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
Acknowledgement is hereby made of receipt and entry of the communication filed on April 13, 2026. Claims 1, 5-8, 15-21 and 32-39 are pending and are currently examined.
Claim Rejections - 35 USC § 112 (Written Description)
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.
(Previous rejection- withdrawn) Claims 9-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is withdrawn in view of the amendment filed on April 13, 2026.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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.
(Previous rejection- withdrawn) Claim 21 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 treating human and mouse breast cancers, does not reasonably provide enablement for using a method being enabling to treat any type of cancer with any type of oncolytic virus.
This rejection is withdrawn in view of the amendment filed on April 13, 2026.
Claim Rejections - 35 USC § 103
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.
(New Rejection-necessitated by amendment) Claims 1, 5-8, 15-21 and 32-39 are rejected under 35 U.S.C. 103 as being unpatentable over Seth et al. (WO2020198293A1, published on Oct. 01, 2020, priority date: March 25, 2019) as evidenced by Sakata et al. (J Signal Transduce. 2014; 2014:970346), Bramante et al. (Oncoimmunology. 2015 Aug 27;5(2):e1078057), Kaufman et al. (Front Mol Biosci. 2022 Feb 22; 9:834841) and Beck et al. (MAbs. 2011 Sep-Oct;3(5):415-6).
The amended base claim 1 is directed to an oncolytic adenovirus comprising a nucleic acid encoding a granulocyte- macrophage colony-stimulating factor (GM-CSF) and a soluble form of the TGF-B receptor-Il (sTGFB- BRII)
Seth et al. describes methods and compositions comprising enhanced targeted immune gene therapy for the treatment of cancer using the adenoviral oncolytic and gene therapy vectors (See Abstract), and teaches that the construct may comprise one or more therapeutic nucleic acids. In particular, the construct may encode a therapeutic decoy receptor transgene to inhibit immunosuppressive agents such as transforming growth factor beta (TGFβ) or interleukin 10 (IL10). Specifically, the therapeutic transgene may be the soluble TGFβ receptor II-Fc fusion protein (sTGβRIIFc) (See [0053]). Seth et al. also teaches that in some aspects, the oncolytic virus is engineered to express a cytokine, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-12 (See [0022]). Although Seth et al. does not disclose, in a single, discrete embodiment, wherein the nucleic acid encoding GM-CSF and the nucleic acid encoding sTGF-BRII are comprised by the same oncolytic virus. It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the oncolytic adenovirus as disclosed by Seth et al. to incorporate a nucleic acid encoding a cytokine, GM-CSF, in addition to sTGβRIIFc.
Nevertheless, Seth et al. teaches that it will be appreciated by those skilled in the art of cancer immunotherapy that other complementary immune therapies may be added to the regimens described above to further enhance their efficacy including but not limited to GM-CSF to increase the number of myeloid derived innate immune system cells, low dose cyclophosphamide or PBK inhibitors (e.g., PBK delta inhibitors) to eliminate T regulatory cells that inhibit innate and adaptive immunity (See [00222]). Indeed, Seth et al. teaches that the construct may comprise one or more therapeutic nucleic acids (See [0053]).
Accordingly, Seth et al. teaches the oncolytic adenovirus comprising a nucleic acid encoding a granulocyte- macrophage colony-stimulating factor (GM-CSF) and a soluble form of the TGF-B receptor-Il (sTGF- BRII), where one of skilled in the art can insert the genes encoding GM-CSF and sTGF- BRII in a single adenoviral vector.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 5-6, Seth et al. teaches exemplary E1b deleted oncolytic adenoviruses are H101 (Oncorine), Onyx 015 or H103 which expresses the heat shock protein 70 (HSP70) or the oncolytic adenovirus H102 in which expression of the Ad E1a gene is driven by the alpha-fetoprotein (AFP) promoter resulting in preferential replication in hepatocellular carcinoma and other AFP overexpressing cancers compared to normal cells (See [00168], where the AFP protomer is a modified TERT Promoter Oncolytic Adenovirus (See [0022], teach claims 5- 6). As evidence for “the expression of genes required for replication of the virus is under the control of a promoter active in the cancer cells” (claim 5), Sakata et al. teaches that AFP promoter is active in fetal liver and hepatocellular carcinoma cancer cell (See Abstract).
