DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application/Claims
The amended claims, filed 10/29/2025, is acknowledged. Claims 1-4, 7-10, 13-16, and 19-22 are currently amended. Claims 1-24 are currently pending. The examiner has withdrawn claims 1-6 and 13-14 in response to applicant election of claims 7-12 (see Election/Restriction section below). Thus, claims 7-12 are currently examined on the merits herein.
Priority
The original application was filed 10/10/2022. No foreign or domestic priority is claimed.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 01/11/2023, 07/11/2023, 09/28/2023, 02/28/2024, 05/09/2024, 02/03/2025, 03/13/2025, 04/02/2025, 06/12/2025, and 11/04/2025 have been fully considered by the examiner.
Election/Restriction
A Restriction/Election of Species requirement was mailed to applicant on 09/12/2025. Applicant’s election of a single disclosed composition comprising at least two specific nucleic acids encoding the disclosed species of amino acids encoded by SEQ ID NOs: 1-247, 6936-6994, 12271-12396, and 49712-49814 in the reply filed on 10/29/2025 is acknowledged as follows:
Regarding species requirement to elect a single composition:
Applicant elects, without traverse, a composition comprising one or more polynucleotides encoding SEQ ID NOs: 6936, 6937, and 6938. Applicant also states that claims 7-12 encompass the elected species.
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.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cancer, does not reasonably provide enablement for the prevention of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) The nature of the invention; (2) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claim 12 is drawn to an immunogenic composition administered for preventing cancer.
The breadth of the claims
The claim is broad in that it encompasses the prevention of any cancer.
The claim is broad and inclusive of all types of cancer. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. For example, there are solid cancers of the brain, spine, live, prostate, testes, ovaries, bile duct, blood vessels, lung and pleural cavity, thyroid, skin (including melanoma), colon, prostate, kidneys, breasts, testicles, vulva and vagina, uterus, cervix, fallopian tubes, thymus, stomach, esophagus, spleen, salivary glands, heart, oral cavity, adrenal glands, eye, head and neck, bladder, bone, and gall bladder. Each of these types of cancer have potentially dozens of sub-categories that each have unique physiological and etiological characteristics.
The amount or direction provided by the inventor/ the existence of working examples
The instant disclosure recites the following regarding “prevention”: “As used herein, the terms "prevent," "preventing", "prevention", "alleviate", or "alleviating" refer to the prevention, inhibition, or lessening of the recurrence, onset, or development of a disorder or a symptom thereof in a subject resulting from the administration of a therapy (e.g., a vaccine), or the administration of a combination of therapies (e.g., a combination of vaccine(s) and/or therapeutic agents)” (p.14, [0086]). There are otherwise no working examples or drawings in the disclosure that provide evidence for a composition that can prevent cancer or a method wherein the prevention of cancer could be determined.
The examples provided do not demonstrate the prevention of recurrence or development of cancer. Additionally, the disclosure does not discuss, or demonstrate through working examples, a product or method that could be used to determine that recurrence or development of cancer was prevented using the claimed agents as there is no disclosed product or method to determine that recurrence or development of cancer would have predictably occurred without treatment.
The state of the prior art/ the level of predictability in the art
There are no art recognized methods that could be used to establish that the cancer was prevented using the claimed therapeutic method. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed cancer in order to determine that the cancer was prevented using the claimed methods.
Regarding biomarkers (and immunotherapies) in cancer, McKean et al. Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291 (herein referred to as McKean) teach that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (abstract). McKean also teach that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
Ahmadzada et al. An update on predictive biomarkers for treatment selection in non-small cell lung cancer. Journal of Clinical Medicine (2018), 7:153, p.1-12 (herein referred to as Ahmadzada) also suggest that it is still difficult to apply classification of cancers to select targeted therapies. For example, Ahmadzada teaches that non-small cell lung cancer is a highly heterogeneous disease that develops from genetic mutations and gene expression patterns that initiate uncontrolled cellular growth, proliferation, and progression (p.2). Ahmadzada also teaches that only 15-25% of non-small cell lung cancer patients benefit from immunotherapy, suggesting the need for novel biomarkers to identify the best candidates for treatments (p.7). Further, Ahhmadzada et al. also recognize that the heterogeneity of NSCLC remains a key barrier to accurate molecular classification and necessitates individualization of treatment (p.8).
