticipating claim 27
Dependent claim 28 recites “wherein the two or more different modified peptides comprising the same modification(s) differ in length and/or position of the modification(s)”. Dependent claim 29 recites “wherein the plurality of modified peptides comprises two or more different modified peptides”. Dependent claim 30 recites “wherein said two or more different modified peptides comprise different amino acid modifications”. Dependent claim 31 recites “wherein the different amino acid modifications are present in the same and/or in different proteins”. Dependent claim 48 recites “wherein the two or more different modified peptides comprising the same amino acid substitution differ in the position of the amino acid substitution”. DeGroot teaches a tool – OptiMatrix – that iteratively substitutes all 20 amino acids in any given position of protein sequence and then re-analyzes the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (i.e. there are cases in which the same amino acid can be substituted at different positions at different iterations) (pg. 7 col. 2 para. 3); anticipating claims 28-31 and 48
Dependent claim 32 recites “which comprises comparing the scores of two or more of said different modified peptides”. DeGroot teaches a tool – OptiMatrix – that iteratively substitutes all 20 amino acids in any given position of protein sequence and then re-analyzes the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (pg. 7 col. 2 para. 3); wherein OptiMatrix identifies critical residues that contribute most to MHC binding affinity across multiple nonomer peptide frames and multiple HLA MHC alleles and averages the contribution of each amino acid to binding across nonomer peptide binding frames and HLA MHC alleles (i.e. allowing the comparison of the averages contributions for each peptide) (pg. 7 col. 2 para. 3); anticipating claim 32.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 34-37 and 46-47 are rejected under 35 U.S.C. 103(a) as being unpatentable over DeGroot as applied to claim 1 in the 102 rejection above further in view of Li et. al. “Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines” Cancers 3(4):4191-4211 (2011) – referred to in the action as Li.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Dependent claim 34 recites “further comprising identifying nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides”. Dependent claim 35 recites “wherein the amino acid modification(s) is/are identified by sequencing a whole or partial genome or transcriptome of one or more cells such as one or more cancer cells and optionally one or more non-cancerous cells and wherein the method further comprises identifying mutations in one or more protein-coding regions encoding at least one of the modified peptides”. Dependent claim 36 recites “wherein said mutations are somatic mutations”. Dependent claim 37 recites “wherein said mutations are cancer mutations”. Dependent claim 46 recites “further comprising the step of determining that tumor cells express the modified peptide”. Dependent claim 47 recites “further comprising the step of determining that normal cells express the parent peptide”.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 34-37 and 46-47; DeGroot does not explicitly teach the recited limitations above. However, Li teaches whole-genome sequencing studies (pg. 4194 para. 2) for comparative analysis of a tumor and normal genome from patients with cancer for the unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes and the identification of candidate unique tumor antigens associated with an alteration in the amino acid sequence (nonsynonymous mutations) (i.e. (pg. 4198 para. 5 to 4199 para. 1); wherein unique tumor antigens are only expressed in a single cancer, and are typically the result of point mutations (i.e. responsible for the expression of modified peptides) or other genetic changes present only in the tumor unique and not expressed in any normal tissues (i.e. no modification identified in normal cells reading on determining that normal cells express the parent peptide) (pg. 4196 para. 3); reading on claims 34-37 and 46-47
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 34-37 and 46-47; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Li to the computational methods used to predict scores as taught by DeGroot to identify nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides; wherein the amino acid modification(s) is/are identified by sequencing a whole or partial genome or transcriptome of one or more cells; wherein the method further comprises identifying mutations in one or more protein-coding regions encoding at least one of the modified peptides; wherein said mutations are somatic mutations; wherein said mutations are cancer mutations; determining that tumor cells express the modified peptide and determining that normal cells express the parent peptide. One of ordinary skill in the art would be motivated to apply the teachings by Li to the method by DeGroot to investigate the identification of mutated tumor antigens for the design of personalized cancer vaccines (pg. 4191 para. 1 Li). 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 controlling immunogenicity.