Regarding claim 7, Seth et al. teaches that the CMV promoter is adopted to express TGFβRIIFc (See 0094).
Regarding claim 8, Seth et al. teaches that the E1 region (E1A and E1B) encodes proteins responsible for the regulation of transcription of the viral genome and a few cellular genes (See [0098]) and multiple genes can be efficiently expressed using a single promoter/enhancer to transcribe a single message (See oo149]). Fig. 1 of Seth et al. shows the Adenoviral Vector Constructs (See [0043] and below) with the Lyp -1 and sTGFβRIIFc expression under E1B promoter. Although the gene encoding GM-CSF is not shown in the Fig. 1, it would have been obvious for one of ordinary skill in the art, at the time of the invention, to insert the GM-CSF gene into the construct because Seth et al. teaches that in some aspects, the least one adenoviral vector with a genetically
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modified fiber incorporating a Lyp-1 peptide motif is engineered to express p53, MDA-7, a cytokine, and/or immune stimulatory gene. In particular aspects, the cytokine is GM-CSF (See [0025]). Therefore, the GM-CSF can be under the control of an adenoviral E1B promoter as claimed.
Regarding claim 15, Seth et al. teaches that the oncolytic virus is engineered to express a cytokine, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-12 (See [0022]), where the nucleic acid of the oncolytic virus may be made by any technique known to one of ordinary skill in the art. non-limiting examples of a synthetic nucleic acid, particularly a synthetic oligonucleotide, include a nucleic acid made by in vitro chemical synthesis (See [00122]). Here the “synthetic nucleic acid” can be a human codon-optimized because Seth et al. teaches that the treated subject can be a human (See [0030]).
Regarding claim 16, Seth et al. teaches that the oncolytic viral agent is talimogene laherparepvec (T-VEC) which is an oncolytic herpes simplex virus genetically engineered to express GM-CSF (See [00167]), where the T-VEC is modified by inserting two copies of the human granulocyte-macrophage colony stimulating factor (GM-CSF) genes to promote dendritic cell recruitment and activation following antigen uptake from lysing tumor cells as evidenced by Kaufman’s study (See Kaufman et al. page 2, right column, paragraph 2). Also, Seth teaches the Talimogene laherparepvec (T-VEC) is HSV-1 [strain JSl] ICP34.5-/ICP47-/hGM-CSF (See [00240]).
Regarding claims 17-19, Seth et al. teaches that a 1.2-kb HindIII-ApaI fragment from pcDNA3/SR2F containing cDNA of the soluble form of TGF-β receptor II fused to human IgG Fc is first cloned in HindIIIand ApaI digested pBS-SK (See [0088]; teach claims 17)), where the human IgG Fc can be a half-life-extending moiety (Teach claims 18-19), which can be evidenced Beck’s study. Beck et al. teaches that the primary reason for fusion of a binding moiety with Fc is half-life extension. Many biologically active proteins and peptides have very short serum half-lives due to fast renal clearance, which limits their exposure in the target tissue and, consequently, their pharmacological effects. The Fc domain prolongs the serum half-life of antibodies and Fc-fusion proteins due to pH-dependent binding to the neonatal Fc receptor (FcRn), which salvages the protein from being degraded in endosomes (See page 2, middle column, paragraph 3).
Regarding claims 20, Seth et al. teaches "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio (See [0070]) and the person responsible for administration will, in any event, determine the appropriate dose for the individual subject (See [00212]).
Regarding claim 21, Seth et al. teaches a method of treating cancer in a subject comprising administering an effective amount of adenoviral vector with a cytokine such as GM-CSF or the immune stimulatory gene is an inhibitor of TGFβ or IL-10 (See [0025]) as described above, where the cancer can be breast cancer ([00193]). Also, Seth teaches that the therapeutic transgene can be the soluble TGFβ receptor II-Fc fusion protein (sTGβRIIFc) (See e.g., [0010]).
