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 04/14/2026, has been fully considered.
In view of the amendment and remarks from 04/14/2026, the objection to the specification and the rejection of the following claims are withdrawn:
claims 1-39 and 43-49 under 35 USC § 112(b);
claim 50 under statutory double patenting rejection.
The following rejections and/or objections are either maintained or newly applied for claims 1-37 and 43-49. They constitute the complete set applied to the instant application. Herein, "the previous Office action" refers to the Non-Final Rejection of 11/17/2025.
Status of the Claims
Claims 38-42 and 50-51 are canceled.
Claims 1-37 and 43-49 are pending.
Claims 1-37 and 43-49 are rejected.
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 1-37 and 43-49 is 05/10/2013.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/14/2026 was considered by the examiner.
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 1-37 and 43-49 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 method (claims 1-37 and 43-49), which falls within one of the categories of statutory subject matter.
[Step 1: claims 1-37 and 43-49: 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 mathematical concepts (in particular mathematical relationships and formulas) and mental processes (in particular procedures for observing, analyzing and organizing information) as well as a law of nature or a natural phenomenon are as follows.
Mathematical concepts (in particular mathematical relationships and formulas) include:
• “score” (claims 1, 8-10, 13-15, 18-19, 21-22, 32-33, 44 and 49).
The claims identified above read on math. 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, for each of the plurality of modified peptides, …, 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 c) a third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors" (independent claim 1);
• "identifying, …, 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" (independent claim 1);
• "identifying nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides" (claim 34)
• "identifying mutations in one or more protein-coding regions encoding at least one of the modified peptides" (claim 35);
• "determining that tumor cells express the modified peptide" (claim 46); and
• "determining that normal cells express the parent peptide" (claim 47).
Under the BRI, the recited limitations are mental processes because a human mind is also sufficiently capable of integrating, eliminating data and arrange data presented to reduce visual overlap.
Dependent claims 2-33, 36-37, 43-45 and 48-49 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, 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; claims 7-15, 17-22, 32-33 and 43-44 recite further details about “scores ascertained" and claim 45 further recites details about the subject.
Furthermore, the instant claims recite a natural correlation by correlating the measurement of nucleic acid and/or peptide sequence data naturally found in the body with its score classification. (see MPEP 2106.04(b).I).
[Step 2A Prong One: claims 1-37 and 43-49: 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 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 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" (independent claim 1);
• "computer-based analytical process” (claim 1 and 8);
• “sequencing a whole or partial genome or transcriptome” (claim 35).
Considerations under Step 2A, Prong Two
The recited limitations in claims 1-37 and 43-49 are interpreted as requiring the use of a computer. 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. The instant claims state nothing more than that a generic computer performs the functions that constitute the abstract idea (MPEP 2106.05(f)).
The judicial exceptions in the claims are considered to perform the claimed abstract idea with a computer, 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.
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 claims do not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)).
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs).
In this Step 2A, Prong Two immediately above claim steps and/or elements were identified as part of one or more additional elements. Additional elements are further discussed in Step 2B below.
Here in Step 2A, Prong Two, no additional step or element clearly demonstrates integration of the JE(s) into a practical application.
[Step 2A Prong Two: claims 1-37 and 43-49: 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 1-37 and 43-49 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)).
Further, the courts have found that receiving data well-understood, routine, and conventional functions of a computer when claimed in a generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versa ta Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(Il)(i)).
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).
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 1-37 and 43-49: 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 04/14/2026 have been fully considered but are not persuasive for the reasons below:
Applicant asserts starting in pg. 13 para. 3:
The subject matter of the present claims includes, inter alia, a particular combination of computer-based processing steps that, among other things, utilize complex computational models to quantify binding likelihoods and similarity between biological molecules in a manner that the human mind is not equipped to do. As such, as an initial matter, Applicants respectfully disagree with the Office Action's assertion that the claimed invention is merely "using a computer to perform an abstract idea" (Office Action, page 10). Moreover, Applicants' unique combination of steps, as recited in claim 1, carry out a particular solution to the challenge of predicting immunogenicity and identifying target peptides suitable for cancer vaccines. Claim 1 thus represents a particular solution to a particular problem and is far from a mere abstract idea. Applicants' approach is based on a unique model of a particular combination of physical factors influencing immunogenicity. Applicants' approach. leverages this model to provide more accurate predictions of immunogenicity, as demonstrated in the Examples of the specification, thereby offering a route to identifying one or more immunogenic peptides for inclusion in cancer vaccines. Accordingly, for at least these reasons, Applicants submit that claim 1, and the claims depending therefrom, are not directed to an abstract idea, but rather, a particular approach for identifying certain modified peptides predicted as being immunogenic (for inclusion in a cancer vaccine) with a computer based analytical approach, and indeed are patent eligible under 35 U.S.C. § 101. As such, reconsideration and withdrawal of the rejection are respectfully requested
It is respectfully submitted that this is not persuasive because the argued "a particular solution to the challenge of predicting immunogenicity and identifying target peptides suitable for cancer vaccines" is related to the claimed "ascertaining and identifying binding affinities" which have been identified as judicial elements in the examination. See claim rejections above. In regards to an improvement over what is available in the state of the art, the analysis at Step 2A, Prong 2, considers the claims as a whole, i.e., the additional elements in combination with the judicial exceptions (see MPEP 2106.05(a)), although the integration or improvement provided in the claim must flow from the additional elements and not the judicial exceptions to be considered persuasive. However, Step 2B instructs that an inventive concept cannot be provided the by judicial exception. An “inventive concept” is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself (Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966)). In the instant claims, the identified additional elements (i.e. receiving data and the argued computer-based analytical process) are not sufficient to integrate an abstract idea into a practical application as explained in the claim rejections above.
