Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/21/2025 has been entered.
Status of the Claims
2. Claims 1-13 are the original claims filed 1/4/2023. In the Preliminary Amendment of 6/5/2023, Claim 1 is amended and new Claim 14 is added. In the Response of 6/30/2025, claims 1-6 and 8-14 are amended and new claims 15-28 are added. In the Response of 10/21/2025, claims 1, 4-8, 11, 15, 17, 19, 20, 22 are amended and claims 9, 10, 12-14, 23-24, and 26-28 are canceled. Claims 1-8, 11, 15-22 and 25 are all the claims.
Applicants’ amendment of the claims raises new grounds for rejection. Applicants’ amendment of the drawings and specification raises new grounds for objection.
Priority
3. USAN 18/150,136, filed 01/04/2023, and having 1 RCE-type filing therein is a Continuation of 16/390,946, filed 04/22/2019, now U.S. Patent # 11590217 and having 2 RCE-type filing therein, 16/390,946 Claims Priority from Provisional Application 62/661,298, filed 04/23/2018.
Information Disclosure Statement
4. As of 11/3/2025, a total of four (4) IDS are filed: 7/31/2024; 11/8/2024; 3/18/2025; and 10/22/2025. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
5. The objection to the disclosure because of informalities is withdrawn.
Applicants have amended Figure 1 to delete the phrase shown in the figure for “NANTAI Engine for Cancer/ Augmented Intelligence, Machine Learning Super Computer.”
Claim Objections
6. The objection to Claims 1-14 and 28 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
i. Claim 1 is amended to recite “…an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is administered after or concurrently with the Alt-803 and
ii. Claims 6-8 are amended to recite “The combination of claim 1.”
iii. Claim 4 is amended to recite “a second boost vaccination dose, wherein the second boost vaccination dose is administered at least one year after the first dose of the vaccine composition.”
iv. Claim 28 is canceled.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claims 15-28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims and withdrawn for the pending claims.
a) Generic Claim 15 is amended to recite the properties for the neopeptide and the appropriate number of vials for the dosage regimen of the corresponding kit components.
b) Claims 23-24 are canceled.
Claim Rejections - 35 USC § 112(d)
8. The rejection of Claims 5, 9-10, 12-13 and 22 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter is moot for the canceled claims and withdrawn for the pending claims.
i. Claim 5 is amended to replace IL-15 or derivative thereof with Alt-803.
ii. Claims 9-10 are canceled.
iii. Claims 12-13 are canceled.
iv. Claim 22 is amended to “at least four tumor specific or tumor associated antigenic peptides.
Double Patenting
9. The rejection of Claims 1-14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11590217 is moot for the canceled claims and withdrawn for the pending claims.
The terminal disclaimer filed on 10/22/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11590217 has been reviewed and is accepted. The terminal disclaimer has been recorded.
10. The rejection of Claims 1-14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11564980 is moot for the canceled claims and withdrawn for the pending claims.
The terminal disclaimer filed on 10/22/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11564980 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Objections Maintained
Claim Objections
11. The objections to Claims 18 and 20-22 because of informalities is maintained. Applicants have not responded to the objection. The response is incomplete.
i) Amend claim 18 to recite that the kit comprises a
ii) Amend claims 20-22 to replace “The vaccine composition of claim 15” with “The kit of claim 15” for consistency.
Appropriate correction is required.
Rejections Withdrawn-in Part/ Maintained-in-Part
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
12. The rejection of Claims 1-8, 11, 15-22 and 25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn-in-part and maintained in part.
Withdrawn-in-part
A. Applicants have provided a copy of PCT Application No. PCT/US2016/056550 (WO 2017/066256) in the IDS of 10/22/2025 and amended the specification to recite, per se, the material text relevant to the claims and from the PCT application for the step(s) of identifying patient-specific neoepitope 9-mer peptides.