The American Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention. 1/1/2025. Internet – Wayback Machine. p.1-4).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Studies regarding treatment and prevention of tumors/cancer are underway that aim to improve earlier detection and better treatments for tumors/cancer. However, based on the disclosure and the prior art, there is no known or disclosed method through which an ordinarily skilled artisan would have been able to predictably identify subjects who would have predictably developed tumors in order to determine that the tumors were prevented using the claimed methods. Therefore, in order to practice the invention as claimed, an ordinarily skilled artisan would have to participate in undue experimentation to determine a method that would allow for the prevention of recurrence of cancer.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claim was determined to not meet the scope of enablement requirement of 35 U.S.C. 112(a).
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.
Claims 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Pan, et al. Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. Oncotarget (2017), 8:47, p.82689-82699 (herein referred to as Pan); further in view of Weng, et al. DNA vaccine elicits an efficient antitumor response by targeting the mutant KRAS in a transgenic mouse lung cancer model. Gene Therapy (2014), 21, p.888-896 (herein referred to as Weng); further in view of Zirlik, et al. Cytotoxic T cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide. Blood (2006), 108:12, p.3865-3870 (herein referred to as Zirlik); and, further in view of Jensen, et al. Improved methods for predicting peptide binding affinity to MHC class II molecules. Immunology (2018), 154, p.394-406 (herein referred to as Jensen).
Pan teaches a multipeptide vaccine that is immunogenic and efficacious in treating KRAS-induced lung cancer (title; abstract). Pan teaches that mutations in KRAS are detected in up to 30% of lung cancer cases but that no specific targeted therapies have been developed from KRAS mutations except for KRAS G12C, which is partially due to the lack of druggable pockets and cavities on the RAS surface (p.82689, col.2, para.1). Pan teaches that whole organism vaccines are still limited by difficulties in large-scale manufacturing, as well as repeat dosing to enhance vaccine efficiency (p.82690, col.1, para.1). Pan teaches that numerous investigators have attempted to inhibit mutant KRAS, often employing relatively short MHC class I restricted peptides with minimal to moderate success; but, that Pan’s study takes a different approach by using peptides with affinity toward MHC class II molecules where one can prime the development of a robust immune response against a particular epitope/peptide, or generate effective MHC class II-mediated immune responses against a variety of target peptides despite potential tolerance (p.82690, col.1, para.1). Pan teaches vaccination of mice expressing murine KRAS G12D mutation (p.82696, col.2, para.2). Pan teaches that the multipeptide KRAS vaccine approach can potentially be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities (p.82690, col.1 para.2). Further, Pan teaches the entire KRAS protein sequence and immunogenic MHC-II binding “hotspots” identified through a multi-scoring system based solely on MHC class II epitopes (p.82690, col.2, para.1); and, specifically teaches a 10-amino acid hotspot peptide region comprising the KRAS protein amino acid sequence LVVVGAGGVG, which comprises positions 6-15, including the KRAS driver mutation position G12 (underlined in aforementioned sequence; see below excerpt, Pan, p.82691, Fig.1A); and, additionally Pan identifies the high-affinity binding A11 (position A6 of the short peptide; bolded in aforementioned sequence):
This hotspot comprises amino acid positions of instant SEQ ID NOs: 6936, 6937, and 6938 for heteroclitic KRAS sequences derived from the same region of the KRAS protein.
Pan does not teach that the peptides of the vaccine composition are encoded by one or more polynucleotides contained in a construct for in vivo expression (instant claims 7 and 8).
Weng teaches a Kras DNA vaccine as a immunotherapeutic agent in lung cancer driven by the Kras G12D gene (abstract). Weng teaches that mutant Kras peptides have been developed as antitumor drugs by inducing antigen-specific cytotoxic T lymphocyte (CTL), including dendritic cells, response in vivo (p.888, col.1, para.2 – col.2, para.1). Weng teaches that DNA vaccines are able to elicit antitumor response via expressing tumor-associated antigens and offer several advantages, including ease of development, production, and persistent expression of the immunogen (p.888, col.2, para.2). Weng teaches a DNA vaccine wherein the Kras DNA sequence is expressed from a vector (i.e., a DNA construct; title; abstract; p.894, col.1, para.5).
