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
This action is in response to the papers filed August 13, 2025.
Amendments
Applicant's amendments, filed August 13, 2025, is acknowledged. Applicant has cancelled Claims 1-13 and 15, and amended Claims 14, 16, and 18-19.
Claims 14 and 16-20 are pending and under examination.
Priority
This application is a continuation of application 16/095,077 filed October 19, 2018, now abandoned, which is a 371 of PCT/US2017/030308 filed April 29, 2017. Applicant’s claim for the benefit of a prior-filed application provisional application 62/329,877 filed on April 29, 2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Specification
1. The disclosure is objected to because of the following informalities:
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022,That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application-process/filing-online/legal-framework-efs-web), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
The specification [003] does not disclose the size of the XML file in bytes.
Appropriate correction is required.
Response to Arguments
Applicant argues that [0003] discloses file size of 60.0kb.
Applicant’s argument(s) has been fully considered, but is not persuasive.
CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
c. the size of the XML file in bytes.
Claim Objections
2. The prior objection to Claim 14 is withdrawn in light of Applicant’s amendment to the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. The prior rejection of Claims 18-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claims cancelling “patient” and instead reciting “subject”.
4. The prior rejection of Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claim.
5. Claim 18 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation "of claim 13". There is insufficient antecedent basis for this limitation in the claim because Claim 13 has been cancelled.
Appropriate correction is required. See, for example, Claim 19.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
6. Claims 14, 16 and 18-20 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kuroda et al (Effective Treatment of Tumors with Strong B-Catenin/T-Cell Factor Activity by Transcriptionally Targeted Oncolytic Herpes Simplex Virus Vector, Cancer Res. 66(20): 10127-10135, 2006) in view of Zhang et al (A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4, Oncotarget 6(24): 20345-20355, available May 6, 2015), Hu et al (Targeting cancer stem cells: a new therapy to cure cancer patients, Am. J. Cancer Res. 2(3): 340-356, 2012), Jia et al (A novel strategy for cancer treatment: Targeting cancer stem cells, Chinese Science Bulletin 53(12): 1777-1783, 2008), Wu et al (Tumor-Selective Replication of an Oncolytic Adenovirus Carrying Oct-3/4 Response Elements in Murine Metastatic Bladder Cancer Models, Clinical Cancer Res. 14(4): 1228-1238, 2008; of record in parent application 16/095,077), Jessup et al (U.S. 2016/0032290; priority to October 19, 2015), Petruzzelli et al (HIF-2a Regulates NANOG Expression in Human Embryonic Stem Cells following Hypoxia and Reoxygenation through the Interaction with an Oct-Sox Cis Regulatory Element, PLoS ONE 9(10): e108309, 11 pages, available online October 1, 2014), Lu et al (Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer, Gene Therapy 22: 305-315, available online January 15, 2015; co-authors to Wu et al (2008)), Shen et al (High Expression of SOX2 and OCT4 Indicates Radiation Resistance and an Independent Negative Prognosis in Cervical Squamous Cell Carcinoma, J. Histochem. & Cytochem. 62(7): 499-509, 2014; of record in parent application 16/095,077), and Ellis et al (U.S. 2011/0053166).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Kuroda et al is considered relevant prior art for having taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene (Abstract; Figure 2A).
Kuroda et al taught the vector efficiently and specifically replicated in and killed tumor cells with strong beta-catenin/Tcf signaling (Abstract).
Kuroda et al taught that the Wnt/beta-catenin/Tcf pathway is inactive in most adult tissues, except in some stem cells (e.g. pg 10127, col. 2).
Similarly, Zhang et al is considered relevant prior art for having taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene (e.g. Title; Figure 1), thereby providing tumor-selective replication of the oncolytic HSV-1.
Hu et al is considered relevant prior art for having taught that the Wnt/beta-catenin/Tcf pathway is naturally expressed in cancer stem cells (e.g. pg 343, col. 2-pg 344, col. 1).