Regarding claim 32, Seth et al. teaches a breast cancer in their invention (See e.g., [00193]), where the triple-negative breast cancer can be a subtype of breast cancer. It would be obvious for one of ordinary skill in the art, at the time of the invention, to include treating the triple negative breast cancer, and the result would be predictable based on the administration method taught by Seth. Treating triple-negative breast cancer using oncolytic adenovirus can be evidenced by Bramante’s study. Bramante teaches that breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis (See Abstract). The oncolytic adenovirus Ad5/3-D24-GMCSF can treat triple negative breast cancer (See Table 1 and below).
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Regarding claims 33-34 and 37, Seth teaches that the sTGF-βRII is under the control of a cytomegalovirus (CMV) promoter (See 0094). As for the E1B promoter for the GM-CSF, Fig. 1 of Seth et al. teaches the E1B promoter regulates the inserted genes in the Adenoviral Vector Constructs (See [0043] and above Fig. 1). Although the gene encoding GM-CSF is not shown in the Fig. 1, it would be obvious for one of ordinary skill in the art, at the time of the invention, to insert the GM-CSF gene into the construct because Seth et al. teaches that in some aspects, the least one adenoviral vector with a genetically modified fiber incorporating a Lyp-1 peptide motif is engineered to express p53, MDA-7, a cytokine, and/or immune stimulatory gene. In particular aspects, the cytokine is GM-CSF (See [0025]). Therefore, the GM-CSF can be under the control of an adenoviral E1B promoter as claimed. Here the description teaches claims 33 and 37. As for the limitation at “the subject is human, and the GM-CSF is a human GM-CSF and the sTGF-BRII is a human sTGF-BRII’ in claim 34, Seth teaches that the subject can be human (See 0030]), and the vector of Adenovirus type 5 is a human adenovirus (See 00100]). Although Seth does not explicitly point out the “the GM-CSF is a human GM-CSF and the sTGF-BRII is a human sTGF-BRII”, one of skilled in the art can develop a method to treat breast cancer using the oncolytic adenovirus comprising human GM-CSF and sTGF-BRII. For example, the T-VEC taught in Seth comprises the human GM-CSF as it contains the HSV-1 [strain JSl] ICP34.5-/ICP47-/hGM-CSF, (previously known as OncoVEXGM csF), which is an intratumorally delivered oncolytic immunotherapy comprising an immune-enhanced HSV-1 that selectively replicates in solid tumors and constructed by the human GM-CSF (See [00240]).
Regarding claims 35-36 and 38-39, Seth teaches that further examples of antibodies include Zanulimumab (anti-CD4 mAb), Keliximab (anti-CD4 mAb); Ipilimumab (MDX-101; anti-CTLA-4 mAb) (See e.g., [00233]) (teach claims 35 and 38) where the anti-CTLA-4 antibody is immune checkpoint inhibitor (teach claims 36 and 39).
(New Rejection-necessitated by amendment) Claims 1, 5-8, 15-21, 32-34 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Hum Gene Ther. 2017 Aug;28(8):667-680, hereinafter “Liu”) in view of Hu et al. (Hum Gene Ther. 2012 Aug;23(8):871-82, hereinafter “Hu”) as evidenced by Haviv et al. (J Gene Med. 2003 Oct;5(10):839-851, hereinafter “Haviv”), Beck et al. (MAbs. 2011 Sep-Oct;3(5):415-6, hereinafter “Beck”) and Bramante et al. (Oncoimmunology. 2015 Aug 27;5(2):e1078057, hereinafter “Bramante”).
The amended base claim 1 is directed to an oncolytic adenovirus comprising a nucleic acid encoding a granulocyte- macrophage colony-stimulating factor (GM-CSF) and a soluble form of the TGF-B receptor-Il (sTGFB- BRII).
