DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Herein, “the previous Office action” refers to the Final Rejection filed 3/21/2025.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/23/2025 has been entered.
Priority
As detailed on the Filing Receipt filed 10/21/2024, the instant application claims priority to as early as 8/28/2018. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Claim Status
Claims 2 and 33-35 are canceled.
Claims 1, 3-32 and 36-38 are pending.
Claims 13-14, 16-20, 24, 27-32 and 36-38 stand withdrawn pursuant to 37 CFR 1.142(b) as being directed to a nonelected invention, there being no currently allowable generic or linking claim. Election without traverse was made in the reply filed 7/14/2023.
Claims 1, 3-12, 15, 21-23 and 25-26 are under examination.
Withdrawn Rejections
The rejection of claims 22-23 under 35 USC § 112(d), as being of improper dependent form, is hereby withdrawn in view of Applicant’s amendment of claim 22 to incorporate all elements of the claim on which claim 22 depends.
The rejection of claims 22-23 under 35 USC § 101, as being directed to nonstatutory subject matter, is hereby withdrawn in view of Applicant’s amendment of claim 22 to incorporate all elements of 1 claim including the integrating step of administering a personalized vaccine.
The rejection of claim 2 under 35 USC § 103, as being unpatentable over Velculescu, in view of Chu and McGranahan, is hereby withdrawn in view of Applicant’s cancelation of the claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC § 102 and 103 is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 USC § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 USC § 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 USC § 102(b)(2)(C) for any potential 35 USC § 102(a)(2) prior art against the later invention.
Claims 1, 3-12, 15, 21-23 and 25-26 are rejected under 35 USC § 103 as being unpatentable over Velculescu (US 2017/0016075; published 1/19/2017; analogous to WO 2017/011660 on IDS filed 4/13/2021), in view of Chu et al (Theranostics 8(15): 4238-4246; published 7/30/2018; previously cited).
Claim 1 recites “a method for developing a personalized neoantigen-based vaccine for a subject having cancer using an individual physical library of neoantigens based on one or more neoantigens present in a subject having cancer… wherein one or more potential neoantigens… carry at least one tumor-specific mutation… comprising”:
a) “generating… a library of potential neoantigens”;
b) “determining, for each potential neoantigen… the library including at least four potential neoantigens, at least two descriptors… includ[ing]”:
1. “an indicative descriptor indicating whether the neoantigen is known… or… not known to reside within a cancer-related gene”, and
2. “a classifying descriptor relating to a binning of a value indicative for a binding affinity of the potential neoantigen to a particular HLA allele present according to the subject’s HLA type, into one of at least three different classes ordered according to the intervals of values binned into each”;
c) “the determination of at least one… descriptor[] being such that the number of different classes into which… values are binned is smaller than a number of the potential neoantigens”;
d) “determining a combined score for each of the potential neoantigens… based on the… descriptors… such that a maximum possible contribution of at least one descriptor… is lower than a maximum possible contribution to the combined score of at least one other descriptor”, wherein:
1. “the combined score for each of the potential neoantigens in the library is determined in a manner weighted such that, for at least one classifying descriptor, a class dependent contribution to the combined score deviates, for at least one class, from a linear relation with class order or is a penalty”;
e) “ranking the… potential neoantigens… based on the combined score”;
f) “filtering out potential neoantigens”;
g) “generating, using the remaining potential neoantigens and based on the ranking and the filtering, an individual physical library having one or more of potential neoantigens”, wherein:
1. “the individual physical library is generated by having at least one of: one or more neoantigen peptides of at least one… remaining potential neoantigen[], one or more nucleic acids encoding at least one… remaining potential neoantigen[], one or more vectors encoding at least one… remaining potential neoantigen[], or any combination thereof synthesized”;
h) “developing the personalized neoantigen-based vaccine using the individual physical library… by selecting at least one of: at least one peptide… in the individual physical library, at least one nucleic acid… in the individual physical library… encoding at least one or more neoantigens, at least one vector… in the individual physical library… encoding at least one or more neoantigens, or any combination thereof”, wherein:
1. “the at least one peptide activates neoantigen-specific CD8+ T cells or neoantigen-specific CD4+ T cells or both, and/or the at least one nucleic acid and/or vector encodes at least one neoantigen that activates neoantigen specific CD8+ T cells or neoantigen-specific CD4+ T cells or both, in the subject”; and
i) “administering the personalized neoantigen-based vaccine to the subject”.