Similarly, Jia et al is considered relevant prior art for having taught that the hTERT promoter is naturally higher in cancer stem cells than in normal stem cells (e.g. pgs 1779-1780, joining para), thereby providing selective replication of oncolytic viruses in cancer stem cells.
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of operably linking an HSV viral gene important for viral replication efficiency, i.e. the HSV ICP4 gene, to a transcriptional control element that drives expression of the ICP4 gene in cancer cells, including cancer stem cells.
Neither Kuroda et al nor Zhang et al teach wherein the heterologous transcriptional control element comprises an Oct-3/4-Sox2 (syn. Oct/Sox) response element.
However, prior to the effective filing date of the instantly claimed invention, Wu et al is considered relevant prior art for having taught an oncolytic adenovirus comprising Oct-3/4 enhancer elements to enhance tumor-selective viral replication, oncolysis, antitumor efficacy, and survival advantage in mouse patients suffering from cancer (e.g. pg 1229, col. 1). Wu et al taught that the Oct-3/4 is expressed in several human cancer cells, but not in normal somatic tissues (e.g. pg 1228, col. 2).
Similarly, Jessup et al is considered relevant prior art for having disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication (e.g. Figure 8, CRAD5/3; NanogP8 promoter-Ad5 E1a), whereby the Nanog promoter drives expression of the E1a viral gene to initiate replication of the virus in cells that express Nanog, and therefore, the oncolytic virus only replicates in, and lyses, those cells that actively express Nanog (e.g. [0142]).
Petruzzelli et al is considered relevant prior art for having taught that the Nanog promoter naturally comprises an Oct/Sox element (e.g. Figure 4a).
Lu et al (co-authors to Wu et al (2008)) is considered relevant prior art for having taught that most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs) (Abstract), and that the oncolytic adenovirus comprising the Oct-4 response elements (as per Wu et al) is useful for treating hypoxic bladder tumors and cancer stem cells (Abstract).
Shen et al is considered relevant prior art for having taught that Sox2 and Oct4 are naturally over-expressed in radiation-resistant tumors, and that expression of Sox2 and Oct4 in tumor cells indicates resistance to radiotherapy and are important predictors of poor survival in cancer patients (e.g. Title, Abstract).
Ellis et al is considered relevant prior art for having disclosed a viral vector, e.g. lentiviral or retroviral vector [0044-45], comprising a pluripotent stem cells specific enhancer sequence, CR4 [0014, 40], which comprises an Oct/Sox element operatively linked to the artisan’s gene of interest (e.g. Figure8a, CR4 x3 + ETn promoter; SEQ ID NO:3), wherein the Oct/Sox element has a nucleotide sequence that is a reverse-complement of instant SEQ ID NO:35, as shown below:
CTTTGTTATGCATCT
|||||||||||||||
CTTTGTTATGCATCT
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer (e.g. [0041]).
Ellis et al disclosed the enhancer sequence, e.g. CR4, is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase [0060, 163].
