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 Mar. 29, 2024. Claims 1-2 and 4-21 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.
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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings. See MPEP 2163. I.
In Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997), the Court decided that adequate written description of genetic material "requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention." Id. 43 USPQ2d at 1404 (quoting Fiefs, 984 F.2d at 1171, 25 USPQ2d at 1606). In AbbVie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (Court of Appeals, Federal Circuit 2014), the Court ruled that “[W]ith the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . .cover any compound later actually invented and determined to fall within the claim' s functional boundaries.”).”
The claim 9 is directed to the oncolytic virus of claim 1 wherein the virus comprises a capsid protein that specifically binds to a cancer cell that overexpresses an adenovirus receptor.
Based on the claim above, a generic oncolytic virus, a generic capsid protein and a generic cancer cell are claimed.
The instant specification discloses that Adenovirus produced using Ad5 vector can transduce cell expressing Coxsackie-Adenovirus Receptor (CAR), and specific receptors found exclusively or preferentially on the surface of cancer cells may be used as a target for adenoviral binding and infection, such as EGFRvIII (See [0059]), however, it does not provide evidence to support that any capsid of any virus can bind the CAR, and does not provide evidence to support any cancer cell can overexpress the adenoviral receptor.
Based on the description above, the skilled artisan cannot envision the detailed method/process for using any capsid of any virus to bind adenovirus receptor overexpressed in any cancer cell. Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph
Accordingly, the specification does not provide sufficient written description to support for the invention as claimed in claims 9-14.
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.
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.
Claim 21 is directed to a method of treating cancer in a subject by administering a therapeutically effective amount of the oncolytic virus of claim 1, where the cancer claimed is a generic cancer, and the virus claimed is a generic oncolytic virus.
The instant specification discloses that rAd.sT.GM Inhibits 4T1 Tumor Growth in Immune Competent Balb/c Mice and can replicate in human breast cancer cells, MDA-MB-231 and MCF-7 (See e.g., [0146], [0270] and [0287]), which indicates that the oncolytic virus used for treating cancer is Adenovirus and the cancer cell lines are human breast cancer cells (MDA-MB-231 and MCF-7) and mouse breast cancer cells (4T1-luc2) (See [0261]). Thus, the instant specification does not provide examples to support that any oncolytic virus of claim 1 can treat any type of cancers as claimed in claim 21. Accordingly, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
In the instant invention, the disclosure fails to provide adequate guidance pertaining to a number of these considerations as listed above:
Nature of the invention/Breadth of the claims. The instant claims 1-2 and 4-20 are drawn to an oncolytic virus/composition 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). A generic oncolytic virus is claimed. At the same time, the claim 21 is drawn to a method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of the oncolytic virus of claim 1 to the subject. The treated cancer in the claim is any type of cancers.
State of the prior art/Predictability of the art. The concept of oncolytic virus is known in the art for cancer treatment. Using oncolytic virus expressing GM-CSF or sTGF- BRII to treat certain types of cancers are also known in the art. The references of Seth, Liu and Hu adopted in the current office action are examples for teaching the constructs of oncolytic virus with either GM-CSF or sTGF- βRII in the cancer treatment studies. Especially, Liu teaches that an inhibitor of TGF-β, Decorin, can be cloned with GM-CSF together to build a construct of rAd.DCN.GM that can combines the advantages of both decorin and GM-CSF in evoking antitumor immune responses in vivo. With the teaching of Hu that the soluble TGF-β receptor type II (sTGF-βRII) can effectively block TGF-β signaling by binding the TGF-β ligand to treat the bone Metastasis in a Prostate Cancer, it provides a motivation for one of skilled in art to express GM-CSF and sTGF- BRII sumptuously in an oncolytic virus vector.
The level of one of ordinary skill/. The existence of working examples. Although the instant invention is taught by the cited art references, the instant working examples 1-8 only disclose using one specific oncolytic virus, Adenoviral-Mediated sTGFbRIIFc and GM-CSF, to treat one type of cancers, breast cancer. Accordingly, the invention does not provide sufficient evidence showing that any type of cancers can be treated by any oncolytic virus with expressing sTGFbRIIFc and GM-CSF as claimed.
The amount of direction provided by the inventor/ The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Based on the description above, the specification only discloses one specific example for construct the oncolytic virus to express the sTGFbRIIFc and GM-CSF and only discloses a single in vivo model, a mouse model with 4T1 tumor, and does not provide sufficient evidence showing any oncolytic virus 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) can treat a generic cancer by administering a therapeutically effective amount of the oncolytic virus into a subject as claimed.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Based on the descriptions above, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim.
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.
Claims 1-2 and 4-21 are rejected under 35 U.S.C. 103 as being unpatentable over Seth et al. (WO2020198293A1, published on Oct. 01, 2020, priority data: March 25, 2019) as evidenced by Sakata et al. (J Signal Transduce. 2014; 2014:970346), Hensen et al. (Int J Mol Sci. 2020 Sep 17;21(18):6828), Bramante et al. (Oncoimmunology. 2015 Aug 27;5(2):e1078057), Kaufman et al. (Front Mol Biosci. 2022 Feb 22; 9:834841), Beck et al. (MAbs. 2011 Sep-Oct;3(5):415-6).
The base claim 1 is directed to an oncolytic virus 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 a 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 virus 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 an oncolytic virus 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 claim 2, Seth et al. teaches that the oncolytic virus is adenovirus.
Regarding claims 4-6, 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], teach claim 4)., 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 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
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E1B promoter as claimed.