Claim Rejections - 35 USC § 102
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)(l) 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-15, 18-19, 24-32, 43-45 and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DeGroot (“Prediction of immunogenicity for therapeutic proteins: State of the art” Curr. Opin. Drug. Discov. Devel. 10(3):332-340 (2007)), as cited in the 04/11/2022 IDS. Any newly recited portions are necessitated by claim amendment.
Claim 1 recites:
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
c) a third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors
• 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 database are used in validated T-cell epitope-mapping tools (i.e. receiving data related to nucleic acid and/or peptide sequence data for a plurality of modified peptides) (pg. 4 Table 1); wherein protein derived T-cell epitopes binding to MHC can be predicted (i.e. reading on ascertaining a score) 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 of a modified peptide to one or more MHC molecules) (pg. 4 col. 1 para. 2); wherein both T-cell response to the whole wild-type therapeutic protein (i.e. reading on a second score for binding of the corresponding parent peptide to the one or more MHC molecules) and T-cell response to epitopes derived from the wild-type therapeutic protein (i.e. reading on peptides derived from a protein) are measured (pg. 7 col. 1 para. 3); wherein prediction matrices were used for eight MHC class II alleles and the number of potential T-helper epitopes that would occur in random sequence pseudo proteins composed of amino acids at their naturally occurring frequencies were measured so that the tool EpiMatrix could compare 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. reading on a third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors) (pg. 5 col. 1 para. 2). Further, DeGroot teaches using tools to measure (i) T-cell response to the whole wild-type protein; (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (i.e. also reading on the recited second, first and third score, respectively) (pg. 8 col. 1 para. 1).
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
(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
• 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 database are used in validated T-cell epitope-mapping tools (i.e. receiving data related to nucleic acid and/or peptide sequence data for a plurality of modified peptides) (pg. 4 Table 1); wherein protein derived T-cell epitopes binding to MHC can be predicted (i.e. reading on identifying a score) 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 of a modified peptide to one or more MHC molecules) (pg. 4 col. 1 para. 2); wherein both T-cell response to the whole wild-type therapeutic protein and T-cell response to epitopes derived (i.e. reading on peptides derived from a protein) from the wild-type therapeutic protein are measured (i.e. reading on second score indicates binding to the one or more MHC molecules) (pg. 7 col. 1 para. 3); wherein prediction matrices were used for eight MHC class II alleles and the number of potential T-helper epitopes that would occur in random sequence pseudo proteins (i.e. modified peptides) composed of amino acids at their naturally occurring frequencies were measured so that the tool EpiMatrix could compare 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. reading on a 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) (pg. 5 col. 1 para. 2). DeGroot also teaches a tool – OptiMatrix – (i.e. computer-based analytical process) that 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).
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
• De Groot teaches a tool – OptiMatrix – (i.e. computer-based analytical process) that 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).
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
• De Groot 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 (i.e. reading on germline amino acid at the position(s) corresponding to the position(s) of the amino acid modification) of antibody framework and complementarity determining regions (pg. 7 col. 2 para. 4).
Claim 4 recites:
wherein the parent peptide and the modified peptide are identical but for the amino acid modification(s)
• De Groot 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 peptides derived from a protein) 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).
Claim 5 recites:
wherein the parent peptide and the modified peptide are each 8 to 15 amino acids in length
• De Groot teaches tool named OptiMatrix that 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), identifying critical residues that contribute most to MHC binding affinity across multiple nonomer peptide frames (i.e. reading on peptides of 8 to 15 amino acids) 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).
Claim 6 recites:
wherein the one or more MHC molecules each comprise different MHC molecule types corresponding to different MHC alleles
Claim 7 recites:
wherein the one or more MHC molecules are each MHC class I molecules and/or MHC class II molecules
• De Groot immunogenicity predictions made for a number of MHC class I and MHC class II molecules (i.e. reading om the different MHC molecule types as in claim 6 and each MHC class I molecules and/or MHC class II molecules as in claim 7) (pg. 4 Table 1).
Claim 8 recites:
wherein the first score and/or the second score are each 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).
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
• De Groot 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) (pg. 5 col. 1 para.2)
Claim 10 recites:
wherein the second score that indicates binding to the one or more MHC molecules satisfies a second pre-determined threshold for binding to the one or more MHC molecules
• De Groot teaches other tools providing a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second pre-determined threshold for binding to the one or more MHC molecules) (pg. 5 col. 2 para. 2). Here, standardized scores are interpreted as being compared to a threshold (e.g., ±1, ±2, or ±3 standard deviations) thus, reading on a pre-determined threshold.