It would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to combine the teachings of Pan with the teachings of Weng by modifying the multipeptide KRAS vaccine composition for cancer treatment that comprises multiple KRAS immunogenic peptides, as taught by Pan, to be expressed by a polynucleotide construct in vivo, as taught by Weng, in order to arrive at a vaccine composition comprising a polynucleotide expressed in vivo from a vector construct (taught by Weng) encoding at least two amino acid sequences corresponding to a G12D-containing MHC-II hotspot of KRAS (taught by Pan), in order to receive the expected benefits of ease of development, production, and persistent expression of immunogens. One of ordinary skill in the art would be motivated to do so because Pan teaches that mutations in KRAS mutation-induced lung cancers are common in lung cancer but therapies KRAS G12D-mediated cancers are lacking. Additionally, one of ordinary skill would be motivated to use multiple KRAS G12D peptides (taught by Weng and Pan) with affinity toward MHC class II molecules (as taught by Pan) in order to receive the expected benefit of priming and generating the development of a robust MHC class II-mediated immune response despite potential [AltContent: textbox (Pan Figure 1A excerpt: hotspot containing KRAS G12 position (range is from highest score = red to lowest score = blue as determined by three algorithms: SYFPEITHI, IEDB, and Rankpep)
[img-media_image1.png])]tolerance (instant claims 7-9, and 12).
The combination of Pan and Weng does not teach that the amino acid residues encoding the remaining “hotspot” amino acids (i.e., non-G12D amino acids) of the peptides are different (i.e., heteroclitic) from those of the hotspot KRAS sequence, which harbors the G12D driver mutation position as well as the remaining amino acid positions of instant SEQ ID NOs: 6936, 6937, and 6938 (instant claims 7 and 11); that the peptides encoded are comprised of instant SEQ ID NOs: 6936, 6937, and 6938 (instant claims 7 and 11); or, that the administration of the composition causes a first peptide to be displayed by a first plurality of HLA class II alleles, and a second peptide to be displayed by a second plurality of HLA class II alleles, wherein the first and second plurality of HLA class II alleles differ by at least one HLA class allele (instant claim 10).
Zirlik teaches that heteroclitic peptide modifications can increase binding of low-binding tumor-associated antigen peptides to MHC class I and class II molecules and increase immunogenicity while leaving T-cell recognition residues intact, and that the heteroclitic peptides lead to improved ability to generate cytotoxic T lymphocytes (CTL) responses against primary tumors is needed (p.3865, col.1, para.1). Zirlik teaches that cytotoxic T cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide (title).
Jensen teaches that understanding which peptides will be presented by MHC class II molecules is important for understanding the activation of T helper cells and can be used to identify T-cell epitopes (abstract). Jensen teaches that the MHC-II molecule is a heterodimeric glycoprotein that consists of an α-chain and a β-chain; that in humans, the two chains are encoded in the human leucocyte antigen (HLA) gene complex in one of three loci called HLA-DR, -DP, and -DQ; and, that each locus is comprised of many different allelic variants, which makes the MHC-II molecule highly polymorphic (p.394, para.1). Jensen teaches that peptides presented by the MHC-II molecule bind to a binding groove formed by residues of the MHC chains; and that MHC-II molecules can accommodate peptides of variable lengths and that the peptide ligand interaction and affinity with the MHC binding groove via a “peptide binding core” that is usually nine amino acids with “anchor positions” P1, P4, P6, and P9 (p.395, col.1, para.1). Jensen further teaches accurate and reliable peptide binding affinity prediction methods that can be used for in silico screening peptides with the purpose of identifying T-cell epitopes that match MHC-II molecules in a given host, including NetMHCII, NetMHCIIpan, TEPITOPE, TEPITOPEpan, PROPRED, RANKPEP, and SVRMHC; and, Jensen specifically highlights that both NetMHCII and NetMHCIIpan have been shown to be among the best methods for predicting binding affinities to MHC-II molecules; and, that the methods are based on training using the NAlign framework and are based on ensembles of artificial neural networks that are trained on quantitative peptide binding affinity data from the Immune Epitope Database (IEDB; p.395, col.1, para.3). Jensen also teaches that both NetMHCII and NetMHCIIpan predict peptide binding affinities to MHC-II molecules covering HLA-DR, HLA-DQ, and HLA-DP (p.395, col.2, para.1). Jensen further teaches that there is a strong correlation between MHC binding strength and peptide immunogenicity and that the two computational methods have been used extensively for identifying T-cell epitopes that can be used in the design of peptide-based diagnostics, therapeutics, and vaccines.