B. Applicants have amended the claims to clarify that the tumor specific- or tumor associated- antigenic peptides are derived or obtained from the individual in need of the timed treatment combination, i.e., autologous.
Maintained-in-part
Applicants’ response is incomplete.
Applicants have not responded to the outstanding grounds for rejection.
C. “The claimed invention comprising the combination of elements and the coordinated administration thereof with resultant effect of stimulating any immune response, in vivo, (e.g., towards a Th1 profile (see the abstract)) is not demonstrated for a representative number of embodiments in the original specification nor by extrinsic evidence. Applicants have not demonstrated a representative number of 9-mer neopeptides identified under the steps of claims 1or 15 that bind the HLA-type of the subject individual with an affinity of <500nM much less that when incorporated into the generic claimed regimen result in the stimulation of just any immune response, in vivo.
“immune response”: the specification does not provide a generic definition for the meaning of the phrase. The specification identifies a preferred immune response towards a Th1 bias at [0008; 0014-0016] and a Th1 response:
[0012] Contemplated Th1 stimulations typically comprise administration of a cytokine or small molecule drug that biases an immune response towards a Th1 response. Therefore, especially preferred cytokines include IL-12 or a derivative thereof (e.g., comprising an antibody portion that binds to a tumor cell or a necrotic component of a tumor cell).
The POSA could reasonably conclude that the required step of IL-12 administration would bias the immune response towards in a Th1 profile and not just any immune response.
MPEP 2163 (II)(A) (3)(a)(ii):
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)
The allegations are not substantiated by extrinsic evidence showing, in vitro or in vivo, use of any cancer- related antigenic peptide in combination with Alt-803, any anti-PD-L1 antibody, and IL -12 that provides any immune stimulating benefit to the individual including humans. MPEP 716.01 and 2145 (The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)).”
D. Applicants’ response is incomplete.
Applicants have not responded to the outstanding grounds for rejection.
“Generic definitions for claimed reagents
Vaccines: e.g., see www.historyofvaccines.org/content/articles/cancer-vaccines-and-immunotherapy listing for some therapeutic vaccines: autologous cancer vaccines; allogeneic cancer vaccines; protein or peptide cancer vaccines; DNA vaccines.
Checkpoint inhibitors: e.g., see Marin-Acevedo et al. (Journal of Hematology & Oncology (2018) 11:39); see Barrueto et al. (Translational Oncology 13(3):1-10 (March 2020)) for a list of some checkpoint inhibitors.
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Th1 stimulators: see Waldman (Cold Spring Harb Perspect Biol pp. 1-23 10.1101/cshperspect.a028472 originally published online November 3, 2017) for a list of some Th1 stimulators which is overlapping in the art with some immune stimulators. Immune stimulators (anti-cancer cytokines; immune system modulators): e.g., see www.cancer.gov/about-cancer/treatment/types/immunotherapy/immune-system-modulators; Conlon et al. (JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 39(1):6-21 (2019)); and Berraondo et al (British Journal of Cancer volume 120, pages 6–15 (2019) for a list of some therapeutic cytokines:
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Disclosure in the Specification
Example 1 shows the timed treatment combination for each of the vaccine regimen, immune stimulation regimen, checkpoint regimen and Th1 regimen as follows:
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From these the data, it is the use of only the following reagents: neoantigen (undefined by structure), ALT-803 (immune stimulation regimen), anti-PD-L1 (checkpoint regimen) and NHS-IL-12 (Th1 regimen) that have been tested in the timed treatment protocol.
The specification does not identify a starting population of “SNV” nor an “indel” tumor-associated antigenic peptides from which the predicted antigenicity and binding affinity are based for a neoepitope antigen. The specification does not disclose a single example of a neoepitope antigen by a partial and/or full structure obtained from the screening methods described under [0066]. The specification states in [0070] “…neoepitopes were kindly produced and provided by the Etubics/NantCell Corporation.”
The application does not contain a sequence listing on file that demonstrates Applicants possession of the myriad and undefined neoepitope peptides (9-mer or otherwise) that are imbued with the functional properties required of the instant claimed invention.