Thus, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concept(s) of synthesizing a viral vector whose genome comprises an Oct/Sox element operably linked to the artisan’s gene of interest. There is no undue experimentation to perform routine molecular biology cloning reactions when making the claimed vector.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, virology, and cancer biology. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first transcriptional response element active in cancer stem cells, e.g. hTERT (Zhang et al) and/or Tcf (Kuroda et al), with a second transcriptional response element active in cancer stem cells, to wit, comprising an Oct/Sox response element, as disclosed by Jessup et al and Ellis et al, operably linked to an HSV viral gene important for viral replication, i.e. the HSV ICP4 gene, in an oncolytic HSV virus with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
An artisan would be motivated to substitute a first transcriptional response element active in cancer stem cells, e.g. hTERT and/or Tcf, with a second transcriptional response element active in cancer stem cells, to wit, comprising an Oct/Sox response element operably linked to an HSV viral gene important for viral replication, i.e. the HSV ICP4 gene, in an oncolytic HSV virus with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) oncolytic viral vectors may be improved for enhancing tumor-selective viral replication, oncolysis, antitumor efficacy and survival of cancer subject when a viral gene that affects viral replication efficiency is operably Inked to a transcriptional response element that is active in cancer stem cells (Kuroda et al; Zhang et al; Jessup et al; Wu et al);
ii) the use of a transcriptional response element that is active in cancer stem cells to promote expression of a viral gene important for viral replication had already been successfully reduced to practice by the routineers, e.g. Tcf-ICP4 (Kuroda et al), hTERT-ICP4 (Zhang et al), Nanog-E1a (Jessup), and Oct-3/4 response elements (Wu et al);
iii) Jia et al taught that Oct-3/4, Nanog, and Sox2, like hTERT (pg 1780, col. 1), play important roles in maintaining the function of CSCs (e.g. pg 1780, col. 2);
iv) Oct4/Sox2 response elements were known in the prior art (e.g. Ellis et al); and
v) high levels of Sox2 and Oct4 indicate resistance to radiation therapy (Shen et al), and thus the ordinary artisan would reasonably expect that an oncolytic viral vectors comprising a viral gene that affects viral replication efficiency operably linked to an Oct4/Sox2 response element would enhance tumor-selective viral replication, oncolysis, antitumor efficacy and survival of cancer subject, especially those suffering from cancers known or predicted to be resistant to radiation therapy.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 16, Jia et al taught that viral vectors were previously recognized in the art, and successfully reduced to practice, to deliver therapeutic nucleic acid sequences to tumors (e.g. pg 1779, col. 1, 1.2 Viral Vector; pg 1780, col. 1, ‘oncolytic [virus]…augment the copies of therapeutic genes in the process of viral production’, ‘so the anti-tumor efficacy of therapeutic genes can be greatly raised by oncolytic [viral] vectors’).
With respect to Claims 18-19, Kuroda et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer, the method comprising the step of administering to said subjects the oncolytic HSV virus (e.g. pg 10130, col. 1, Methods, In vivo treatment model; Figure 6).
Zhang et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer, the method comprising the step of administering to said subjects the oncolytic HSV virus (e.g. pg 20348, col. 2, In vivo model; Figure 5).
Hu et al is considered relevant prior art for having taught that the Wnt/beta-catenin/Tcf pathway is naturally expressed in cancer stem cells (e.g. pg 343, col. 2-pg 344, col. 1).
Similarly, Jia et al is considered relevant prior art for having taught that the hTERT promoter is naturally higher in cancer stem cells than in normal stem cells (e.g. pgs 1779-1780, joining para), thereby providing selective replication of oncolytic viruses in cancer stem cells.
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of operably linking an HSV viral gene important for viral replication efficiency, i.e. the HSV ICP4 gene, to a transcriptional control element that drives expression of the ICP4 gene in cancer cells, including cancer stem cells.
Wu et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from bladder cancer (e.g. pg 1230, col. 1, Methods, Animal studies; pg 1233, col’s 1-2; Figure 4), the method comprising the step of administering to said subjects the oncolytic adenovirus. The Oct-3/4 gene is specifically expressed in stem cell and in tumor cells, but not differentiated tissues, as well as in the bladder cancer cells (e.g. pg 1234, col. 2), whereby those of ordinary skill in the art had long-recognized the stem cell theory of cancer origin (syn. cancer stem cells; pg 1234, col. 1).
Lu et al (co-authors to Wu et al (2008)) taught that the oncolytic adenovirus comprising the Oct-4 response elements (as per Wu et al) is useful for treating hypoxic bladder tumors and cancer stem cells (Abstract).