Claim 11 recites:
wherein the first pre-determined threshold is different from the second pre-determined threshold
• De Groot 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) (pg. 5 col. 1 para.2); wherein other tools provide a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second pre-determined threshold for binding to the one or more MHC molecules – different than the first threshold) (pg. 5 col. 2 para. 2).
Claim 12 recites:
wherein the first and/or second pre- determined threshold reflects a probability for binding to one or more MHC molecules
• 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 probability for binding to one or more MHC molecules) (pg. 4 col. 1 para. 2).
Claim 13 recites:
wherein the ascertaining of the third score comprises ascertaining a score for chemical and physical dissimilarity between the amino acids at the position(s) in the parent and modified peptides
• 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 ascertaining a score for chemical and physical dissimilarity between the amino acids at the position(s) in the parent and modified peptides) (pg. 4 col. 1 para. 2).
Claim 14 recites:
wherein the ascertaining of the third score comprises ascertaining whether said score satisfies a pre-determined threshold for the chemical and physical dissimilarity between amino acids
• De Groot teaches protein derived T-cell epitopes binding to MHC predicted based on the presence or absence of specific amino acid side chains (i.e. chemical and physical dissimilarity), determining how tightly an epitope binds to MHC (i.e. reading on ascertaining a score for chemical and physical dissimilarity between the amino acids at the position(s) in the parent and modified peptides) (pg. 4 col. 1 para. 2); wherein the tool 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. pre-determined threshold for binding to the one or more MHC molecules) (pg. 5 col. 1 para.2).
Claim 15 recites:
wherein the score for the chemical and physical dissimilarity is ascertained based on the probability of amino acids being interchanged in nature
• De Groot teaches protein derived T-cell epitopes binding to MHC predicted based on the presence or absence of specific amino acid side chains (i.e. chemical and physical dissimilarity), determining how tightly an epitope binds to MHC (pg. 4 col. 1 para. 2); wherein prediction matrices using eight MHC class II alleles and the number of potential T-helper epitopes that would occur in random sequence pseudo proteins composed of amino acids at their naturally occurring frequencies (i.e. reading on probability of amino acids being interchanged in nature) were measured so that the tool EpiMatrix could compare 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) (pg. 5 col. 1 para. 2).
Claim 18 recites:
comprising identifying a modified peptide as immunogenic to the subject's TCR repertoire by determining that
(i) the modified peptide has a first score for binding to one or more MHC molecules that satisfies a first pre-determined threshold indicating binding to one or more MHC molecules such that the modified peptide is MHC-presented,
(ii) the parent peptide has a second score for binding to one or more MHC molecules that satisfies a second pre-determined threshold indicating binding to one or more MHC molecules such that TCRs binding the corresponding parent peptide would have been deleted during a subject's development, and
(iii) the amino acid modification(s) in the modified peptide has/have a score for the chemical and physical dissimilarity that satisfies a pre-determined threshold indicating that the modified amino acid has sufficiently different physico-chemical properties from the parent amino acid
• DeGroot teaches using immunoinformatics analysis tools to measure (i) T-cell response to the whole wild-type protein; (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (pg. 8 col. 1 para. 1); wherein a tool 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) (pg. 5 col. 1 para.2); wherein other tools also provide a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second pre-determined threshold for binding to the one or more MHC molecules) (pg. 5 col. 2 para. 2). Here, standardized scores are interpreted as being compared to a threshold (e.g., ±1, ±2, or ±3 standard deviations) thus, reading on a pre-determined threshold. DeGroot teaches another tool analyzes protein derived T-cell epitopes binding to MHC predicted based on the presence or absence of specific amino acid side chains (i.e. chemical and physical dissimilarity), determining how tightly an epitope binds to MHC (pg. 4 col. 1 para. 2) (i.e. reading on a score for the chemical and physical dissimilarity that satisfies a pre-determined threshold).
Claim 19 recites:
comprising identifying a modified peptide as immunogenic to the subject's TCR repertoire by determining that
(i) the modified peptide has the first score that is indicative of a probability for binding to one or more MHC molecules,
(ii) the parent peptide has the second score that is indicative of a probability for binding to one or more MHC molecules, and
(iii) the amino acid modification(s) in the modified peptide has/have the score that is indicative of a probability of the modified and parent amino acids being chemically and physically dissimilar
• DeGroot teaches using immunoinformatics analysis tools to measure (i) T-cell response to the whole wild-type protein; (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (pg. 8 col. 1 para. 1); wherein a tool 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. modified peptide has the first score that is indicative of a probability for binding to one or more MHC molecules) (pg. 5 col. 1 para.2); wherein other tools also provide a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second score that is indicative of a probability for binding to one or more MHC molecules) (pg. 5 col. 2 para. 2). Here, standardized scores are interpreted as being compared to a threshold (e.g., ±1, ±2, or ±3 standard deviations) thus, reading on a pre-determined threshold. DeGroot teaches another tool analyzes protein derived T-cell epitopes binding to MHC predicted based on the presence or absence of specific amino acid side chains (i.e. chemical and physical dissimilarity), determining how tightly an epitope binds to MHC (pg. 4 col. 1 para. 2) (i.e. reading on amino acid modification(s) in the modified peptide has/have the score that is indicative of a probability of the modified and parent amino acids being chemically and physically dissimilar).