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Pan and Weng with the teachings of Zirlik and Jensen by modifying a “multipeptide” vaccine composition comprising a polynucleotide encoding KRAS peptides derived from the hotspot KRAS sequence (taught by the combination of Pan and Weng) by using heteroclitic peptides (taught by Zirlik) harboring mutations in anchor positions P1, P4, P6, and/or P9 (taught by Jensen) and harboring the G12D driver mutation (taught by Pan and Weng), to arrive at the instantly claimed invention, in order to receive the expected benefit, as taught by Zirlik and Jensen, that generation of heteroclitic peptides provides increased binding to MHC molecules and increased immunogenicity (instant claims 7 and 11). One of ordinary skill in the art would have a reasonable expectation of success because Pan teaches a 10-amino acid “hotspot” corresponding to instant SEQ ID NOs: 6936, 6937, and 6938, as well as a high-affinity MHC-II binding amino acid A6; and, because Jensen teaches a 9-amino acid MHC “peptide binding core” where anchor MHC-II binding positions are located at P1, P4, P6, and P9. Thus, the combination of prior art elements results in a predictable design of a KRAS G12D-containing heteroclitic MHC peptide binding core that both aligns with the MHC binding hotspot (taught by Pan) and places the high-affinity A6 in an MHC-II binding anchoring position (taught by Jensen); thus, arriving at the “MHC-II peptide binding core” of the instantly claimed invention. That is, the only resulting peptide would be a heteroclitic peptide that retains the high-affinity A6 residue in the P6 position. One would also be motivated to retain the A6 residue as Pan teaches that this residue has very high MHC-II binding affinity (see figure below, dashed box for P6=A6). As a result, the placement of A6 at P6 necessarily results in the following numbered positions for the residues at P1, P4, and P9 (according to Pan’s WT short peptide sequence): L1 at P1, V4 at P4, and V9 at P9 (see figure below). The only residues that differ between instant SEQ ID NOs: 6936 and Pan’s hotspot are Jensen’s remaining MHC-II peptide binding core residues P1, P4, and P9; the only resulting residues that differ between instant SEQ ID NOs: 6937 and Pan’s hotspot are also Jensen’s remaining MHC-II peptide binding core residues P1, P4, and P9; and, the only resulting residues that differ between instant SEQ ID NOs: 6938 and Pan’s hotspot are Jensen’s [AltContent: textbox ([img-media_image2.png])]MHC-II peptide binding core residues P1 and P4 (see figure below).
Given the limited number of possible remaining MHC-II heteroclitic mutations that can be made at P1, P4, and P9, along with Jensen’s teaching of NetMHCII and NetMHCIIpan computational methods for identifying high-binding residues for MHC-II molecules spanning HLA-DR, HLA-DQ, and HLA-DP alleles, it would have been obvious to try F/phenylalanine in the P1 position, A/alanine in the P4 position, and I/isoleucine or L/leucine in the P9 position because this involves a simple substitution of one amino acid for another where the MHC-II binding affinity could be determined by Jensen’s methods; and, one would additionally be motivated to use Jensen’s known computational techniques using the above-mentioned computational methods/programs (also taught by Jensen) to improve the peptide products for enhanced MHC-II binding in order to enhance immunogenicity for a vaccine composition (taught by the combination of Pan and Weng) and to identify peptides that bind HLA-DR, HLA-DQ, and HLA-DP alleles. Regarding instant claim 10, a vaccine composition that results in a combination of peptides where a first and second peptide function to bind HLA class II alleles that are different is a matter of identification using Jensen’s methods and routine optimization using known techniques in the field to assess HLA class II allele binding and optimal immunogenicity (instant claim 10).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647