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 .
Priority
The instant application is a 371 of PCT/US2020/055083 filed on 10/09/2020, which claims the benefit of US Provisional application 62/913,658 filed on 10/10/2019. The instant application will be examined with an effective filing date of 10/10/2019.
Status of the Claims/Application
Claims 21-47 have been previously canceled. Claims 1 and 1 are currently amended. Claims 1-20 are pending, and are herein under examination on the merits.
Withdrawn Rejections
Applicant’s amendments/arguments, see Remarks pg. 5 para. 2-3, filed on 12/16/2025, with respect to the rejections of claims 1-20 under 35 USC 103 and claims 1-4, 5-8, 10 and 12 under non-statutory double patenting (NSDP) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of applicant amendments to instant claims 1 and 2.
New Grounds for Rejection
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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017123675 A1, and further in view of Thorne SH. Adding STING to the Tale of Oncolytic Virotherapy. Trends Cancer. 2016 Feb 1;2(2):67-68, herein further referred to as Falb and Thorne respectively.
Regarding claim 1, Falb teaches that oncolytic virus can be engineered to produce one or more anti-cancer molecules such as immune modulators, and that some oncolytic viruses are naturally able to specifically target, infect and lyse cancer cells and leave non-cancer cells intact and also that other oncolytic viruses can be genetically engineered for safe and selective cancer cell targeting, by imploring insertion of foreign sequences or deletion of native viral sequences to exploit tumor-specific attributes or defects in gene engineering (Falb pg. 4 para 11). Falb further teaches that the genetically engineered oncolytic virus maybe engineered to be able to produce immune modulators such as Stimulator of interferon genes (STING) (Falb pg. 252 Tab. 33). Falb also teaches that myxoma virus (MYXV) as an exemplary oncolytic virus that can be genetically modified to produce immune modulators (Falb pg. 74 para 212). Falb further teaches that the oncolytic viruses are capable of local and tumor specific delivery of the anti-cancer molecules, thereby reducing systemic cytotoxicity and/or immune dysfunction associated with systemic administration (Falb pg. 73 para 211).
Although Falb provides working examples of genetically modifying a bacteria for the production of immune modulators such as STING, Falb teaches that MYXV can also be genetically modified to encode a transgene for STING or other immune modulator proteins.
Thorne teaches that STING has been identified as a key cytosolic DNA sensor for the detection of intracellular pathogens, notably DNA viruses and that STING is required for successful induction of anti-cancer adaptive immunity (Thorne pg. 1 para 1-2). Thorne further teaches colon cancers containing mutations in the cGAS-STING pathway are highly susceptible to DNA-virus based oncolytic viral therapies (Thorne pg. 1 para 3). Thorne further teaches that cancers containing a mutation in the STING pathway have been associated with limited responses to many immunotherapies, including both therapeutic vaccines and immune checkpoints inhibitors, meaning their increased sensitivity to some oncolytic viruses could represent an “Achilles heel”. Thorne also teach that because of the effect of STING on immune response in cancers, and because viral therapies replicate selectively in the tumor microenvironment, amplifying the therapy within the tumor itself and expressing any encoded therapeutic transgenes to high levels within the tumor microenvironment, they are uniquely effective at altering the tumor micro environment and to sensitizing tumors that are resistant to other immunotherapies (Thorne pg. 2 para 2-3).
Therefore, it would have being obvious before the effective filing date for a skilled artisan to modify the teachings of Falb in view of Thorne with a reasonable high degree of predictable success so as to genetically engineer an oncolytic virus such as MYXV with a transgene encoding STING instead of a bacteria because an artisan would have picked either a bacteria or virus because both are shown to be used successfully to lyse cancer cells. As indicated by Thorne, the cGAS-STING pathway which is critical for immune modulation in the microenvironment in tumors are highly susceptible to DNA-virus based therapies and that because viral therapies replicate selectively in the tumor microenvironment, amplifying the therapy within the tumor itself and expressing any encoded therapeutic transgenes to high levels within the tumor microenvironment. Therefore, a skilled artisan would have been motivated to genetically engineer MYXV and encode a transgene for STING for targeting the cGAS-STING pathway in the cancer microenvironment.
Regarding claims 2-7, and incorporating the analysis of claim 1 above, Falb further teaches that the oncolytic virus can be genetically engineered to comprise transgene encoding one or more immunomodulatory proteins such as interleukin-12 (IL-12), wherein IL-12 can be IL-12α or IL-12ß (Falb pg. 584 Tab. 103), tumor necrosis factor (TNF) (Falb pg. 202 para 462) and/or an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an PD-L1 inhibitor and wherein the PD-L1 inhibitor is an anti-PD-L1 antibody or a single chain antibody (Falb pg. 85 para 241). Falb further teaches that the genetically engineered oncolytic viruses can also generate anti-tur immune response (Falb pg. 6 para 14), whereby pattern recognition receptors (PPRs) such as toll-like receptors (TLRs) present in the tumor microenvironment will recognize pathogen-associated molecular patterns (PAMPs) that are unique to each pathogen (oncolytic viral DNA) (Falb pg. 6 para 14-15) and thereby activating the Nuclear factor-κB (NF-κB) (Falb pg. 7 para 16).