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)
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. reading on cases in which the same amino acid can be substituted at the same position at different iterations as in claims 24-25) (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 (pg. 7 col. 2 para. 3).
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).
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).
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)
Claim 29 recites:
wherein the plurality of modified peptides comprises two or more different modified peptide
Claim 30 recites:
wherein said two or more different modified peptides comprise different amino acid modifications
Claim 31 recites:
wherein the different amino acid modifications are present in the same and/or in different proteins
Claim 32 recites:
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 (i.e. reading on different amino acid modifications are present in the same and/or in different proteins as in claim 31) and then re-analyzes (i.e. comparing the scores of two or more of said different modified peptides as in claim 32) the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (i.e. reading on: cases in which the same amino acid can be substituted at different positions at different iterations as in claim 28 - modified peptides comprises two or more different modified peptide as in claim 29 and two or more different modified peptides comprise different amino acid modifications as in claim 30) (pg. 7 col. 2 para. 3).
Claim 43 recites:
wherein the one or more MHC molecules are MHC class II molecules
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
• DeGroot teaches predictions made for MHC class I and MHC class II (i.e. reading on one or more MHC molecules are MHC class II molecules) (pg. 4 Table 1); wherein immunogenicity is related to the strength of epitope binding to MHC molecules (pg. 4 col. 1 para. 1) and Table 1 presents multiple tool for scoring T-cell epitopes for MHC molecules (pg. 4 Table 1) (i.e. reading on score indicating binding to the one or more MHC molecules as in claim 44).
Claim 45 recites:
wherein the subject is a human individual
• DeGroot teaches that the best approach to measure and/or predict a T-cell response to a protein therapeutic is to couple rapid in silico mapping of the protein sequence to find potential epitopes with in vitro confirmation using human leukocyte antigen [HLA] binding assays or T-cell assays (pg. 2 col. 1 para. 1) such as optimize human epitope-driven vaccines (pg. 7 col. 1 para. 3).
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 (i.e. reading on different amino acid modifications are present in the same and/or in different proteins as in claim 31) and then re-analyzes (i.e. comparing the scores of two or more of said different modified peptides as in claim 32) the predicted immunogenicity of the sequence (strength of epitope binding to MHC molecules), following the change (i.e. reading on: cases in which the same amino acid can be substituted at different positions at different iterations as in claim 28 - modified peptides comprises two or more different modified peptide as in claim 29 and two or more different modified peptides comprise different amino acid modifications as in claim 30) (pg. 7 col. 2 para. 3).
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 16-17, 20, 23, 33 and 49 are rejected under 35 U.S.C. 103(a) as being unpatentable over DeGroot as applied to claims 1, 15, 18, 21, 32 and 29 in the 102 rejection above further in view of Rajapakse ("Evolutionary approaches for predicting MHC peptide binding." Dissertation Nanyang University (2009)), as cited on the attached PTO-892 form. Any newly recited portions are necessitated by claim amendment.
Claim 16 recites:
wherein the more frequently amino acids are interchanged in nature, the more similar the amino acids are considered
Claim 17 recites:
wherein the chemical and physical dissimilarity is determined using evolutionary based log-odds matrices
• De Groot does not teach the recitation above. However, Rajapakse teaches the use of evolutionary approaches for predicting MHC binding (pg. 1 Title); wherein evolutionary algorithms use nature inspired heuristics for search, being robust to noise present in the evaluation of the objective function (pg. 10 para. 1); wherein an ant colony approach for prediction of MHC class II binders (pg. 56 para. 2) was proposed and adopted the information content of log-odd matrices (i.e. as in claim 17) (pg. 57 para. 1); wherein the method uses an optimized search strategy for selection of the alignment used for derivation of a position specific scoring matrix (pg. 56 para. 2) and estimate the significance of an alignment in comparison to the background amino acid frequencies (i.e. reading on the more frequently amino acids are interchanged in nature, the more similar the amino acids are considered as in claim 16) (pg. 57 para. 1).
Claim 20 recites:
wherein the modification(s) is/are not in anchor position(s) for binding to one or more MHC molecules
• DeGroot does not teach the recitation above. However, Rajapakse teaches the use of evolutionary approaches for predicting MHC binding (pg. 1 Title); wherein high binding peptides are often tolerant to non-preferred amino acids at anchor positions (pg. 91 para. 2). Here, the presence of non-preferred amino acids indicates positions not preferred for binding, hence anchor positions are not preferred for modified amino acids – since a modification aims to increase the binding affinity.