Claim 50 is rejected under 35 U.S.C. 103(a) as being unpatentable over Li in view of Haan et. al. “Structure-based Design and Evaluation of MHC Class II Binding Peptides” Biologicals 29:289–292 (2001) – referred to in the action as Haan – in view of Kosmrlj et. al. "How the thymus designs antigen-specific and self-tolerant T cell receptor sequences." Proceedings of the National Academy of Sciences 105(43):16671-16676 (2008) – referred to in the action as Kosmrlj – in view of Yu et. al. "The compositional adjustment of amino acid substitution matrices." Proceedings of the National Academy of Sciences 100(26):15688-15693 (2003) – referred to in the action as Yu – in view of Graur et. al. “Amino Acid Composition and the Evolutionary Rates of Protein-Coding Genes” J. MoI. Evol. 22:53-62(1985) – referred to in the action as Graur – in view of DeGroot.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Independent claim 50 recites “a method for producing a personalized cancer vaccine for a subject having a tumor, the method comprising the steps of: … identifying from nucleic acid and/or peptide sequence data that is obtained from tumor and normal cells of a subject, a plurality of modified peptides expressed in the tumor, each comprising an amino acid substitution at a position, relative to a corresponding parent peptide expressed in the normal cells”. Li teaches whole-genome sequencing studies (pg. 4194 para. 2) for the design of personalized cancer vaccines (pg. 4191 para. 1); wherein analyses of epitope landscape in breast cancer suggest that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines (pg. 4192 para. 1); wherein comparative analysis of a tumor from patients with cancer and normal genome led to the unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes and the identification of candidate unique tumor antigens associated with an alteration in the amino acid sequence (nonsynonymous mutations) (i.e. (pg. 4198 para. 5 to 4199 para. 1); wherein unique tumor antigens are only expressed in a single cancer, and are typically the result of point mutations (i.e. responsible for the expression of modified peptides) or other genetic changes present only in the tumor unique and not expressed in any normal tissues (i.e. no modification identified in normal cells reading on determining that normal cells express the parent peptide) (pg. 4196 para. 3); reading on the recited limitation in claim 50.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claim 50; Li does not explicitly teach “ascertaining, for each of the plurality of modified peptides, via a computer-based analytical process each of: a) a first score for binding of the modified peptide to one or more MHC molecules by using a peptide: MHC binding predictive model, wherein the first score is indicative of a likelihood of the modified peptide binding to one or more MHC molecules and b) a second score for binding of the corresponding parent peptide to the one or more MHC molecules by using the peptide: MHC binding predictive model, wherein the second score is indicative of a likelihood of the corresponding parent peptide binding to one or more MHC molecules” and “(i) the first score satisfies a first pre-determined threshold indicating binding to the one or more MHC molecules such that the candidate modified peptide is MHC- presented”. Haan teaches the structure-based design and evaluation of MHC class II binding peptides (pg. 289 title); wherein peptide gpMBP72-85 is the wild type – QKSQRSQDENPV (i.e. parent sequence) (pg. 291 col. 2 para. 1); wherein gpMBP72-85 was modeled by first replacing its residues by alanine (i.e. modifications from parent peptide) and then manually docking the original amino acid residue into the groove by changing the alanine (pg. 289 col. 2 para. 2); wherein a molecular docking modelling program (i.e. computer-based analytical process) (pg. 289 col. 2 para. 2) was used to score the docking substitutions at each amino acid position to the groove of the MHC class II molecule - RT1.BL (pg. 290 Table 1); wherein each score indicated the level of preference for that sequence in the binding motif while the score being compared to the aligned parent gpMBP72-85 (i.e. reading on the first and second score regarding binding of modified peptide and parent to MHC molecules) (pg. 290 col. 2 para. 1); reading on the recited limitation in claim 50.
Regarding claim 50; Li does not explicitly teach “ thus the likelihood that TCRs binding the corresponding parent peptide would have been deleted during the subject's development” and “(ii) the second score satisfies a second pre-determined threshold indicating binding to the one or more MHC molecules such that TCRs binding the corresponding parent peptide would have been deleted during the subject's development” and “such that the subject's TCR repertoire is able to detect the modified peptide”. However, Kosmrlj teaches a computational model that studies the contributions of positive and negative selection of TCRs in the recognition of antigenic peptides with specificity wherein diverse repertoire of self-pMHC-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection (pg. 16671 col.1 para. 1); wherein if the interaction/binding energy between a TCR and self-pMHC – self-antigen (i.e. parent/unmodified) and MHC complex – is more attractive than (exceeds) a threshold value, EN, this TCR is negatively selected (deleted during development) (pg. 16672 col. 2 para. 2); wherein each amino acid on the antigenic peptides was then mutated to the 19 other possibilities, and recognition by the reactive TCRs was again assessed (i.e. TCR repertoire being able to detect the modified peptide (pg. 16673 col. 1 para. 2); reading on the recited limitation in claim 50.
Regarding claim 50; Li does not explicitly teach “c) a third score for chemical and physical dissimilarity between the amino acids at the position in the parent and modified peptides by referencing a substitution matrix that describes a rate at which one amino acid in a sequence changes over evolutionary time to determine the probability of observing the amino acid substitution over evolutionary time, and thus identifying those modified peptides in which the substituted amino acid has sufficiently different physico-chemical properties from the parent amino acid”. Yu teaches the protein-comparison methods using amino acid substitution matrices (i.e. computer-based analytical process) (pg. 15688 col. 1 para. 2) comprising comparison of the parent sequence with the substituted/modified peptide sequence (pg. 15691 Fig. 1) with the sequences assessed by a score composed by the sum of substitution and gap scores to estimate evolutionary distances and reflect as accurately as possible the physicochemical correspondences (i.e. identifying chemical and physical dissimilarity between the amino acids at the position in the parent and modified peptides by referencing a substitution matrix) and evolved mutational differences between amino acid sequences (pg. 15688 col. 1 para. 2); wherein the substitution scores take a log-odds form (i.e. determine the probability of observing the amino acid substitution over evolutionary time), involving the ratio of ‘‘target’’ to ‘‘background’’ frequencies (i.e. rate at which one amino acid in a sequence changes) derived from large, carefully curated sets of protein alignments (pg. 15688 col. 1 para. 1); reading on the recited limitation in claim 50.