Liu teaches an oncolytic adenovirus encoding decorin and granulocyte macrophage colony stimulating factor (GM-CSF) inhibits tumor growth in a colorectal tumor model by targeting pro-tumorigenic signals and via immune activation (See Abstract). Liu discloses that it has been previously shown that decorin could block TGF-β signaling, which plays pivotal role in tumor growth and metastasis. It was hypothesized that oncolytic adenovirus expressing decorin could offer a potential therapeutic approach for CRC, as suggested earlier for breast and prostate cancers. To enhance the antitumor responses further, GM-CSF and decorin were co-expressed in the recombinant oncolytic adenovirus, as described in the Materials and Methods. rAd.DCN.GM is an oncolytic adenovirus that contains both decorin and GM-CSF. The two genes are regulated by CMV and E1B promoter, respectively. rAd.DCN, an oncolytic adenovirus containing only decorin gene; rAd.GM, an oncolytic adenovirus containing only GM-CSF gene; and rAd.Null, an oncolytic adenoviruswithout any transgene (Fig. 2A) was used as the controls in these studies. These oncolytic adenoviruses could infect both tumor and normal tissues, but would not spread among normal tissues (See page 672, left column, paragraph 3).
Accordingly, Liu teaches an oncolytic virus comprising a nucleic acid encoding GM-CSF and a TGF-β inhibitor, decorin. However, Liu is silent on the soluble form of the TGF-B receptor-Il (sTGF- BRII) as claimed.
Hu describes a systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model and teaches that they have examined whether Ad.sTbRFc and TAd.sTbRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFbRIIFc), can be developed to treat bone metastasis of prostate cancer (See Abstract). The result of Hu teaches that the infection of prostate tumor cells with Ad(E1-).sTbRFc, Ad.sTbRFc, and TAd.sTbRFc produced sTGFbRIIFc protein resulting in the inhibition of TGF-β signaling and the aberrant TGFβ signaling is known to promote bone metastases in prostate cancer (See page 872, left column, paragraph 2). Accordingly, Hu teaches an oncolytic virus comprising a nucleic acid encoding a soluble form of the TGF-B receptor-Il (sTGF- BRII) that can inhibit Prostate Cancer metastasis.
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liu and Hu to arrive at an invention as claimed to construct an oncolytic adenovirus co-expressing GM-CSF and sTGF- BRII. Because Liu teaches that TGF-β functions as a well-known immune suppresser in advanced and metastatic cancers and block the TGF-β signaling can abolish TGF-β-mediated immune tolerance in the tumor microenvironments, and rAd.DCN.GM combines the advantages of both decorin and GM-CSF in evoking antitumor immune responses in vivo (See bridging left and right column, page 668), and Hu teaches that oncolytic viruses expressing sTGFbRIIFc can be potentially developed for the treatment of skeletal metastases secondary to prostate cancer, one would have been motivated to introduce the teaching of Hu into Liu’s study to replace the decorin by sTGFbRIIFc and test the effects on treating breast cancer. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 5-6, Liu teaches that “Keeping that in mind, a telomerase reverse transcriptase promoter (TERTp) regulated oncolytic adenovirus expressing decorin and GMCSF, rAd.DCN.GM, has been developed using an established system (See page 668, right column, paragraph 1), where the human telomerase reverse transcriptase (TERT) promoter is generally expressed at higher levels in prostate cancer as taught by Hu (See Hu, page 872, left column, paragraph 2), which indicates a active promoter in cancer cells as claimed.
Regarding claims 7-8, Liu teaches that rAd.DCN.GM is an oncolytic adenovirus, in which the expression of DCN and GM-CSF is regulated by the cytomegalovirus (CMV) promoter and E1B promoter, respectively (claim 8). Based on the description above, one of skilled in the art, before the effective filing date of the claimed invention, would have the motivation to replace the Decorin with the gene encoding sTGFbRIIFc under the CMV promoter as the Decorin does. Expression of sTGF- BRII under the CMV promoter can be evidenced by Haviv’s study. Haviv teaches that AdTβ-ExR is a recombinant E1−, E3− adenoviral vector, expressing a soluble TGF-β type II receptor (sTβIIR) under the control of the CA promoter (comprised of the CMV enhancer and the chicken β-actin promoter). sTβIIR comprises the first 159 amino acids of the human TGF-β type II receptor ectodomain, inclusive of the critical TGF-β binding domain 22-24, genetically fused to the human IgG1 Fc portion with an Spe1 restriction site (See page 840, left column, paragraph 3).