Shen et al taught that Sox2 and Oct4 are naturally over-expressed in radiation-resistant tumors, that expression of Sox2 and Oct4 in tumor cells indicates resistance to radiotherapy and are important predictors of poor survival in cancer patients (e.g. Title, Abstract). Shen et al taught that cancer stem cells have a higher radioresistance than non-stem cells from the same tumor (e.g. pg 504, col. 2), and that Sox2 and Oct 4 are biomarkers for cancer stem cells (e.g. pg 505, col. 2).
With respect to Claim 20, Kuroda et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer (e.g. Abstract).
Wu et al taught the use of the oncolytic adenovirus to treat bladder cancer (e.g. pg 1230, col. 2, Results, e.g. “human bladder tumor tissues and bladder cancer cell lines”).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that neither Kuroda et al, Zhang et al, Hu et al, nor Jia et al disclose or teach an HSV vector wherein the heterologous transcriptional control element comprises an Oct-3/4-Sox2(syn. Oct/Sox) response element, and neither Wu et al, Jessup et al, Lu et al, nor Shen et al taught or motivated those of ordinary skill in the art to substitute other response element with a Oct/Sox response element.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Kuroda et al taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene.
Zhang et al taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene, thereby providing tumor-selective replication of the oncolytic HSV-1.
Wu et al taught an oncolytic adenovirus comprising Oct-3/4 enhancer elements to enhance tumor-selective viral replication, oncolysis, antitumor efficacy, and survival advantage in mouse patients suffering from cancer, whereby the Oct-3/4 is expressed in several human cancer cells, but not in normal somatic tissues.
Jessup et al disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication, whereby the Nanog promoter was previously recognized in the art to naturally comprises an Oct/Sox element (Petruzzeli et al), and whereby the Nanog promoter drives expression of the E1a viral gene to initiate replication of the virus in cells that express Nanog, and therefore, the oncolytic virus only replicates in, and lyses, those cells that actively express Nanog.
Lu et al (co-authors to Wu et al (2008)) taught that most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs), and that the oncolytic adenovirus comprising the Oct-4 response elements (as per Wu et al) is useful for treating hypoxic bladder tumors and cancer stem cells.
Shen et al taught that Sox2 and Oct4 are naturally over-expressed in radiation-resistant tumors, and that expression of Sox2 and Oct4 in tumor cells indicates resistance to radiotherapy and are important predictors of poor survival in cancer patients.
Ellis et al disclosed a viral vector, e.g. lentiviral or retroviral vector comprising a pluripotent stem cells specific enhancer sequence, CR4, which comprises an Oct/Sox element operatively linked to the artisan’s gene of interest, wherein the Oct/Sox element has a nucleotide sequence that is a reverse-complement of instant SEQ ID NO:35, as shown below:
CTTTGTTATGCATCT
|||||||||||||||
CTTTGTTATGCATCT
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer, and is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Kuroda et al taught the vector efficiently and specifically replicated in and killed tumor cells with strong beta-catenin/Tcf signaling (Abstract), and that the Wnt/beta-catenin/Tcf pathway is inactive in most adult tissues, except in some stem cella.
Hu et al taught that the Wnt/beta-catenin/Tcf pathway is naturally expressed in cancer stem cells.
Jia et al taught that the hTERT promoter is naturally higher in cancer stem cells, thereby providing selective replication of oncolytic viruses in cancer stem cells.
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of operably linking an HSV viral gene important for viral replication efficiency, i.e. the HSV ICP4 gene, to a transcriptional control element that drives expression of the ICP4 gene in cancer cells, including cancer stem cells.
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concept(s) of synthesizing a viral vector whose genome comprises an Oct/Sox element operably linked to the artisan’s gene of interest. There is no undue experimentation to perform routine molecular biology cloning reactions when making the claimed vector.
Applicant argues that the claimed Oct/Sox response element be in a regulatory region of the viral gene which encodes ICP4 or ICP27.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Kuroda et al taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene.
Zhang et al taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene, thereby providing tumor-selective replication of the oncolytic HSV-1.