Claims 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over Falb and Thorne as applied to claim 1 above, and further in view of Liu et al. The immunoregulatory properties of oncolytic myxoma virus and their implications in therapeutics. Microbes Infect. 2010 Dec;12(14-15):1144-52, Liu et al. Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits. J Virol 83, Barrett et al. M135R is a novel cell surface virulence factor of myxoma virus. J Virol. 2007 Jan;81(1):106-14 and Teoh et al. Tumorigenic poxviruses up-regulate intracellular superoxide to inhibit apoptosis and promote cell proliferation. J Virol. 2005 May;79(9):5799-811, herein after referred to as Liu(a), Liu(b) and Teoh respectively.
Regarding claim 8-17, and incorporating the analysis of claim 1 above, Falb teaches that oncolytic virus can be engineered to produce one or more anti-cancer molecules such as immune modulators, and that some oncolytic viruses are naturally able to specifically target, infect and lyse cancer cells and leave non-cancer cells intact and also that other oncolytic viruses can be genetically engineered for safe and selective cancer cell targeting, by imploring insertion of foreign sequences or deletion of native viral sequences to exploit tumor-specific attributes or defects in gene engineering (Falb pg. 4 para 11).
Falb does not of specific gene modification of the oncolytic virus (MYXV).
Liu(a) teaches that the immunoregulatory factors encoded by MYXV can suppress some functions of immune effectors from other species and illustrated the mechanism of action of genes and their potential to improve MYXV as an oncolytic agent in humans (Liu Abstract). Liu further teaches that several of the targeted gene knockout constructs of MYXV such as vMyx-M135KO and vMyx-M063KO lost their ability to be pathogenic even in rabbits while maintaining their oncolytic properties against human cancer cells, and thus represents a newer generation oncolytic candidate MYXV variants (Liu pg. 1146 col 2 para 1). Liu(a) teaches other gene encodings including M-T2, M-T7 and M063 of MYXV immunoregulatory factors with potential impacts on MYXV oncolytic applications (Liu(a) pg. 1145 Tab. 1), wherein M135 knockouts have improved oncolysis for human glioma cells in vitro.
Liu(b) teaches a vMyx-IL-15-tdTr construct wherein IL-15 expressing cassette containing IL-15 encoding was inserted in an intergenic region between M135 and M136 genes in the wild type MYXV strain Lausanne (Liu(b) pg. 5933 col 2 para 2 and Fig. 1). Liu(b) further teaches that the construct comprises a tdTr expression cassette, a strong red fluorescent protein that is driven by a poxvirus synthetic early/late promoter (Liu(b) Fig. 1). Liu(b) taches that vMyx-IL-15-tdTr does not cause lethal myxomatosis and therefore is a safe candidate for animal studies of oncolytic therapy (Liu(b) Abstract).
Barrett teaches of an MYXV construct wherein an EGFP/gpt cassette was cloned into the M135R coding region resulting in the deletion of 460 nucleotides or 86% of the ORF, and loss of M135R expression was confirmed, but the construct had no difference in replication with the vMyxgfp (Barrett pg. 110 Fig. 4).
Teoh teaches that M131R is the gene that encodes SOD1 in MYXV (Teoh pg. 5799 col 2 para 2) and that M131R genes are nonessential genes that are packed in large quantities and promote the reduction of SOD1 activity in virus infected cells. Teoh further teaches that this protein cannot bind copper, which is essential for dismutase activity (Teoh pg. 5800 col 1 para 1). Teoh further teaches that M131R are not essential for virus growth, indeed M131R knockout MYXV grew better than wild type MYXV. Teoh further teaches that SOD1 homologs can led to immunoevasive pathways that promotes virus-induced tumorigenesis (Teoh pg. 5810 col 1 para 2-3).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the method of Falb and Thorne in view of Liu(a), Liu(b) and Teoh with a reasonable degree of predictable success to genetically engineer MYXV where the modification of the MYXV is a deletion of M135R and/or SOD (knockouts), replaces a portion of M135R, insertion of the transgene encoding an immune modulator of interest between M135R and M136R to obtain an oncolytic virus. As indicated by Falb, a transgene of interest can be use inserted in the virus, or a gene on the oncovirus can be deleted depending on the desired outcome. As indicated be Liu (a), M135R knockout constructs have shown better oncolytic properties. Furthermore, Teoh also indicated that SOD knockouts had better viral growth. Therefore, it would have been obvious for a skilled artisan to follow the suggestions of Falb to modify the MYXV virus to deleting, inserting or replacing part of a gene such as M135R or SOD that is not beneficial for developing an oncolytic virus therapy.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Falb and Thorne as applied to claim 1 above and further in view Liu(a), Liu(b) and Liu et al. STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2019 Sep;26(9):1735-1749. doi: 10.1038/s41418-018-0251-z. Epub 2018 Dec 19, herein referred to as Liu Dong.