With respect to claim 1, Velculescu discloses a “screening method to identify and prioritize candidate neoantigens using sequencing data” (Abstract) comprising:
a) “obtaining a tumor nucleic acid sequence and a normal nucleic acid sequence for an individual… [and] compar[ing] the… sequence[s] to determine a plurality of possible translated peptide sequences” (pg. 2, para. 0018), i.e., generating a library of candidate neoantigens;
b) “for each candidate neoantigen peptide sequence… using”, i.e., determining, “an individual’s HLA type and two or more of the following” (pg. 1, para. 0007):
1. “the peptide sequence’s similarity to known antigens” (pg. 1, para. 0007), e.g., whether the neoantigen is known to reside within a cancer-related gene, and
2. “predicted major histocompatibility complex (MHC) binding affinity between the peptide sequence and one or more of the individual’s HLA alleles” (pg. 1, para. 0007);
d) using the descriptors in step b, “a neoantigen priority score for each candidate neoantigen peptide sequence is produced”, i.e., a combined score is calculated, wherein “one or more of the terms may be weighted using a weight value to increase or decrease its impact on the neoantigen priority score relative to the other terms” (pg. 6, para. 0047) and “neoantigen priority to one or more characteristics determined or identified for each of a plurality of candidate neoantigens” (pg. 15, para. 4), wherein:
1. “neoantigen priority may be determined through application of a rule or series of rules to [the] one or more characteristics… Rules may comprise exclusionary provisions” (pg. 15, para. 4), i.e., penalties; and
e) “neoantigen priority is used to rank the… candidate neoantigens based on the potential for clinical efficacy in the patient from whom a sample was taken” (pg. 1, para. 0006) to produce an “ordered list… comprising] the prioritized set of candidate neoantigens” (pg. 8, para. 0073), with ranking of at least 30 neoantigens exemplified (pg. 8, para. 0075, Table 1).
Velculescu describes an exemplary “set of rules” pertaining to predicted binding affinity, wherein “All candidate neoantigens with a predicted IC50 affinity greater than, for example, 500 nM may… be removed… [and] remaining candidate neoantigens may… be classified as SB or WB (strong binder or weak binder)” (pg. 7, paras. 0056-0057). In other words, binning of a value indicative for a binding affinity into one of three different classes ordered according to intervals of values binned into each. Velculescu further exemplifies ranking of at least 30 neoantigens (pg. 8, para. 0075, Table 1). In this way, Velculescu discloses filtering potential neoantigens; and classification such that the number of different classes into which values are binned is smaller than a number of the potential neoantigens.
Velculescu does not disclose generating an individual physical library of potential neoantigens having peptide(s), nucleic acid(s), and/or vector(s) encoding neoantigen(s); or developing a personalized neoantigen-based vaccine by selecting neoantigen(s) that activate neoantigen-specific CD4+ or CD8+ cells, or nucleic acid(s) or vector(s) encoding such; or administering the vaccine.
Chu discusses “identification and synthesis of neoantigens” (pg. 4238, Abstract), and illustrates “common approaches to neoantigen identification” wherein “tumour-specific mutations are… ranked by predicted high-affinity binding to autologous HLA types… [and] neopeptides are synthesized based on prioritized mutated alleles” (pg. 4239, Fig. I caption). Chu thus teaches that synthesis of selected neoantigens (i.e., peptides) is a common application of neoantigen ranking methods.