Claim 23 recites:
wherein the modification(s) is/are in anchor position(s) for binding to one or more MHC molecules
• DeGroot does not teach the recitation above. However, Rajapakse teaches the use of evolutionary approaches for predicting MHC binding (pg. 1 Title); wherein guided discovery for prediction of motif patterns uses the anchor positions of MHC class II alleles (pg. 91 para. 2)
Claim 33 recites:
wherein the first score is weighted higher than the third score
• DeGroot does not teach the recitation above. However, Rajapakse teaches the use of evolutionary approaches for predicting MHC binding (pg. 1 Title); wherein profile analyses are carried out with the aid of a scoring scheme that assigns weights to the amino acid at each position with higher weights given to frequently occurring amino acids present in a significant number of ligands (pg. 28 para. 1) and a weighting scheme assigns a relative weighing score to each sequence based on a likelihood ratio (i.e. reading on some scores weighing more than others) (pg. 30 para. 1).
Claim 49 recites:
further comprising ranking at least two or more modified peptides in the plurality with reference to one or more of: their respective first scores, their respective second scores, and their respective third scores, thereby identifying, based on the ranking at least one candidate modified peptide form the plurality of modified peptides that is more immunogenic to the subjects TCR repertoire than at least one other modified peptides in the plurality
• DeGroot teaches the "first, second and third scores" as protein derived T-cell epitopes binding to MHC being 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 of a modified peptide to one or more MHC molecules) (pg. 4 col. 1 para. 2); wherein both T-cell response to the whole wild-type therapeutic protein (i.e. reading on a second score for binding of the corresponding parent peptide to the one or more MHC molecules) and T-cell response to epitopes derived from the wild-type therapeutic protein (i.e. reading on peptides derived from a protein) are measured (pg. 7 col. 1 para. 3); wherein prediction matrices were used for eight MHC class II alleles and the number of potential T-helper epitopes that would occur in random sequence pseudo proteins composed of amino acids at their naturally occurring frequencies were measured so that the tool EpiMatrix could compare 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. reading on a third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors) (pg. 5 col. 1 para. 2). Further, DeGroot teaches using tools to measure (i) T-cell response to the whole wild-type protein; (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (i.e. also reading on the recited second, first and third score, respectively) (pg. 8 col. 1 para. 1).
• DeGroot does not teach the "ranking at least one candidate modified peptide form the plurality of modified peptides that is more immunogenic to the subjects TCR repertoire than at least one other modified peptides in the plurality." However, Rajapakse teaches the use of evolutionary approaches for predicting MHC binding (pg. 1 Title); wherein matrix models give a quantitative a score to peptide enabling the ranking of predicted peptides based on their binding affinity to MHC molecules (i.e. reading on ranking at least one candidate modified peptide form the plurality of modified peptides that is more immunogenic to the subjects TCR repertoire than at least one other modified peptides in the plurality) (pg. 37 para. 2).
Rationale for combining (MPEP §2142-2143)
Regarding claims 16-17, 20, 23, 33 and 49, 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 DeGroot in view of Rajapakse because all references disclose methods for controlling immunogenicity of modified peptides. The motivation would have been to incorporate high accuracy, high sensitivity and high specificity when determining the suitability of peptides in the prediction of binding to MHC molecules (pg. 10 para. 2 Rajapakse).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the method for predicting immunogenicity of modified peptides of DeGroot to the methods by Rajapakse 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 controlling immunogenicity of modified peptides.
B. Claims 21-22, 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 (“Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines” Cancers 3(4):4191-4211 (2011)), as cited in the 04/11/2022 IDS. Any newly recited portions are necessitated by claim amendment.
Claim 21 recites:
comprising identifying a modified peptide as immunogenic by determining that
(i) the modified peptide has a first score for binding to one or more MHC molecules that satisfies a first pre-determined threshold indicating binding to one or more MHC molecules, and
(ii) the parent peptide has a second score for binding to one or more MHC molecules that satisfies a second pre-determined threshold indicating no binding to one or more MHC molecules
• DeGroot teaches using immunoinformatics analysis tools to measure (i) T-cell response to the whole wild-type protein (i.e. immunogenicity of the parent peptide); (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (pg. 8 col. 1 para. 1); wherein a tool 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. modified peptide has a first score for binding to one or more MHC molecules that satisfies a first pre-determined threshold indicating binding to one or more MHC molecules) (pg. 5 col. 1 para.2); wherein other tools also provide a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second score for binding to one or more MHC molecules that satisfies a second pre-determined threshold indicating binding to one or more MHC molecules) (pg. 5 col. 2 para. 2). Here, standardized scores are interpreted as being compared to a threshold (e.g., ±1, ±2, or ±3 standard deviations) thus, reading on a pre-determined threshold.
• DeGroot does not teach "a parent peptide with a score indicating no binding based on a threshold." 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 (i.e. amino acid modifications) (pg. 4198 para. 5 to 4199 para. 1); wherein the predicted affinity of the wild-type and mutated sequences are listed where affinity scores of <50 nM indicate strong binding, scores between 50 and 500 nM indicate weak binding and scores above 500 nM indicate no binding for both wild type and mutated cases in the table (i.e. reading on a parent peptide with a score indicating no binding based on a threshold) (pg. 4200 Table3).