Based on the foregoing analysis, the entire application as filed is a wish for obtaining the tumor-specific 9-mer neoepitope antigen(s) where no single data are revealed for the claimed structure that meets the functional requirements of the claims: binding affinity of <500nM for the HLA-type of the individual; expressed highly from the corresponding RNA; and effective at stimulating an immune response, in vivo.
MPEP 2163II(A)(3)(a)
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
Prior Art and Challenges for the Immunotherapies.
Regimen #1: Vaccines:
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(See www.cancer.net/navigating-cancer-care/how-cancer-treated/ immunotherapy-and-vaccines/what-are-cancer-vaccines).
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(See www.creative-biolabs.com/vaccine/cancer-vaccines.htm?gclid= EAIaIQobChMI_ LqE46S_8QIV72pvBB2ocgY_EAMYASAAEgJ5afD_BwE).
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(See Liu (Yale J Biol Med. 2014 Dec; 87(4): 481–489) (IDS 3/18/2025)).
Regimen #2: immune stimulator (anti-cancer cytokines):
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(See Berraondo et al (British Journal of Cancer volume 120, pages 6–15 (2019) (IDS 3/18/2025)).
Regimen #3: checkpoint inhibitor:
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(See Barrueto et al. (Translational Oncology 13(3):1-10 (March 2020) (IDS 3/18/2025))
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(See Marin-Acevedo et al. (Journal of Hematology & Oncology (2018) 11:39 (IDS 3/18/2025))
MPEP 2163II(A)(3)(a)(i)
If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that inventor was in possession of the claimed invention.
The instant application fails to describe a single amino acid sequence for a tumor-associated neoepitope peptide (9-mer or otherwise) much less a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides general descriptions of how to select and screen neoepitopes and how to test them for desired binding and immune stimulating activities, the structure for no single neoepitope is revealed in the entire application as filed. Accordingly, the specification does not support the written description requirements as of the time of filing.”
The rejection is maintained.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 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 U.S.C. 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.
13. The rejection of Claim(s) 1-8 and 11 under 35 U.S.C. 103 as being unpatentable over Jones et al (US 11149087; filing date 4/20/2016) in view of NCT03127098 (Clinicaltrials.gov; first posted 2017-04-25; pp. 1-11) is moot for the canceled claims and maintained for the pending claims.
Applicants have not addressed the outstanding grounds for rejection in the Response of 10/21/2025. The Response is incomplete.
“A. Applicants allege the claims are now directed to a specific and intentionally sequenced therapeutic regimen comprising: (1) administration of a vaccine composition comprising at least one tumor-specific or tumor-associated antigenic peptide, or a nucleic acid encoding such peptide, as a prime vaccination dose, followed sequentially by (2) administration of ALT-803, followed by (3) an anti-PD-L1 antibody, followed by (4) a boost vaccination dose of the vaccine composition, and finally (5) administration of IL-12 after the boost dose.
Response to Arguments
The actual outline of the claimed therapeutic regimen is not disputed for the amended claims. A recitation of the intended use of the claimed invention (stimulating any immune response) must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
MPEP 2145(II):
Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
B. Applicants allege Jones and NCT03127098 may disclose certain individual components of this combination, neither reference, alone or in combination teaches, suggests, or provides motivation for the specifically timed and ordered sequence of administration claimed herein. The inventive treatment schedule is not a mere aggregation of known agents; rather, it reflects a deliberate strategy designed to prime, expand, and sustain a robust anti-tumor immune response through a novel immunological choreography that is absent from the cited art.
Response to Arguments
Applicants have not shown that the specific and intentionally sequenced therapeutic regimen yields unexpected, improved and/or surprising results (stimulating any immune response) compared to the prior art alone or in combination.
MPEP 2145
Rebuttal evidence may include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation.”
Applicants have not addressed the outstanding grounds for rejection in the Response of 10/21/2025. The rejection is maintained.