Chu also discusses development of personalized cancer vaccines including synthesized antigenic peptides and/or nucleic acids encoding identified neoantigens, teaching that “both peptide-based vaccines and nucleic acid-based vaccines are considered to be fairly easy approaches that can be mass produced” (pg. 4240, l. column) while “In the case of nucleic acid-based vaccines, there exist two delivery platforms for encoding antigenic peptides, including DNA-based and mRNA-based vaccines” (pg. 4240, r. column). Chu mentions prior development of a neoantigen-based vaccine that specifically induced CD4+ and CD8+ cells (pg. 4240, r. column). In this way, Chu teaches generating peptide(s) and/or nucleic acid(s) encoding neoantigen(s) for clinical application; and developing a personalized neoantigen-based vaccine by selecting neoantigen(s) that activate neoantigen-specific CD4+ or CD8+ cells.
Chu discusses clinical advantages of said vaccines at length, stating that “Due to the ability of neoantigens to fire up the body’s natural immune responses directly to the tumour, cancer vaccines exhibit great potential as a therapeutic. Cancer-specific vaccinations with neoantigens have been shown to be equally efficient as checkpoint blockades. With early success demonstrated in clinical stage trials, the personalized mutanome vaccine is likely to selectively target heterogeneous tumours and elicit a strong T-cell response, generating a new age of personalized immunotherapy” (pg. 4239, l. column). In this way, Chu teaches administering a vaccine developed as discussed.
With respect to claim 3, Velculescu discloses calculation of neoantigen priority via a multivariate method wherein inputs are weighted and combined (pg. 2, para. 3; pg. 5, para. 2). Velculescu further describes producing a priority score for each peptide sequence by performing a multivariate operation on two or more terms including MHC binding affinity and a known antigen similarity score, wherein terms can be weighted to increase or decrease their relative impact on the priority score (pg. 15, para. 3). In this way, Velculescu describes priority scoring embodiments involving calculating a multivariate scoring function with two relatively weighted terms. Velculescu does not expressly discuss the recited mathematical expression, but satisfaction of said expression is viewed as a mathematical consequence of the explicitly disclosed subject matter.
Consider a multivariate scoring function with two summed terms denoted ‘a’ and ‘b’, wherein the terms are weighted such that ‘a’ has increased impact on the score relative to ‘b’ (or weighted such that ‘b’ has decreased impact on the score relative to ‘a’, as this would be mathematically equivalent). The increased relative impact of variable ‘a’ means that the difference in score contribution between successive values of ‘a’ is greater than the difference in score contribution between successive values of ‘b’. Thus, the degree to which the priority score (i.e., ‘S’) increases if ‘a’ has a greater value (e.g., ‘a1’) instead of a smaller value (e.g., ‘a2’), is greater than 2) the degree to which the priority score decreases if ‘b’ has a smaller value (e.g., ‘b2’) instead of a greater value (e.g., ‘b1’).
The recited expression S(a1)+S(b1)>S(a2)+S(b1) establishes that the value ‘a1’ is greater than the value ‘a2’. The recited expression S(a2)+S(b1)>S(a2)+S(b2) establishes that the value ‘b1’ is greater than the value ‘b2’. Given ‘a1’>’a2’ and ‘b1’>’b2’, if ‘a’ has increased relative impact on the score relative to ‘b’, there must exist values of (a1, a2) and (b1, b2) such that S(a1)+S(b2)>S(a2)+S(b1). This completes the recited expression set. Satisfaction of the recited expression set by some pairs of values of a first descriptor and a second descriptor in a multivariate scoring function is a necessary mathematical consequence of weighting the descriptors such that either descriptor has relatively increased or decreased impact on the score relative to the other descriptor. Thus, Velculescu inherently discloses the limitations of claim 3.
With respect to claim 4, Velculescu discloses “determining the tumor nucleic acid sequence through whole exome sequencing of a tumor nucleic acid extracted from a tumor tissue of the individual” (pg. 2, para. 0009).
With respect to claim 5, Velculescu discloses “utiliz[ing] sequencing and matched normal controls to… identify[] mutations or variants… mutated sequences are identified, along with corresponding candidate neoantigen peptide sequences” (pg. 1, para. 0007).