Wu et al taught an oncolytic adenovirus comprising Oct-3/4 enhancer elements to enhance tumor-selective viral replication, oncolysis, antitumor efficacy, and survival advantage in mouse patients suffering from cancer, whereby the Oct-3/4 is expressed in several human cancer cells, but not in normal somatic tissues.
Jessup et al disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication, whereby the Nanog promoter was previously recognized in the art to naturally comprises an Oct/Sox element (Petruzzeli et al).
Ellis et al disclosed a viral vector, e.g. lentiviral or retroviral vector comprising a pluripotent stem cells specific enhancer sequence, CR4, which comprises an Oct/Sox element operatively linked to the artisan’s gene of interest, wherein the Oct/Sox element has a nucleotide sequence that is a reverse-complement of instant SEQ ID NO:35, as shown below:
CTTTGTTATGCATCT
|||||||||||||||
CTTTGTTATGCATCT
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer, and is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of operably linking an HSV viral gene important for viral replication efficiency, i.e. the HSV ICP4 gene, to a transcriptional control element that drives expression of the ICP4 gene in cancer cells, including cancer stem cells.
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized Oct-3/4 enhancer elements to enhance tumor-selective viral replication, oncolysis, antitumor efficacy, and survival advantage in subjects suffering from cancer, whereby the Oct-3/4 is expressed in several human cancer cells, but not in normal somatic tissues (Wu et al), whereby a transcriptional regulatory region comprising an Oct/Sox element was operably linked to the artisan’s viral gene of interest (e.g. Ellis et al), including a viral gene that affects viral replication in an oncolytic virus (Jessup et al).
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concept(s) of synthesizing a viral vector whose genome comprises an Oct/Sox element operably linked to the artisan’s gene of interest. There is no undue experimentation to perform routine molecular biology cloning reactions when making the claimed vector.
Applicant argues that because ICP4 and ICP27 have a complex relationship with multiple other HSV genes, exhibiting both positive and negative regulatory activity, the presence of an Oct/Sox response element in the regulatory region of ICP4 or ICP27 is not guaranteed to result in increased production of ICP4 or ICP27.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Kuroda et al taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene.
Zhang et al taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene, thereby providing tumor-selective replication of the oncolytic HSV-1.
Jessup et al disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication, whereby the Nanog promoter was previously recognized in the art to naturally comprises an Oct/Sox element (Petruzzeli et al).
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer, and is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase.
Thus, prior to the effective filing date of the instantly claimed invention, it is considered that those of ordinary skill in the art possessed a reasonable expectation of success that a transcriptional regulatory element comprising an Oct/Sox element, e.g. SEQ ID NO:35, would function when operably linked to, e.g. HSV ICP4 gene.
Applicant argues that the artisan cannot predict the success of inserting the same sequence into a genome of a virus variant without experimenting.
Applicant’s argument(s) has been fully considered, but is not persuasive. The fact that experimentation may be complex does not necessarily make it undue, if the art typically engages in such experimentation. In re Certain Limited-Charge Cell Culture Microcarriers, 221 USPQ 1165, 1174 (Int’l Trade Comm'n 1983), aff’d. sub nom.,Massachusetts Institute of Technologyv.A.B. Fortia, 774 F.2d 1104, 227 USPQ 428 (Fed. Cir. 1985).
Kuroda et al taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene.
Zhang et al taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene, thereby providing tumor-selective replication of the oncolytic HSV-1.
Jessup et al disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication, whereby the Nanog promoter was previously recognized in the art to naturally comprises an Oct/Sox element (Petruzzeli et al).
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer, and is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase.
Prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concept(s) of synthesizing a viral vector whose genome comprises an Oct/Sox element operably linked to the artisan’s gene of interest. There is no undue experimentation to perform routine molecular biology cloning reactions when making the claimed vector.