Claim 22 recites:
comprising identifying a modified peptide as immunogenic by determining that
(i) the modified peptide has the first score that is indicative of a probability for binding to one or more MHC molecules, and
(ii) the parent peptide has the second score that is indicative of a probability for not binding to one or more MHC molecules
• DeGroot teaches using immunoinformatics analysis tools to measure (i) T-cell response to the whole wild-type protein (i.e. immunogenicity of the parent peptide); (ii) T-cell response to epitopes derived from the wild-type protein; and (iii) abrogation of T-cell response to modified versions of immunogenic proteins (pg. 8 col. 1 para. 1); wherein a tool 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. modified peptide has a first score for binding to one or more MHC molecules that satisfies a first pre-determined threshold indicating binding to one or more MHC molecules) (pg. 5 col. 1 para.2); wherein other tools also provide a standardized score, so predictions can be compared across MHC alleles (i.e. reading on second score for binding to one or more MHC molecules that satisfies a second pre-determined threshold indicating binding to one or more MHC molecules) (pg. 5 col. 2 para. 2). Here, standardized scores are interpreted as being compared to a threshold (e.g., ±1, ±2, or ±3 standard deviations) thus, reading on a pre-determined threshold.
• DeGroot does not teach "a parent peptide with a score indicating no binding based on a threshold." 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 (i.e. amino acid modifications) (pg. 4198 para. 5 to 4199 para. 1); wherein the predicted affinity of the wild-type and mutated sequences are listed where affinity scores of <50 nM indicate strong binding, scores between 50 and 500 nM indicate weak binding and scores above 500 nM indicate no binding for both wild type and mutated cases in the table (i.e. here the predicted affinity of no binding reads on the probability for not binding to one or more MHC molecules) (pg. 4200 Table3)
Claim 34 recites:
further comprising identifying nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides
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 cancer cells and 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
Claim 36 recites:
wherein said mutations are somatic mutations
Claim 37 recites:
wherein said mutations are cancer mutations
• 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 (i.e. reading on somatic mutations as in claim 36 and cancer mutations as in claim 37) that alter the protein-coding genes and the identification of candidate unique tumor antigens (i.e. reading on amino acid modification(s) is/are identified by sequencing a whole or partial genome or transcriptome of one or more cancer cells and one or more non-cancerous cells as in claim 35) associated with an alteration in the amino acid sequence in nonsynonymous mutations (i.e. reading on identifying nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides as in claim 34) (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 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).
Claim 46 recites:
further comprising the step of determining that tumor cells express the modified peptide
Claim 47 recites:
further comprising the step of determining that normal cells express the parent peptide
• 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 (i.e. reading on determining that tumor cells express the modified peptide as in claim 46) that alter the protein-coding genes and the identification of candidate unique tumor antigens associated with an alteration in the amino acid sequence in nonsynonymous mutations (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 or other genetic changes present only in the tumor unique and not expressed in any normal tissues (i.e. reading on determining that normal cells express the parent peptide and not the modified peptide as in claim 47) (pg. 4196 para. 3).
Rationale for combining (MPEP §2142-2143)
Regarding claims 21-22, 34-37 and 46-47, 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 DeGroot in view of Li because all references disclose methods for controlling immunogenicity of modified peptides. The motivation would have been to investigate the identification of mutated tumor antigens for the design of personalized cancer vaccines (pg. 4191 para. 1 Li).
Therefore it would have been obvious to one of ordinary skill in the art to substitute the method for predicting immunogenicity of modified peptides of DeGroot to the methods by Li 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 controlling immunogenicity of modified peptides.
Response to applicant's remarks in regard to Claim Rejection 35 U.S.C. ~ 102
The Remarks of 04/14/2026 have been fully considered but are not persuasive for the reasons below:
Applicant asserts starting in pg. 14 para. 5:
As DeGroot fails to teach "ascertaining ... a third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors", claim 1 (and claims that depend from claim 1) are not anticipated by DeGroot. Applicants thus respectfully request reconsideration and withdrawal of the rejection
It is respectfully submitted that this is not persuasive because DeGroot teaches multiple immunoinformatics analysis tools for ascertaining (i.e. hence, discovery based on data evaluation) of modified peptide when present in a MHC-peptide complex to a Tcell receptor. Specifically, DeGroot teaches protein derived T-cell epitopes binding to MHC being predicted (i.e. reading on ascertaining a score) 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 both T-cell response to the whole wild-type therapeutic protein and T-cell response to epitopes derived from the wild-type therapeutic protein are measured (pg. 7 col. 1 para. 3); wherein the T-cell response to a protein therapeutic antigen is dependent on the binding of T-cell epitopes to MHC and presentation of the MHC:epitope complex at the cell surface (i.e. reading on binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors) (pg. 3 col. 2 para. 5). Thus, the teachings by DeGroot indeed anticipate the argued recitation.