With respect to claim 6, Velculescu discloses “samples from an individual or patient may be obtained in forms such as, frozen tissue, FFPE blocks or slides… [and] may be obtained from a tumor tissue” (pg. 3, para. 0019).
With respect to claim 7, Velculescu discloses “A peptide sequence or candidate neoantigen may be given a score which may comprise, for example, a percentage similarity value… from a series of comparisons to a variety of known antigens” (pg. 6, para. 0045). In other words, an indicative descriptor having a first value if the neoantigen is known to be cancer-related (i.e., 100% match to a known antigen) and having one of multiple values different from each other and from the first value depending on the likelihood the neoantigen is not cancer related (i.e., 0-99% match to a known antigen).
With respect to claim 8, Velculescu discloses “Using a MHC binding affinity cutoff such as, for example, an IC50 value of less than 100 nM, 200 nM… 1000 nM, etc”, wherein “candidate neoantigens or peptide sequences with predicted MHC binding affinities above the cutoff may be eliminated from further analysis or consideration” (pg. 5, para. 0042).
With respect to claim 9, Velculescu discloses that “one or more steps of the method may be performed using a computer” (pg. 2, para. 0010).
With respect to claim 10, Velculescu presents an exemplary implementation wherein “The most prevalent HLA class I alleles for the North American population were compiled… each with a population frequency 0.15%... The reported frequencies of HLA alleles in the North American population allows for assessment of the probability that a patient with a specific neoantigen-associated somatic mutation will have at least one of the HLA alleles that recognizes that mutation” (pg. 9, para. 0078). In other words, HLA alleles, for which a lower concentration in tumor cells derived from said subject is predicted, are excluded.
With respect to claim 11, Velculescu discloses prioritizing neoantigens based on “predicted major histocompatibility complex (MHC) binding affinity between the peptide sequence and one or more of the individual’s HLA alleles” (pg. 1, para. 0007). In other words, a neoantigen which is predicted to bind only to one or more HLA alleles not expressed in the tumor of the patient is not scored. This has the effect of excluding such neoantigens.
With respect to claim 12, Velculescu discloses a “set of rules” pertaining to predicted binding affinity, wherein “All candidate neoantigens with a predicted IC50 affinity greater than, for example, 500 nM may… be removed… [and] remaining candidate neoantigens may… be classified as SB or WB (strong binder or weak binder)” (pg. 7, paras. 0056-0057). In other words, binning of a value indicative for a binding affinity into one of three ordered classes.
With respect to claim 15, Velculescu discloses that “one or more of the terms may be weighted using a weight value to increase or decrease its impact on the neoantigen priority score relative to the other terms” (pg. 6, para. 0047).
With respect to claims 21-22, Velculescu discloses “treating a patient with a vaccine or T-cell therapy targeting a”, i.e., one selected, “neoantigen based on its ranking” (pg. 7, para. 0061). In this way, Velculescu discloses selecting least one neoantigen in view of the ranking.
With respect to claim 23, Velculescu discloses that “the neoantigen prioritization may be included in a report prepared according to methods of the invention… the report may consist of… a number”, i.e., one or more, “of identified candidate neoantigens… ordered by, for example priority from highest to lowest” (pg. 6, para. 0049). Velculescu thereby discloses selecting at least the highest ranked neoantigen.
With respect to claim 25, Velculescu discloses “utiliz[ing] sequencing and matched normal controls”, i.e., sequencing of tumor tissue, “to… identify[] mutations or variants”, e.g., mutated HLA alleles, “even at low mutant allele frequencies in the tumor” (pg. 1, para. 0007), wherein “determining the tumor nucleic acid sequence” may comprise “whole exome sequencing of a tumor nucleic acid extracted from a tumor tissue of the individual” (pg. 2, para. 0009).