14. The rejection of Claim(s)
A. Applicants allege the references do not disclose personalized immunotherapy patient specific vaccine with sequential cytokine stimulation and checkpoint blockade.
Response to arguments
A signature refers to characteristics associated to DNA sequences. Many studies analyze genotype–phenotype patterns in a group of genes, thus targeting genomic signatures associated to a given disease or identifying a gene expression profile.
Jones describes an antigen in the context of a “signature” that is interpreted as a personalized therapy for the individual of the method:
“In some embodiments, compositions and methods described herein relate to generating an immune response in an individual against cells expressing and/or presenting a target antigen or a target antigen signature comprising at least one target antigen...”
“Certain embodiments provide a combination immunotherapy and vaccine compositions for the treatment of cancer and infectious diseases. In some aspects, combination immunotherapies and vaccines provided herein can comprise a multi-targeted immunotherapeutic approach against antigens associated with the development of cancer such as tumor associated antigen, (TAA) or antigens know to be involved in a particular infectious disease, such as infectious disease associated antigen (IDAA). In some aspects, combination immunotherapies and vaccines provided herein can comprise a multi-targeted antigen signature immunotherapeutic approach against antigens associated with the development of cancer or infectious disease.”
“Some embodiments provide combination multi-targeted vaccines, immunotherapies and methods for enhanced therapeutic response to complex diseases such as infectious diseases and cancers. Certain embodiments provide compositions, methods and kits for generating an immune response in an individual to fight infectious diseases and cancer. Certain embodiments provide compositions, methods and kits for generating an immune response against a target antigen or cells expressing or presenting a target antigen or a target antigen signature comprising at least one target antigen.
Jones teaches “Whole genome sequencing for identification of mutation correlate with clinical outcome” and where a signature determination is not limited to pre- or post-method treatments. Jones teaches RNA and proteomic analysis for immune signature changes and a signature determination and is not limited to pre- or post-method treatments.
Jones teaches a method of enhancing an immune response in an individual in need thereof, the method comprising: administering to the individual a first pharmaceutical composition comprising a replication-defective adenovirus vector comprising a nucleic acid sequence encoding an antigen; and administering to the individual an immune checkpoint inhibitor.
NCT03127098 is a clinical trial testing the same vaccine, ETBX-011 (Ad5 [E1-, E2b-]-CEA), as described by Jones that includes the IL-15 superagonist, Alt-803. The purpose of the trial is to evaluate ETBX-011 in combination with ALT-803 as a combination of agents in a dose-escalation study with ETBX-011 as a fixed dose with a dose escalation of ALT-803. The target antigen signature of ‘098 is indeterminate from the disclosure.
B. Applicants allege the specification demonstrates epitope spreading and durable immunity resulting from the multi-epitope design ([0085-0088; Fig 11C-D).
Response to Arguments
Despite Applicants allegation that the invention, per se, yields the above -described results, the POSA could reasonably conclude that is for the specific multi-epitope vaccine administered in the regimen depicted in Fig. 11B comprising the JAK1, Olfr99, Ptgtr and Trp53 peptides. The testing conducted in cancer-bearing mice does not allow the POSA to reasonably conclude that the JAK1, Olfr99, Ptgtr and Trp53 peptides are autologous tumor-associated antigenic peptides obtained from the test mice. Applicants do not define the meaning of “durable immunity” to ascribe the immune response to the change in tumor volume. Notably Fig 11G depicts CD8/CD4 ratio of infiltrating T cells, but the immune cell or response is NOT defined in the instant claims. Finally, no epitopes by technical name much less by their 9-mer structure are described in the claims.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e.,” epitope spreading and durable immunity resulting from the multi-epitope design”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
C. Applicants allege the application provides detailed experimental evidence of significant and unexpected synergy shown by those data in Fig 6G, 7C, 7E, 8A and 9-A-9C.