Regarding claims 18-20, and incorporating the analysis of claim 1 above, neither Falb nor Thorne teaches an increase in the killing of infected or uninfected cancer cells when the cancer cells are treated with the MYXV construct compared to the wild type MYXV as determined by either in vitro flow cytometric assay or LC3-I to LC3-II conversion assays.
Liu(a) teaches that by modifying oncolytic MYXV platform by inserting therapeutic genes in the wild-type backbone or knockout viruses with improved tumor cell selectivity or increased safety are under investigation such as the reported in Liu(b) where IL-15 was encoded in MYXV and the variant did failed to cause lethal myxomatosis in European rabbits compared to the wild type MYXV (Liu(a) pg. 1150 col 2 para 1).
Lui(b) teaches that the size of primary lesions of NZW rabbits that were infected with vMyx-Lau, vMyx-tdTr and vMyx-IL-15-tdTr, were significantly reduced for vMyx-IL-15-tdTr infected NZW rabbits and they eventually fully recovered (Liu(b) pg. 5935 col 1 para 2 and Fig. 3).
Liu Dong teaches that STING harbors classic LC-3 interacting regions and mediate autophagy through its direct interaction with LC3 and hat STING functions in activating the immune response and autophagy and that STING is involved in ensuring a measured innate immune response (Liu Dong Abstract). Liu Dong further teaches that STING induces autophagy upon virus infection. Lui Dong further teaches that HSV-induced LC3-II conversion in wild-type cells but not in STING knockout cells and that HSV-1-induced autophagy depends on STING (Liu Dong pg. 1741 col 1 para 2 – col 2 para 1 and Fig. 7).
Therefore it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Falb and Thorne in view of Liu(a), Liu Dong and Liu(b) with a high degree of predictable success that the MYXV encoding a transgene such as STING or IL-15 would increase autophagy or killing of infected and infected cells compared to the wild type MYXV. As indicated by Liu Dong STING is essential to activate autophagy and since wild type MYXV does not carry STING. Furthermore, as indicated by Thorne, cancers containing a mutation in the STING pathway have been associated with limited responses to many immunotherapies, including both therapeutic vaccines and immune checkpoints inhibitors, meaning their increased sensitivity to some oncolytic viruses could represent an “Achilles heel”. Liu(b) also shows that primary lesions of NZW rabbits was significantly reduced by vMyx-IL-15-tdTr. Therefore, a skilled artisan would have been able to construct a MYXV encoding a transgene such as STING and/or IL-15 where the MYXV variant would increase autophagy as determined by LC3-I to LC3-II conversion assays or killing or cancer infected and uninfected cancer cells compared to the wild type MYXV.
Response to Arguments
Applicant’s amendments/arguments, see Remarks pg. 5 para. 2-3, filed on 12/16/2025, with respect to the rejections of claims 1-20 under 35 USC 103 and claims 1-4, 5-8, 10 and 12 under non-statutory double patenting (NSDP) have been fully considered and are persuasive.
However, regarding applicant’s response that the prior art does not teach MYXV comprising a transgene encoding STING, the examiner addresses this in the rejection above.
Regarding the applicant argument (Remarks pg. 7 para 4) that Falb listed 77 bacteria and 23 viruses as microorganisms that can be used for the construct as claimed and that the teachings are directed to genetically engineered bacteria and no data genetically engineered viruses having a STING transgene and therefore a skilled artisan would have had no motivation to combine the teachings without hindsight bias (Remarks pg. 8 para 1). As indicated in MPEP 2145(X)(B), an "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success to use a lytic virus such as MYXV to substitute the bacteria of Falb since both lytic and lytic bacteria have been used successfully in cancer treatment (Falb Abstract and para 10-11). " [A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. Also, "any judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper. Furthermore, Falb indicated that oncolytic viruses are also suitable to be genetically modified to deliver immune response in tumor environments and that myxoma virus (MYXV) as an exemplary oncolytic virus that can be genetically modified to produce immune modulators (Falb pg. 74 para 212). MYXV are known by a skilled artisan to be suitable oncolytic viruses for said purpose. Therefore, a skilled artisan would have been motivated to use MYXV as suggested by Falb.
Regarding applicants arguments (Remarks pg. 8 para 5-6 and pg. 9 para 3-4) and in view of claim 1 amendment, that Falb and Barrett 1 do not teach every element of claim 1 on which claims 7-20 depends, it would not have been obvious to provide a skilled artisan with any predictable expectation of success in arriving at the transgene encoding STING. The examiners obviousness analysis was based on a different immunomodulator as claimed in claim 1 filed on 03/05/2024. Also, a teaching, suggestion, or motivation to combine references that is found in the prior art is an appropriate rationale for determining obviousness. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. However, it is just one of a number of valid rationales for doing so. See MPEP 2145(X)(C). Furthermore, an obviousness analysis is on the basis on a combination of teaching and all the limitations of the claim do not necessarily have to be in any one prior art as indicated in MPEP 2145(IV), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to a PHOSITA."
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683