With respect to claim 26, Chu teaches that “The generation of a multi-epitope vaccine that, in general, contains MHC class I-restricted peptides and MHC class II-restricted peptides, to increase both the breadth and diversity of neoantigen-specific T cells, represents a good solution for overcoming epitope loss” (pg. 4242, l. column).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented generation of an individual library of potential neoantigens comprising peptides and encoding nucleic acids, as taught by Chu, from those output by the neoantigen ranking method of Velculescu, because Chu teaches that such synthesis is a common application of such ranking methods and has great potential for personalized cancer immunotherapy (pg. 4239, l. column and Fig. I caption).
Additionally, said practitioner would have implemented selection of neoantigens comprising at least one HLA class I restricted neoantigen and one HLA class II restricted neoantigen, to enhance the neoantigen ranking method of Velculescu, because Chu teaches that selection of both types of restricted peptides increases odds of successful immune response to clinical application of selected neoantigens (pg. 4242, l. column).
Said practitioner would have had a reasonable expectation of success because Velculescu and Chu both discuss use of neoantigens in cancer immunotherapy.
In this way the disclosure of Velculescu, in view of Chu, makes obvious the limitations of claims 1, 3-12, 15, 21-23 and 25-26. Thus, the invention is prima facie obvious.
Response to Arguments - Claim Rejections Under 35 USC § 103
In the remarks filed 6/23/22025, Applicant traverses the rejection under 35 USC § 103 and presents points of alleged distinction between the claimed invention and teachings of the applied prior art.
Applicant draws distinction between the binary process, disclosed in Velculescu, of prioritizing candidate neoantigens classified as ‘epitope (E)’ over neoantigens classified as “non-antigen (NA)’ and the claimed process of weighting based on a class dependent contribution to the combined score which deviates from a linear relation with class order or is a penalty, i.e., a negative score that attributes a negative weight to the corresponding class (pg. 19, paras. 1-2).
As noted by Applicant, the terms ‘epitope’ and ‘non-antigen’ as recited by Velculescu relate to a certain class within the parameter determined or predicted for the candidate neoantigens according to the antigen peptide processing. As noted by Applicant, a penalty as recited by the instant application is a negative score that attributes a negative weight to a corresponding class. As described by Velculescu, the value of ‘non-antigen’ attributes less priority to candidate neoantigens classified as such. Hence, the class dependent contribution to the combined score of the class ‘non antigen’ is viewed as equivalent to a penalty as defined by Applicant.
Thus, the presented argument of distinction is found unpersuasive.
Applicant alleges that the dependent claims are patentable over the applied references for at least the reasons stated with regard to claim 1 (pg. 19, para. 5 – pg. 20, para. 1). Additional points of distinction and/or particular arguments are not presented. Thus, the argument is found unpersuasive.
Prior art of record McGranahan was particularly relied upon for teaching regarding generating vector(s) encoding potential neoantigen(s), a process that is not required in all embodiments of the claims as written. Reliance on McGranahan is therefore considered unnecessary. The prior § 103 rejection including McGranahan is hereby withdrawn, and this reference is not included in the rejection issued herein.
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of copending Application No. 18/835,168 (hereafter, “‘168”), in view of Velculescu. ‘168 shares joint inventors (Biskup, Saskia; Hadaschik, Dirk; Kyzirakos-Feger, Christina; Kayser, Simone; Feldhahn, Magdalena) and a common assignee (Cecava GmbH) with the instant application. Although the claims at issue are not identical, they are not patentably distinct from each other, in view of Velculescu, for the following reasons.
