DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The Amendment filed 07/27/2026 in which claims 1, 36, 41, and 55 were amended has been entered. Claim 2, 5, 9 and 40 have been cancelled.
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(Previous rejection, withdrawn) Claims 36, 40, 41, and 55 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant has amended claims 36, 41, and 55. Applicant has canceled claim 40.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
(Previous rejection, withdrawn) Claims 2 and 5 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out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.
Applicant has cancelled claims 2 and 5.
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.
(Previous rejection, maintained and modified as necessitated by amendments) Claims 1, 10, 11, 13, 20, 23, 25, 27, 29, 30, 35, 36, 41, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Drug Deliv, 2018, 10.1080/10717544.2018.1451934, hereinafter, “Zhang”), and in further view of Weichselbaum et al (US20030091539A1, hereinafter, “Weichselbaum”) as evidenced by Schumacher et al. (PNAS, 1992, 10.1073/pnas.89.21.10542, hereinafter, “Schumacher”).
Zhang teaches the mucin 16 (MUC16) promoter is a tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas (Abstract). Zhang teaches the screening of promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors (Abstract). The vectors were specifically delivered into ovarian cancer cells via follicle-stimulatin hormone (FSH) peptide-conjugated nanoparticles (Abstract). The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-a protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer (Abstract).
Regarding claim 1, Zhang teaches a MUC16 promoter used in a PGL-4.10 vector used in ovarian cancer cell lines (Results, ¶2). Zhang teaches the MUC16 promoter is within a region from -1200 nucleic acid residues to -500 nucleic acid residues upstream of the MUC16 transcription start site (TSS) and has a length of 191 bp (chr19:8981342-8981533) (Section: Results, Screen of MUC16 promoter sequences, ¶1).
Regarding claim 41, Zhang teaches the use of MUC16 promoter to drive the targeting of gro-α, also known as the chemokine CXCL1, which is involved in the immune response, as evidenced by Schumacher (Zhang – Section: Nanoparticles loaded with MUC16-shGro plasmid decreased gro-α expression ¶1; Schmuacher – Introduction ¶1, Abstract).
Zhang fails to teach the use of the MUC16 promoter encoded in a viral vector and therefore linked to an essential viral gene, with the virus including an anti-cancer protein such as a cytokine, or an immune activating protein, or a detectable protein. Zhang also fails to teach the virus being an oncolytic virus such as adenovirus and a method of producing the virus. Nor does Zhang teach a therapeutic amount of a virus to stimulate an immune response.
However, Weichselbaum teaches an adenovirus vector with a DF3/MUC1 promoter (¶0023). Weichselbaum teaches the increasing selectivity of adenoviruses for more targeted gene therapy (¶0006). Weichselbaum teaches the creation of adenovirus vectors that can target ovarian cancer (¶0045).
Regarding claims 10, 11, and 13, Weichselbaum teaches that the virus further includes a nucleic acid sequence encoding one or more anti-cancer proteins such as the cytokine IL-12 (¶0077).
Regarding claim 20, Weichselbaum teaches a virus further encoding a detectable protein such as GFP (¶0144).
Regarding claims 23 and 25, Weichselbaum teaches the virus is an oncolytic adenovirus (¶0021).
Regarding claim 27, Weichselbaum teaches to produce virion “a packaging cell line containing the gag, pol, and env genes but without the LTR and packaging components is constructed… When a recombinant plasmid containing a cDNA, together with the retroviral LTR and packaging sequences is introduced into a special cell line (e.g., by calcium phosphate precipitation for example), the packaging sequence allows the RNA transcript of the recombinant plasmid to be packaged into viral particles, which are then secreted into the culture media" (¶0032).
Regarding claim 29, Weichselbaum teaches an isolated nucleic acid encoding the virus of claim 1 (¶0023).
Regarding claims 30, 36, and 55 Zhang teaches the use of a MUC16 promoter as a “tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas” (Abstract) therefor inhibiting proliferation in CA-125 expressing cells in combination with MUC16 driven proteins (Figure 5). Weichselbaum teaches a therapeutic amount of the virus formulated in a pharmaceutically acceptable composition comprising a therapeutically effective amount of the virus of claim 1 (¶0023, 0088).
Regarding claim 35, Weichselbaum teaches a cell comprising the virus of claim 1 (¶0023; ¶0079).
Zhang and Weichselbaum are considered to be analogous to the claim invention because they are in the same field of treating cancer by leveraging the mucin protein family. Zhang teaches the use of MUC16 promoter to target and treat ovarian cancer cells. Weichselbaum teaches a known and effective method for producing and applying mucin family driven oncolytic viruses. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to encode target CA-125 expressing ovarian cancer cells with a MUC16 promoter, as taught by Zhang, that is encoded in an adenovirus, as taught by Weichselbaum, because doing so would advantageously targeting of ovarian cancer cells, thereby increasing probability of affecting the affected cancerous region. One of ordinary skill in the art would have reasonable expectation of success in using different promoters within the viral vector backbone to increase efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
(Previous rejection, maintained and modified as necessitated by amendments) Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Weichselbaum as applied to claims 1, 10, 11, 13, 20, 23, 25, 27, 29, 30, 35, 36, 41, and 55 above, and further in view of Kuroki et al (PLOS one, 2017, 10.1371/journal.pone.0190125, hereinafter, “Kuroki”).
As discussed above, claims 1, 10, 11, 13, 20, 23, 25, 27, 29, 30, 35, 36, 41, and 55 were rendered prima facie obvious by the teachings of Zhang and Weichselbaum. The references fail to teach the use of TRAIL with a virus.