Applicant argues that surprisingly found that virus production was significantly enhanced when the virus is engineered to contain the claimed Oct/Sox response element in the regulatory region of ICP4 or ICP27, said enhancement of virus production was unexpected and not predicted by prior art.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Kuroda et al taught an oncolytic HSV vector whose genome comprises a heterologous Tcf response element operably linked to HSV ICP4 gene, whereby the vector efficiently and specifically replicated in and killed tumor cells with strong beta-catenin/Tcf signaling.
Zhang et al taught an oncolytic HSV-1 viral vector comprising a heterologous hTERT promoter operably linked to the viral ICP4 gene, thereby providing tumor-selective replication of the oncolytic HSV-1.
Jessup et al disclosed an oncolytic virus whose genome comprises a Nanog promoter operably linked to a viral gene that affects viral replication, whereby the Nanog promoter was previously recognized in the art to naturally comprises an Oct/Sox element (Petruzzeli et al), and whereby the Nanog promoter drives expression of the E1a viral gene to initiate replication of the virus in cells that express Nanog, and therefore, the oncolytic virus only replicates in, and lyses, those cells that actively express Nanog.
Ellis et al disclosed the enhancer sequence, e.g. CR4, which comprises an Oct/Sox element, works as an embryonic stem cell-specific enhancer, and is operatively linked to gene encoding a viral protein, e.g. HSV thymidine kinase.
Thus, it is unclear how Applicant’s observation is considered a surprising and/or unexpected result when the prior art previously recognized and successfully reduced to practice the use of transcriptional regulatory elements, including transcriptional regulatory elements comprising an Oct/Sox element, including SEQ ID NO:35, to successfully induce expression of the operably linked viral gene.
7. Claims 16-20 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kuroda et al (2006) in view of Zhang et al (May 6, 2015), Hu et al (2012), Jia et al (2008), Wu et al (2008; of record in parent application 16/095,077), Jessup et al (U.S. 2016/0032290; priority to October 19, 2015), Petruzzelli et al (October 1, 2014), Lu et al (January 15, 2015; co-authors to Wu et al (2008)), Shen et al (2014; of record in parent application 16/095,077), and Ellis et al (U.S. 2011/0053166), as applied to Claims 14, 16 and 18-20 above, and in further view of Chiocca et al (U.S. Patent 6,897,057).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 16, Jia et al taught that viral vectors were previously recognized in the art, and successfully reduced to practice, to deliver therapeutic nucleic acid sequences to tumors (e.g. pg 1779, col. 1, 1.2 Viral Vector; pg 1780, col. 1, ‘oncolytic [virus]…augment the copies of therapeutic genes in the process of viral production’, ‘so the anti-tumor efficacy of therapeutic genes can be greatly raised by oncolytic [viral] vectors’).
Neither Kuroda et al, Zhang et al, Hu et al, Jia et al, Wu et al, Jessup et al, Petruzzelli et al, Lu et al, Shen et al, nor Ellis et al teach/disclose wherein the therapeutic substance is IL-12.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 16-17, Chiocca et al disclosed the modified HSV vector further comprises a sequence encoding a therapeutic substance for cancer treatment, e.g. interleukins (col. 8, lines 54-62).
Chiocca et al disclosed wherein the therapeutic substance for cancer treatment includes interleukins (col. 8, lines 54-62), which may also include IL-12 (per citation of Toda et al (pg 4, col. 2, Other Publications, HSV-IL12 induces antitumor activity).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify an oncolytic HSV vector comprising an Oct/Sox element operably linked to a viral gene that affects viral replication efficiency, i.e. ICP4, to further comprise a nucleic acid encoding a therapeutic substance to treat cancer, e.g. an IL-12 transgene, with a reasonable expectation of success because those of ordinary skill in the art had long-recognized, and successfully reduced to practice, the scientific and technical concepts of using oncolytic viral vectors to delivery therapeutic gene to treat cancer (e.g. Jia et al; pg 1780, col. 1, ‘oncolytic [virus]…augment the copies of therapeutic genes in the process of viral production’, ‘so the anti-tumor efficacy of therapeutic genes can be greatly raised by oncolytic [viral] vectors’), and Chiocca et al disclosed the modified HSV vector further comprises a sequence encoding a therapeutic substance for cancer treatment, e.g. interleukins (col. 8, lines 54-62), including IL-12 (per citation of Toda et al (pg 4, col. 2, Other Publications, HSV-IL12 induces antitumor activity).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 18-19, Kuroda et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer, the method comprising the step of administering to said subjects the oncolytic HSV virus (e.g. pg 10130, col. 1, Methods, In vivo treatment model; Figure 6).