Regarding claim 50; Li does not explicitly teach “(iii) the third score for at least one amino acid substitution in the candidate modified peptide indicates a lower probability of observing the amino acid substitution over evolutionary time than at least one other modified peptides in the plurality”. Graur teaches that the propensity of a polypeptide to evolve fast or slowly may be predicted from an index or indices of protein mutability directly derivable from the amino acid composition; wherein amino acids differ from one another in their evolutionarily effective mutation rates (i.e., substitution rates) and different probabilities (i.e. reading on a lower probability for one modified sequence to the other of observing the amino acid substitution over evolutionary time) (pg. 55 col. 1 para. 3); wherein for example, methionine (Met) changes to arginine (Arg), isoleucine (Ile), leucine (Lea), Lysine (Lys), threonine (Thr), and valine (Vat) with relative probabilities of 1/9, 3/9, 2/9, 1/9, 1/9, and 1/9 (i.e. reading on a score – sum of different amino acids substitutions in a sequence – indicating a probability) (pg. 55 col. 2 para. 2); reading on the recited limitation in claim 50.
Regarding claim 50; Li does not explicitly teach “selecting, via a computer-based analytical process, from the plurality of modified peptides, as immunogenic to the subject's TCR repertoire at least one candidate modified peptide … producing a personalized cancer vaccine for the subject, which comprises a peptide or polypeptide comprising the at least one candidate modified peptide selected as immunogenic to the subject's TCR repertoire or a nucleic acid encoding the peptide or polypeptide”. De Groot teaches immunoinformatics analysis tools searching epitopes and immune-related molecules for vaccine design (pg. 3 col. 2 para. 4) for humans (pg. 3 col. 2 para. 2); wherein protein derived T-cell epitopes binding to MHC can be predicted based on the presence or absence of specific amino acid side chains, determining how tightly an epitope binds to MHC (pg. 4 col. 1 para. 2); wherein a tool – OptiMatrix – (i.e. computer-based analytical process) iteratively substitutes all 20 amino acids in any given position of protein sequence (i.e. amino acid modifications in peptide sequences) and then re-analyzes the predicted immunogenicity of the sequence, following the change (pg. 7 col. 2 para. 3); wherein immunogenicity is related to the strength of epitope binding to MHC (pg. 4 col. 1 para. 1); wherein human epitope-driven vaccines have been produced and used in preclinical studies (pg. 7 col. 1 para. 3); reading on the recited limitation in claim 50.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 50; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Haan, Kosmrlj, Yu, Graur and DeGroot to the whole-genome sequencing studies for the design of personalized cancer vaccines wherein analyses of epitope landscape in breast cancer suggest that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines as taught by Li to ascertain for each of the plurality of modified peptides: a) a first score for binding of the modified peptide to one or more MHC molecules, and b) a second score for binding of the corresponding parent peptide to the one or more MHC molecules by using the peptide: MHC binding predictive model, wherein the second score is indicative of a likelihood of the corresponding parent peptide binding to one or more MHC molecules, and thus the likelihood that TCRs binding the corresponding parent peptide would have been deleted during the subject's development, and c) a third score for chemical and physical dissimilarity between the amino acids at the position in the parent and modified peptides by referencing a substitution matrix that describes a rate at which one amino acid in a sequence changes over evolutionary time to determine the probability of observing the amino acid substitution over evolutionary time, and thus identifying those modified peptides in which the substituted amino acid has sufficiently different physico-chemical properties from the parent amino acid such that the subject's TCR repertoire is able to detect the modified peptide; and selecting, via a computer-based analytical process, from the plurality of modified peptides, as immunogenic to the subject's TCR repertoire at least one candidate modified peptide with respect to which: (i) the first score satisfies a first pre-determined threshold indicating binding to the one or more MHC molecules such that the candidate modified peptide is MHC- presented; and (ii) the second score satisfies a second pre-determined threshold indicating binding to the one or more MHC molecules such that TCRs binding the corresponding parent peptide would have been deleted during the subject's development; and (iii) the third score for at least one amino acid substitution in the candidate modified peptide indicates a lower probability of observing the amino acid substitution over evolutionary time than at least one other modified peptides in the plurality; and producing a personalized cancer vaccine for the subject, which comprises a peptide or polypeptide comprising the at least one candidate modified peptide selected as immunogenic to the subject's TCR repertoire or a nucleic acid encoding the peptide or polypeptide. One of ordinary skill in the art would be motivated to apply the teachings by Haan, Kosmrlj, Yu, Graur and DeGroot to the method by Li to use structural information regarding binding of peptides to the major histocompatibility complex (MHC) class II molecule is of great use for the design of compounds that intervene in the interaction between the MHC-peptide-T-cell receptor (TCR) complex (pg. 289 col. 1 para. 1 Haan); to i