Response to applicant's remarks in regard to Claim Rejection 35 U.S.C. ~ 103
The Remarks of 04/14/2026 have been fully considered but are not persuasive for the reasons below:
Applicant asserts starting in pg. 15 para. 2:
Applicants respectfully submit that the Office Action has not established a prima facie case of obviousness, at least because the Office Action has neither shown that the combination of references discloses all the elements of the claims, nor 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. As discussed above, DeGroot fails to teach or suggest any "third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors". Li fails to cure this deficiency of DeGroot….Indeed, DeGroot does not suggest or provide any rationale for extending MHC-binding prediction tools to computationally ascertain peptide-MHC-TCR interactions, nor for generating a quantitative score representing a likelihood of TCR binding…. As DeGroot and Li do not teach or suggest every feature of the present claims, no prima facie case of obviousness has been established
It is respectfully submitted that this is not persuasive because DeGroot teaches the argued "third score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors" as described in detail in the paragraph above. Therefore, there is no need for deficiencies to be curated by any other art because the recitation is anticipated by DeGroot. In the previous office action, claims that were described as non-requirements, have now been addressed in detail due to the amendments made by the Applicant. Also in the explanation above is evidence that DeGroot does teach the argued "ascertaining peptide-MHC-TCR interactions" and "generating a quantitative score representing a likelihood of TCR binding." Therefore, anticipation of the claimed invention have been established for claims 1-15, 18-19, 24-32, 43-45 and 48. Additionally, regarding the prior art to Rajapakse and Li, 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." The motivation would have been to incorporate high accuracy, high sensitivity and high specificity when determining the suitability of peptides in the prediction of binding to MHC molecules (pg. 10 para. 2 Rajapakse) and to investigate the identification of mutated tumor antigens for the design of personalized cancer vaccines (pg. 4191 para. 1 Li). Furthermore, in this instant application, the amendments support existing claim rejections, in which the recited limitations are all addressed, see Claim Rejections above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-2, 5-14, 17, 20, 23-26, 28-37 and 43-49 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 4-10, 12-16, 18-30 and 33-34 of US Patent No. 11,222,711. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims of the reference patent, as set forth in the following table.
Instant application
US Patent No. 11,222,711
Claim
Limitation
Claim
Limitation
1
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 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 (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.
1
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; ascertaining , for each of the plurality of modified peptides ,via a computer - based analytical process each of: 65 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 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 immunogenic to the subject's TCR repertoire or a nucleic acid encoding the peptide or polypeptide.
2
wherein the modified peptides each comprise a fragment of a modified protein, said fragment comprising the amino acid modification(s) present in the protein.
15
wherein the two or more different modified peptides comprising the same amino acid substitution comprise different fragments of a modified protein, said different fragments comprising the same amino acid substitution present in the modified protein.
5
wherein the parent peptide and the modified peptide are each 8 to 15, preferably 8 to 12, amino acids in length.
4
wherein the parent peptide and the modified peptide are each 8 to 15 amino acids in length.
6
wherein the one or more MHC molecules each comprise different MHC molecule types, in particular different MHC alleles.
5
wherein the first score and the second score are each ascertained for binding to more than
one MHC molecule, and the MHC molecules comprise different MHC molecule types corresponding to different MHC alleles.
7
wherein the one or more MHC molecules are each MHC class I molecules and/or MHC class II molecules.
6
26
wherein the one or more MHC molecules are MHC class I molecules
wherein the one or more MHC molecules are MHC class II molecules.
8
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.
7
wherein the first score and/or the second score is/are ascertained by a computer-based analytical process comprising a sequence comparison with a database of MHC-binding motifs.
9
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.
50
(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
10
wherein the second score that indicates binding to the one or more MHC molecules satisfies a second pre-determined threshold for binding to the one or more MHC molecules.
50
(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
11
wherein the first pre-determined threshold is different from the second pre-determined threshold.
8
wherein the threshold applied with respect to the first score is different from the threshold
applied with respect to the second score
12
wherein the first and/or second pre-determined threshold reflects a probability for binding to one or more MHC molecules.
9
wherein the first and/or second pre-determined threshold reflects a probability for binding to one or more MHC molecules.
13 and 14
wherein the ascertaining of the third score comprises ascertaining a score for chemical and physical dissimilarity between the amino acids at the position(s) in the parent and modified peptides.
50
(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
17
wherein the chemical and physical dissimilarity is determined using evolutionary based log- odds matrices.
50
10
(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
wherein the substitution matrix
is or comprises an evolutionary based log-odds matrix.
20
wherein the modification(s is/are not in anchor position(s) for binding to one or more MHC molecules.
12
wherein the position of the amino acid substitution is not an anchor position for binding to one or more WIC molecules.
23
wherein the modification(s) is/are in anchor position(s) for binding to one or more MHC molecules.
13
wherein the position of the ammo acid substitution is an anchor position for binding to
one or more WIC molecules.
24
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).
14
wherein the plurality of modified peptides comprises two or more different modified peptides comprising the same amino acid substitution.
25
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.
15
wherein the two or more different modified peptides comprising the same amino acid
substitution comprise different fragments of a modified protein, said different fragments comprising the same amino acid substitution present in the modified protein
26
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.
16
wherein the two or more different modified peptides comprising the same amino acid substitution comprise all potential MHC binding fragments of a modified protein, said fragments comprising the same amino acid substitution present in the protein.