Zhang et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer, the method comprising the step of administering to said subjects the oncolytic HSV virus (e.g. pg 20348, col. 2, In vivo model; Figure 5).
Hu et al is considered relevant prior art for having taught that the Wnt/beta-catenin/Tcf pathway is naturally expressed in cancer stem cells (e.g. pg 343, col. 2-pg 344, col. 1).
Similarly, Jia et al is considered relevant prior art for having taught that the hTERT promoter is naturally higher in cancer stem cells than in normal stem cells (e.g. pgs 1779-1780, joining para), thereby providing selective replication of oncolytic viruses in cancer stem cells.
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of operably linking an HSV viral gene important for viral replication efficiency, i.e. the HSV ICP4 gene, to a transcriptional control element that drives expression of the ICP4 gene in cancer cells, including cancer stem cells.
Wu et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from bladder cancer (e.g. pg 1230, col. 1, Methods, Animal studies; pg 1233, col’s 1-2; Figure 4), the method comprising the step of administering to said subjects the oncolytic adenovirus. The Oct-3/4 gene is specifically expressed in stem cell and in tumor cells, but not differentiated tissues, as well as in the bladder cancer cells (e.g. pg 1234, col. 2), whereby those of ordinary skill in the art had long-recognized the stem cell theory of cancer origin (syn. cancer stem cells; pg 1234, col. 1).
Lu et al (co-authors to Wu et al (2008)) taught that the oncolytic adenovirus comprising the Oct-4 response elements (as per Wu et al) is useful for treating hypoxic bladder tumors and cancer stem cells (Abstract).
Shen et al taught that Sox2 and Oct4 are naturally over-expressed in radiation-resistant tumors, that expression of Sox2 and Oct4 in tumor cells indicates resistance to radiotherapy and are important predictors of poor survival in cancer patients (e.g. Title, Abstract). Shen et al taught that cancer stem cells have a higher radioresistance than non-stem cells from the same tumor (e.g. pg 504, col. 2), and that Sox2 and Oct 4 are biomarkers for cancer stem cells (e.g. pg 505, col. 2).
Chiocca et al disclosed the modified HSV may be used in a method of treating a patient with a treatment-resistant cancer (e.g. col. 24, lines 20-25, glioblastoma resistant to chemotherapeutic agents).
With respect to Claim 20, Kuroda et al taught a method of treating cancer in a mouse patient, to wit, mouse subjects suffering from colorectal cancer (e.g. Abstract).
Wu et al taught the use of the oncolytic adenovirus to treat bladder cancer (e.g. pg 1230, col. 2, Results, e.g. “human bladder tumor tissues and bladder cancer cell lines”).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Chiocca et al disclosed wherein the cancers are, e.g. colon cancer, cancer, lung cancer, or brain cancer (col. 22, lines 16-18).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that there is no suggestion to combine Chiocca et al with Zhang et al (May 6, 2015), Hu et al (2012), Jia et al (2008), Wu et al (2008; of record in parent application 16/095,077), Jessup et al (U.S. 2016/0032290; priority to October 19, 2015), Petruzzelli et al (October 1, 2014), Lu et al (January 15, 2015; co-authors to Wu et al (2008)), Shen et al (2014;