Instant claim 1 recites “a method for developing a personalized neoantigen-based vaccine for a subject having cancer using an individual physical library of neoantigens based on one or more neoantigens present in a subject having cancer… wherein one or more potential neoantigens… carry at least one tumor-specific mutation… comprising”:
a) “generating… a library of potential neoantigens”;
b) “determining, for each potential neoantigen… the library including at least four potential neoantigens, at least two descriptors… includ[ing]”:
1. “an indicative descriptor indicating whether the neoantigen is known… or… not known to reside within a cancer-related gene”, and
2. “a classifying descriptor relating to a binning of a value indicative for a binding affinity of the potential neoantigen to a particular HLA allele present according to the subject’s HLA type, into one of at least three different classes ordered according to the intervals of values binned into each”;
c) “the determination of at least one… descriptor[] being such that the number of different classes into which… values are binned is smaller than a number of the potential neoantigens”;
d) “determining a combined score for each of the potential neoantigens… based on the… descriptors… such that a maximum possible contribution of at least one descriptor… is lower than a maximum possible contribution to the combined score of at least one other descriptor”, wherein:
1. “the combined score for each of the potential neoantigens in the library is determined in a manner weighted such that, for at least one classifying descriptor, a class dependent contribution to the combined score deviates, for at least one class, from a linear relation with class order or is a penalty”;
e) “ranking the… potential neoantigens… based on the combined score”;
f) “filtering out potential neoantigens”;
g) “generating, using the remaining potential neoantigens and based on the ranking and the filtering, an individual physical library having one or more of potential neoantigens”, wherein:
1. “the individual physical library is generated by having at least one of: one or more neoantigen peptides of at least one… remaining potential neoantigen[], one or more nucleic acids encoding at least one… remaining potential neoantigen[], one or more vectors encoding at least one… remaining potential neoantigen[], or any combination thereof synthesized”;
h) “developing the personalized neoantigen-based vaccine using the individual physical library… by selecting at least one of: at least one peptide… in the individual physical library, at least one nucleic acid… in the individual physical library… encoding at least one or more neoantigens, at least one vector… in the individual physical library… encoding at least one or more neoantigens, or any combination thereof”, wherein:
1. “the at least one peptide activates neoantigen-specific CD8+ T cells or neoantigen-specific CD4+ T cells or both, and/or the at least one nucleic acid and/or vector encodes at least one neoantigen that activates neoantigen specific CD8+ T cells or neoantigen-specific CD4+ T cells or both, in the subject”; and
i) “administering the personalized neoantigen-based vaccine to the subject”.
With respect to claim 1, ‘168 discloses a method for preparing a subject-specific vaccine composition for use in cancer therapy, comprising steps of:
a/b) “obtaining tumour and normal DNA or tumour and normal RNA sequence
information for a subject diagnosed with cancer; [and] identifying subject- specific tumour-mutations and subject-specific MHC I and MHC II restricted tumour neoantigens based on the sequence information obtained” (claim 26);
g) “determining the sequence of a first peptide… comprising a subject-specific tumour neoantigen identified… determining the sequence of a corresponding second peptide… comprising a subject-specific tumour neoantigen identified… preparing the first peptide or a nucleic acid encoding the first peptide… [and] preparing the second peptide or a nucleic acid encoding the second peptide” (claim 26); and
h/i) “formulating the subject-specific vaccine composition using the preparations”, wherein the peptides encoded by nucleic acid preparations “can be expressed upon administration of said nucleic acid to a subject” (claim 26).
‘168 specifically claims formulation of a subject-specific vaccine composition using preparations of a first peptide, or nucleic acid encoding such, which is an MHC I antigen and a second peptide, or nucleic acid encoding such, which is an MHC II antigen (claim 26). As would be known to one of ordinary skill in the art, MHC I antigens are recognized by CD8 T cell receptors (and thus activate CD8+ T cells) while MHC II antigens are recognized by CD4 T cell receptors (and thus activate CD4+ T cells). Hence, ‘168 implicitly discloses development of a personalized neoantigen-based vaccine by selecting both a peptide, or nucleic acid encoding such, that activates neoantigen-specific CD8+ T cells in the subject and a peptide, or nucleic acid encoding such, that activates neoantigen-specific CD4+ T cells in the subject.
‘168 claims identification of subject-specific MHC I and MHC II restricted tumour neoantigens based on sequence information, which necessarily involves evaluation of binding affinity of potential neoantigens to a particular subject-specific HLA allele. However, ‘168 does not further specify the process of identifying said neoantigens based on the obtained sequence information. For example, ‘168 does not disclose particular steps of ranking neoantigens based on a combined score as claimed by the instant application.