Response to Arguments
Fig. 6 at [0077] This enhancement in immunogenicity seen when combining our 9-mer neoepitope vaccine with N-803 and anti-PD-L1 correlated with only a slight, but significant increase in the survival of treated, as compared to control, animals (FIG. 6G). Because the POSA cannot ascertain the nature and kind of neopetide(s) used in the vaccine component of the composition for the instant example, any neopeptide in the art renders obvious that aspect of the instant claimed invention.
Fig. 7C: [0079] In the presence or absence of vaccination, animals treated with N-803 and anti-PD-L1 showed no evidence of tumor control (FIG. 7C); in addition, animals treated with the combination of N-803, anti-PD-L1 and NHS-IL12, and no vaccine, had transient tumor control (FIG. 7C), with the median overall survival increasing from 21 days in non-treated animals to 39 days in animals treated with the triple combination. The addition of a neoepitope vaccine to this combination, however resulted in a dramatic regression of the majority of MC38 tumors (FIG. 7C, right panel).
Because the POSA cannot ascertain the nature and kind of neopetide(s) used in the vaccine component of the composition for the instant example, any neopeptide in the art renders obvious that aspect of the instant claimed invention.
Fig. 7E: Animals whose tumors resolved following treatment remained tumor- free after the cessation of vaccination on day 39, and 4/6 animals subsequently resisted tumor rechallenge with MC38 on day 76. These re-challenged animals likely were able to completely clear any residual MC38 cells, as the inventors did not observe tumor outgrowth, even after depleting animals of CD8+ T cells 81 days after the second tumor implantation (FIG. 7E).
Because the POSA cannot ascertain the nature and kind of neopetide(s) used in the vaccine component of the composition for the instant example, any neopeptide in the art renders obvious that aspect of the instant claimed invention.
Fig. 8A: [0081] To ascertain if a vaccine consisting of a single neoepitope was capable of mediating tumor regression, tumor-bearing animals were treated with either a single 9-mer or a pool of all four neoepitope peptides in combination with N-803, anti-PD-L1 and NHS-IL12. The pool of neoepitopes was more efficient at inducing the regression of MC38 tumors than any of the single peptide vaccinations (FIG. 8A).
Because the POSA cannot ascertain the nature and kind of neopetide(s) used in the vaccine component of the composition for the instant example, any neopeptide in the art renders obvious that aspect of the instant claimed invention.
Fig. 9A-9C: [0082] Using the same treatment regimen depicted in FIG. 7A, the inventors assessed which components of the immune system were modulated by each of the different agents and their combinations within the tumor microenvironment. The quadruple treatment regimen was shown to maximally enhance the infiltration of CD8+ T cells into the tumor (FIGS. 9A and 9B). The addition of NHS- IL12 to the treatment regimen had a profound impact on both the innate and adaptive immune cells within the tumor microenvironment. It promoted the expansion of M1 macrophages with a coordinate contraction of M2 macrophages (FIG. 9C).
Because the POSA cannot ascertain the nature and kind of neopetide(s) used in the vaccine component of the composition for the instant examples, any neopeptide in the art renders obvious that aspect of the instant claimed invention.
The rejection is maintained.
New Grounds for Objection
Drawings
15. The replacement drawing sheet for Figure 1 is newly objected to because the explanation for the object
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has been entirely deleted from the drawing sheet filed 10/21/2025. The absence of any description for the object is not provided for in the corresponding figure legend for the substitute specification filed 10/21/2025.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
16. The substitute specification filed 10/21/2025 has not been entered because it does not conform to 37 CFR 1.125(b) and (c) because: it omits paragraph numbering between paragraphs [0037] and [0038].
Claim Objections
17. Claims 1-8, 11, 15-22 and 25 are objected to because of the following informalities:
a) Amend Claims 1-8, 11, 15-22 and 25 to recite “tumor-specific or tumor-associated antigenic peptides.”
Appropriate correction is required.
Conclusion
18. No claims are allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached on Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643