Regarding claims 15 and 16, Liu teaches that the expression of GM-CSF was detected by using a human GM-CSF ELISA kit (See page 669, left column, paragraph 4), which teaches claim 16. Liu also teaches that the rAd.DCN.GM is an oncolytic adenovirus expressing transgenes of DCN and GM-CSF (See page 669, left column), where the transgene can be a synthesized gene through human codon-optimization in order to facility a better expression in human cell line based on the needs (teach claim 15), which is a routine technique in the art.
Regarding claims 17-19, Liu teaches a soluble transforming growth factor-b receptor II (sTGF-BRIl) is fused with a human Fc to become the construct of sTGFbRIIFc (See Abstract) (teach claims 17 and 19), where the human Fc (Fragment crystallizable) region of antibodies is a highly effective "half-life-extending moiety". This can be evidenced by Beck’s study. Beck et al. teaches that the primary reason for fusion of a binding moiety with Fc is half-life extension. Many biologically active proteins and peptides have very short serum half-lives due to fast renal clearance, which limits their exposure in the target tissue and, consequently, their pharmacological effects. The Fc domain prolongs the serum half-life of antibodies and Fc-fusion proteins due to pH-dependent binding to the neonatal Fc receptor (FcRn), which salvages the protein from being degraded in endosomes (See page 2, middle column, paragraph 3) (teach claim 18).
Regarding claims 20- 21, Liu teaches to treat the Murine colon-cancer CT26 xenografts model mice by intratumorally inject rAd.DCN.GM, rAd.DCN, rAd.GM, rAd.Null (2.5 · 1010 vp/injection), or 100 lL of phosphate-buffered saline (PBS), and all procedures of animal experiments were approved by the Institutional Animal Care and Use Committee of the Beijing Institute of Radiation Medicine. (See page 670, left column, paragraph 1). Hu teaches conducting an animal experiment according to animal protocols approved by the Institutional Animal Care and Use Committee of the NorthShore University Health-System (Evanston, IL) to establish a bone metastasis mice model, and various viral vectors were administered via the tail vein on days 10, 13, and 17 (2.5 · 1010 VP per injection per mouse, each injection in a 0.1-ml volume) to test the effect of intravenous injection of adenoviral vectors on prostate cancer bone metastasis. The control group of mice was administered buffer alone (See page 873, left column, paragraph 2). Based on the descriptions here, the injection buffers containing PBS or saline buffer of Liu and Hu can be considered as the pharmaceutical composition as claimed in claim 20. Because Liu teaches that rAd.DCN.GM inhibits tumor growth and lung metastasis in CT26 xenograft model (See page 672, right column), which indicates the injection amounts is a therapeutically effective amount for the oncolytic virus to treat the cancer of the subject (mice) as claimed. As for the newly added limitation on breast cancer in claim 21, Liu teaches that GM-CSF and decorin were co-expressed in the recombinant oncolytic adenovirus can enhance the therapeutic effect for treating breast and prostate cancers (See page 672, left column, paragraph 3).
Regarding claim 32, Liu teaches treating a breast cancer in their article (See page 672, left column, paragraph 3), where the triple-negative breast cancer can be a subtype of breast cancer. It would be obvious for one of ordinary skill in the art, at the time of the invention, to include treating the triple negative breast cancer, and the result would be predictable based on the administration method taught by Liu. Treating triple-negative breast cancer using oncolytic adenovirus can be evidenced by Bramante’s study. Bramante teaches that breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis (See Abstract). The oncolytic adenovirus Ad5/3-D24-GMCSF can treat triple negative breast cancer (See Table 1 and below).
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Regarding claims 33-34 and 37, Liu teaches that GM-CSF is regulated under E1B promoter (See page 672, left column, paragraph 3). Liu in view of Hu teaches the sTGFβRIIFC is under TERT promoter, but not CMV promoter. However, Liu teaches rAd.DCN.GM is an oncolytic adenovirus that contains both decorin and GM-CSF. The two genes are regulated by CMV and E1B promoter, respectively (See page 672, left column, paragraph 3), which indicates that the fused gene to GM-CSF can be regulated under CMV promoter. Thus, it is obvious that one of skilled in the art can replace the decorin by sTGFβRIIFC to express the sTGFβRIIFC under the CMV promoter as claimed, and the result is predictable because the success of expression of DCN and GM-CSF under CMV promoter and E1B promoter, respectively. Here the description teaches claims 33 and 37. As for the claim 34, Liu teaches the GM-CSF is human GM-CSF (See e.g., page 670, right column, paragraph 2). Although Liu in view of Hu does not discloses if the sTGFβRIIFC is human, however, the Fc is human Fc (See Abstract). It is obvious that one of skilled in the art can select a human soluble transforming growth factor-b receptor II fused with human Fc (sTGFβRIIFc) through routine experimentations.