Velculescu teaches a “screening method to identify and prioritize candidate neoantigens using sequencing data” (Abstract) comprising steps of: “obtaining a tumor nucleic acid sequence and a normal nucleic acid sequence for an individual… [and] compar[ing] the… sequence[s] to determine a plurality of possible translated peptide sequences” (pg. 2, para. 0018), i.e., candidate neoantigens.
Velculescu further teaches calculation of a priority score for each candidate neoantigen, based on an individual’s HLA type and two or more of various descriptors including 1) the peptide sequence’s similarity to known antigens (e.g., whether the neoantigen is known to reside within a cancer-related gene) and 2) predicted major histocompatibility complex (MHC) binding affinity between the peptide sequence and one or more of the individual’s HLA allele (pg. 1, para. 0007), wherein “terms may be weighted using a weight value to increase or decrease its impact on the neoantigen priority score relative to the other terms” (pg. 6, para. 0047). In this way, Velculescu exemplifies determining a combined score for each of the potential neoantigens based on at least two descriptors such that a maximum possible contribution of at least one descriptor is lower than a maximum possible contribution of at least one other descriptor.
Velculescu also teaches determination of neoantigen priority through application of a rule or series of rules, which can comprise exclusionary provisions (i.e., penalties), to the considered characteristics (pg. 15, para. 4). Velculescu describes an exemplary set of rules pertaining to predicted binding affinity, whereby “All candidate neoantigens with a predicted IC50 affinity greater than, for example, 500 nM may… be removed (pg. 7, para. 0056). In this way, Velculescu teaches filtering potential neoantigens.
Velculescu further describes the exemplary rule set, stating that “remaining candidate neoantigens may… be classified as SB or WB (strong binder or weak binder)” (pg. 7, paras. 0056-0057), i.e., binning of a value indicative for a binding affinity into one of three different classes (removed, SB and WB) ordered according to intervals of values binned into each. Velculescu also depicts ranking of at least 30 neoantigens (pg. 8, para. 0075, Table 1), and so exemplifies classification of neoantigens such that the number of different classes into which values are binned is smaller than a number of the potential neoantigens.
Velculescu additionally teaches ranking the candidate neoantigens based on priority to produce an ordered list, and indicates that priority represents potential for clinical efficacy in the patient (pg. 1, para. 0006; pg. 8, para. 0073).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. ‘168 requires identification of neoantigens based on tumor and normal sequence data obtained from an individual but does not further describe any particular method for achieving this process. Velculescu presents an method that produces a prioritized list of neoantigens based on tumor and normal sequence data obtained from an individual. Said practitioner would implement the neoantigen ranking method of Velculescu to identify neoantigens for the method of ‘168, because the method of Velculescu presents an enabled means for achieving this required step, using the required type of data, of the method of ‘168.
In this way, instant claim 1 is patentably indistinct from claim 26 of ‘168, in view of Velculescu. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
At this point in prosecution, no claim is allowed.
The following prior art, made of record and not relied upon, is considered pertinent to applicant's disclosure:
Bullik-Sullivan et al (WO 2018/227030; effectively filed 6/9/2017) discloses a system and methods for determining neoantigens and vaccine composition based on an individual’s tumor mutations;
Lynn et al (US 2020/0054741; effectively filed 4/4/2017) discloses methods for manufacturing peptide-based vaccines and uses thereof for delivering peptide antigens to induce an immune response;
Sahin et al (US 2014/0178438; published 6/26/2014) discloses a method for providing an individualized cancer vaccine comprising identifying cancer specific somatic mutations in a tumor specimen of a cancer patient;
Srivastava et al (US 2015/0252427; published 9/10/2015) discloses methods of identifying tumor-specific epitopes from cancer tissue DNA of cancer patients, and providing pharmaceutical compositions for personalized immunotherapy.
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 November 12, 2025