28
wherein the two or more different modified peptides comprising the same modification(s) differ in length and/or position of the modification(s).
18
wherein the two or more different modified peptides comprising the same amino acid substitution differ in length.
29
30
31
wherein the plurality of modified peptides comprises two or more different modified peptides
wherein said two or more different modified peptides comprise different amino acid modifications
wherein the different amino acid modifications are present in the same and/or in different proteins
19
wherein the plurality of modified peptides comprises two or more different modified peptides each comprising a different amino acid substitution and the different amino acid substitutions are present in the same protein
32
which comprises comparing the scores of two or more of said different modified peptides.
20
which comprises comparing the first scores of two or more of said different modified peptides
33
wherein the first score is weighted higher than the third score, preferably a score for the chemical and physical dissimilarity between the parent and modified amino acids and a score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors, preferably a score for the chemical and physical dissimilarity between the parent and modified amino acids is weighted higher than the second score.
21
wherein the first score is weighted higher than the third score.
Note: the instantly recited “preferably a score for the chemical and physical dissimilarity between the parent and modified amino acids and a score for binding of the modified peptide when present in a MHC-peptide complex to one or more T cell receptors, preferably a score for the chemical and physical dissimilarity between the parent and modified amino acids is weighted higher than the second score” reads on a preference not a requirement.
34
further comprising identifying nonsynonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides.
22
further comprising, prior to the step of identifying from the sequence data the plurality of modified peptides expressed in the tumor cells, identifying one or more non synonymous mutations in one or more protein-coding regions encoding at least one of the modified peptides.
35
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.
23
wherein the amino acid substitution is identified by sequencing a whole or partial genome or transcriptome of one or more cells.
Note: the instantly recited “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” reads on a preference not a requirement.
36
wherein said mutations are somatic mutations.
24
wherein said mutations are somatic mutations.
37
wherein said mutations are cancer mutations.
25
wherein said mutations are cancer mutations.
43
wherein the one or more MHC molecules are MHC class II molecules.
6
26
wherein the one or more MHC molecules are MHC class I molecules
wherein the one or more MHC molecules are MHC class II molecules.
44
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.
27
wherein the first score and the second scores are ascertained for binding to more than one MHC molecule, and the more than one MHC molecule comprise one or more MHC class I molecules and one or more MHC class II molecules.
45
wherein the subject is a human individual.
28
wherein the subject is a human individual.
46
further comprising the step of determining that tumor cells express the modified peptide.
29
further comprising the step of determining that the tumor cells express the modified peptide.
47
further comprising the step of determining that normal cells express the parent peptide.
30
further comprising the step of determining that the normal cells express the parent peptide.
48
wherein the two or more different modified peptides comprising the same amino acid substitution differ in the position of the amino acid substitution.
33
wherein the two or more different modified peptides comprising the same amino acid substitution differ in the position of the amino acid substitution.
49
further comprising ranking at least two or more modified peptides in the plurality with reference to one or more of: their respective first scores, their respective second scores, and their respective third scores, thereby identifying, based on the ranking at least one candidate modified peptide form the plurality of modified peptides that is more immunogenic to the subjects TCR repertoire than at least one other modified peptides in the plurality.
34
wherein the step of selecting comprises ranking at least two or more modified peptides in the plurality with reference to one or more of: their respective first scores, their respective second scores, and their respective third scores, thereby selecting, based on the ranking, at least one candidate modified peptide from the plurality of modified peptides that is more immunogenic to the subject's TCR repertoire than at least one other modified peptides in the plurality.
Response to applicant's remarks in regard to Double Patenting
The Remarks of 04/14/2026 have been fully considered but are not persuasive for the reasons below:
Applicant asserts starting in pg. 16 para. 6:
Applicants respectfully traverse the rejection.35 U.S.C. § 121 provides a safe harbor against double patenting when a restriction requirement divided the patentable subject matter. Claims 1-37 and 43-49 are subject to the safe harbor provision of 35 U.S.C. § 121, as claims 1-37 and 43-49 are encompassed by, and consonant with, claims that were included in nonelected Group I of a Restriction Requirement mailed June 19, 2018 in the '711 patent.
It is respectfully submitted that this is not persuasive because the argued prohibition against NSDP does not apply here. The instant application is not a proper divisional from a parent application in which the argued restriction took place. When directly comparing the instant claims to the 10/26/2015 claim set in parent Application 14787110, the instant claims have changed distinctly from the time the requirement was originally made which makes the prohibition to be not applicable (see MPEP 804.01). The distinction is that, in the preamble claim 1 of the parent compared to the instant claim 1, there is evidence that the claims are materially different. The parent claim 1 recites steps related to identifying immunogenic amino acid modifications, but that is not necessarily the same as predicting an immunogenic peptide for use in a cancer vaccine as in the instant claims. The fact that an amino acid modification itself is immunogenic does not translate to the entire peptide being immunogenic or that it would be useful in a cancer vaccine. Therefore, the NSDP rejection is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCINI A FONSECA LOPEZ whose telephone number is (571)270-0899. The examiner can normally be reached Monday - Friday 8AM - 5PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/F.F.L./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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