Regarding claim 9, it requires the virus comprises a capsid protein that specifically binds to a cancer cell that overexpresses an adenovirus receptor.
Seth et al. teaches a chimeric adenoviral vector with a genetically modified fiber (See 0007) that is used to infect breast cancer cells (See [00249]), where the fiber is one of the three major proteins of the Capsid protein. As evidence, Hensen et al. teaches that the HAdV types that use CAR (coxsackie and adenovirus receptor) for attachment, bind to the receptor via the fiber protein head (See page 4, paragraph 1). Also, Hensen et al. teaches that they found that CAR is upregulated in a diverse range of tumor types, from lung cancer to ovarian and cervical cancer (See page 4, paragraph 2).
Regarding claims 10-11 and 13-14, Seth et al. teaches that the cancer cell is breast cancer cell (teach claims 10-11) and melanoma that originates from skin cells called melanocytes (teach claims 13-14) (See e.g, [00193]).
Regarding claim 12, it requires the breast cancer cell is a triple negative breast cancer cell. Based on the description above, 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 the cancer cells from the triple negative breast cancer that express the adenovirus receptor to bind the Capsid protein, and the result would be predictable because Bramante’s study can be evidence. As an evidence, Bramante et al. teaches that the oncolytic adenovirus Ad5/3-D24-GMCSF can infect the TNBC (triple-negative breast cancer (TNBC)) cell line (See Abstract; Figure 1 and below).
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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).
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 that the present disclosure provides methods of treating cancer and hyperproliferative disorders in a subject comprising administering to the subject an effective amount of an adenoviral vector with a genetically modified fiber incorporating a Ly Pl peptide (See [0008]).
Claims 1-2, 4-12 and 15-21 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”), Hensen et al. (Int J Mol Sci. 2020 Sep 17;21(18):6828, hereinafter “Hensen”), 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 base claim 1 is directed to an oncolytic virus 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 virus 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 with sTGFbRIIFc and test the effects on treating both colorectal tumor and the prostate cancer bone metastasis. 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 claim 2, Liu teaches that the oncolytic virus is an adenovirus (See Title).
Regarding claim 4, Liu teaches that the oncolytic adenoviruses, rAd.DCN.GM, could infect both tumor and normal tissues, but would not spread among normal tissues (See page 672. Left column, paragraph 3), which is comparable to the “the oncolytic virus preferentially replicates in cancer cells” as claimed.
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 claim 9, Hu teaches that to reduce liver sequestration of Ad5-based viruses, they have begun creating Ad5/48 chimeric hexon-containing, liver-detargeted oncolytic adenoviruses, in which seven hypervariable regions of Ad48 hexon are inserted in the Ad5 backbone such liver-detargeted chimeric oncolytic viruses can also be developed to target prostate cancers (See page 881, left column, paragraph 2), which indicates the hexon, the major capsid protein of the adenovirus, can target liver cell and the prostate cancer cells. As evidence, Hensen et al. teaches that the HAdV types that use CAR (coxsackie and adenovirus receptor) for attachment, bind to the receptor via the fiber protein head (See page 4, paragraph 1), where the fiber is one of the three major proteins of the Capsid protein, and HAdV-C5 binds to FX via the hexon hypervariable region, upon which FX binds to heparan sulfate proteoglycans (HSPGs) on liver cells (See page 10). In addition, Hensen et al. teaches that they found that CAR is upregulated in a diverse range of tumor types, from lung cancer to ovarian and cervical cancer (See page 4, paragraph 2).
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Regarding claims 10-12, Liu teaches that oncolytic adenovirus expressing decorin could offer a potential therapeutic approach for CRC, as suggested earlier for breast and prostate cancers (teach claims 10-11) (See page 672, left column, paragraph 3), where the breast cancers can include the triple negative breast cancer type (teach claim 12). It would be obvious for one of ordinary skill in the art, at the time of the invention, to use the cancer cells from the triple negative breast cancer, and the result would be predictable because Bramante’s study can be evidenced for the expected result. As an evidence, Bramante et al. teaches that the oncolytic adenovirus Ad5/3-D24-GM-CSF can infect the TNBC (triple-negative breast cancer (TNBC)) cell line (See Abstract; Figure 1 and below).
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 21-22, 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.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Hu as evidenced by Haviv, Hensen, Beck and Bramante as applied on claims 1-2 and 4-12 and 15-21 above, and further in view of Olivares et al. (Clin Cancer Res. 2011 Jan 1;17(1):183-92, hereinafter, “Olivares”).
These two claims require the cancer cell is a skin cancer cell and melanocyte respectively.
Based on the descriptions above, Liu teaches using rAd.DCN.GM to treat advanced and metastatic stages of colorectal cancer (CRC), and Hu teaches to use oncolytic adenoviruses expressing soluble transforming sTGFbRIIFc to treat bone metastasis in a prostate cancer mouse model (See abstract). However, they both silent on the skin cancer and melanocyte.
Olivares teaches that a combined GM-CSF and antitumor suppressor TGF-β2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, they constructed an expression plasmid [the tumor-associated glycoprotein(TAG) plasmid] that coexpresses GM-CSF and TGF-β2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine (See Abstract). Olivares discloses that the treatment includes to treat a skin cancer, Melanoma (See Table 1, page 186 and below), which originates from skin cells called melanocytes.
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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, Hu and Olivares to arrive at an invention as claimed. One would have been motivated to introduce to the combined teachings of Liu and Hu for the treatment of Melanoma using the oncolytic virus with co-expressed GM-CSF and sRGF-BRII. 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.
Conclusion
No claims are allowed.
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/RUIXUE WANG/Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672