(New rejection) Claims 35-36 and claims 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Hu as evidenced by Haviv, Beck and Bramante as applied to claims 1, 5-8, 15-21, 32-34 and 37 above, and further in view of Sato-Dahlman et al. (Cancers (Basel). 2020 May 21;12(5):1295).
These claims require an immune checkpoint inhibitor to the subject, and the immune checkpoint inhibitor comprises an anti-CTLA-4 or anti-PD-L1 antibody.
Liu in view of Hu teaches an oncolytic adenovirus encoding GM-CSF and sTGFβRIIFc. However, it is silent on further comprising the immune checkpoint inhibitor such as anti-CTLA-4 or anti-PD-L1 antibody.
Sato-Dahlman reviews the potential strategies and therapeutic effects of Ad-based therapies by combination of immunotherapeutic reagents in preclinical and clinical studies (See page 2, paragraph 5). It teaches that the oncolytic adenovirus-based cancer immunotherapies comprise the immunostimulatory molecules expressing oncolytic Ad vectors and combine with OAds and immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibody and Anti-CTLA-4 antibody and discloses that blocking the binding of immune checkpoint signal with an immune checkpoint inhibitor (such as anti-PD-L1, anti-PD-1 and anti-CTLA-4) allows the T cells to be active and to kill cancer cells. (See Figure 2 and below).
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Liu and Sato-Dahlman to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to combine the oncolytic adenovirus of Liu with the anti-PD-L1 or anti-CTLA-4 antibodies to block the binding of immune checkpoint signal. There would be a reasonable expectation of success to develop such a method to treat breast cancer as claimed.
Responses to Applicant’s Remarks
Applicant’s arguments filed on April 13, 2026 has been received and fully considered.
1). Applicant’s amendments regarding the rejections under 35 U.S.C. 112(a) are considered. The rejections are withdrawn.
2). Applicant’s argument on the unexpected results is fully considered and not found persuasive.
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(i). Applicant allegedly discloses the unexpected results based on the Fig. 2A with the tumor volume changes in the days of treatment (See Remarks, page 8 and below).
The argument is not persuasive.
The prior art Liu teaches that rAd.GM.DCN, rAd.DCN, and rAd.GM produced much stronger inhibitory effects than rAd.Null, indicating that decorin and GM-CSF alone or in combination could enhance oncolytic adenoviral mediated antitumor responses (Fig. 3A and B, page 674 and below). Based on the Fig. 3A, it teaches a similar analysis platform as the instant Fig. 2A did by using statistical comparison to analyze the tumor volume in a 29 days treatment, and found rAd.GM alone can achieve a statistical different result.
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2). Applicant allegedly argued their unexpected results by disclosing a construct of rAd.LIGHT adenovirus that can inhibit tumor growth via activation of anti-tumor immune responses, but the adenovirus expressing both LIGHT and sTGFbRIIFc (referred to as "rAd.sT.LIGHT") was less effective in inhibiting tumor growth and volume
compared to rAd. LIGHT and rAd.sT alone (See Remarks, page 8).
The argument is not persuasive.
Seth teaches that there was enhanced efficacy of AdLyp.sT+P+C treatment compared to either P+C or AdLyp.sT therapy alone. The combined treatment with AdLyp.sT+P+C induced a large decrease in primary tumor volume, as compared to either P+C or AdLyp.sT therapy alone (See e.g., Fig. 6A and below; [0048]), which teaches the tumor volume changes in the 25 days treatment.
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3). As an initial matter, “the burden of showing unexpected results rests on one who asserts them. Thus, it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-5:00 pm, EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached on (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RUIXUE WANG/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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