However, Kuroki teaches adenovirus vectors were chosen due to their ability to infect dividing and non-dividing cells and because of their limited restrictions regarding the packaging capacity of their genetic payload (Abstract). Kuroki teaches the use of adenovirus 5 vectors to target and destroy MUC-16 expressing ovarian cancer (Abstract). Regarding claim 16, Kuroki teaches the use of adenovirus encoding the CA-125/MUC16 targeted variant of TRAIL to target and kill MUC16 expressing ovarian cancer cells (Abstract).
Kuroki, Zhang, and Weichselbaum are considered to be analogous to the claim invention because they are in the same field of treating cancer. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to use the MUC16 promoter, as taught by Zhang, to drive expression of the MUC16 targeted TRAIL in the adenovirus as taught by Kuroki, because doing so would advantageously targeting of ovarian cancer cells, thereby increasing probability of killing MUC16 positive ovarian cancer cells. One of ordinary skill in the art would have reasonable expectation of success in using the MUC16 promoter driving the TRAIL in the adenovirus to increase targeting and therefor efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
(Previous rejection, maintained and modified as necessitated by amendments) Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Weichselbaum as applied to claims 1, 10, 11, 13, 20, 23, 25, 27, 29, 30, 35, 36, 41, and 55 above, and further in view of Du et al. (Cancer Gene Therapy, 2014, 10.1038/cgt.2014.34, hereinafter, "Du").
As discussed above, claims 1, 10, 11, 13, 20, 23, 25, 27, 29, 30, 35, 36, 41, and 55 were rendered prima facie obvious by the teachings of Zhang and Weichselbaum. The references fail to teach the use of an anti-CTLA-4 antibody encoded in adenovirus.
However, Du teaches two conditional replicating oncolytic adenoviruses which express granulocyte macrophage colony-stimulating factor (GM-CSF) or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA4) antibody (Abstract). Du teaches the optimization of the viruses to increase expression in target cells (Abstract). Du also teaches the efficacy of the viruses in different types of cells (Abstract). Regarding claim 18, Du teaches the use of adenovirus encoding the anti-CTLA-4 antibody (Abstract, Figure 6).
Du, Zhang, and Weichselbaum are considered to be analogous to the claim invention because they are in the same field of treating cancer. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to use the MUC16 promoter, as taught by Zhang, to drive expression of anti-CTLA-4 antibody encoded in the adenovirus as taught by Du, because doing so would advantageously target ovarian cancer cells, thereby increasing probability of killing the ovarian cancer cells. One of ordinary skill in the art would have reasonable expectation of success in using the MUC16 promoter driving the anti-CTLA-4 antibody in the adenovirus to increase targeting and therefor efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
1) Applicant states amendments made to claims 36, 41, and 55overcomes the U.S.C. § 112 – Scope of Enablement
Applicant has amended claims 36, 41, and 55. Applicant has cancelled claim 40. Examiner has withdrawn the rejection.
2) Applicant states cancellation of claims 2 and 5 overcomes the U.S.C. § 112 – Indefiniteness
Examiner has withdrawn the rejection.
3) Applicant states amendments made to claims 1, 36, 41, and 55 overcomes the U.S.C. § 103 rejection
Applicant’s arguments have been fully considered but are not persuasive.
a) Applicant states “based on the teachings of Zhang, a person having ordinary skill in the art would have not expected that a sequence having at least 150 bp of the claimed portion of the MUC16 promoter would functionally increase transcriptional activity.”
As discussed above, Zhang teaches a 191bp sequence that has increased transcriptional activity.
b) Applicant also states “Zhang teaches that embodiments of MUC16 promoter sequences as claimed fail to increase transcriptional activity relative to a control CMV promoter” and the MUC16 promoter of encoded by SEQ ID NO: 2 has “has 12 times higher transcriptional activity than the wild-type adenovirus E1A promoter in CA-125 expressing cancer cells (e.g. HeLa cervical cancer cells). In contrast, Zhang teaches that embodiments of the claimed promoter fail to exhibit enhanced promoter activity”
The examples cited by the Applicant cannot reasonably be determined as surprising or unexpected. The instant application and Zhang use different cell lines to test the MUC16 promoters (Instant application Figure 2, Zhang Figure 1). The instant application uses HeLa cells, while Zhang uses HEY, Caov3, SKOV-3, and RMUG-L cells (Instant application Figure 2, Zhang Figure 1). Furthermore, Zhang teaches that the cell line can greatly affect MUC16 driven expression (Section: Results, Screen of MUC16 promoter sequences).
The control promoters used in the instant application and Zhang are different. The instant application uses the E1A promoter as a control while Zhang uses a CMV promoter as a control (Instant application Figure 2, Zhang Figure 1).
Solely to rebut the argument, Schaack et al (Virology, 2001, 10.1006/viro.2001.1211, hereinafter, “Schaack”) teaches the comparison of different promoter used to drive transgene expression in 293 cells and HeLa cells (Abstract). Schaak teaches that E1A is a weak promoter in both 293 cells and HeLa cells, while CMV is a strong promoter that drives much more expression in both cell lines (Figure 3, Figure, 4). Therefore, there is not enough data to reasonably determine whether the results of the instant application are unexpected. On the contrary, based, e.g., on Schaack, one of ordinary skill in the art would have expected to have a higher amount of gene expression when MUC16 driven adenoviruses infect MUC16 expressing cells compared to E1A promoter.
c) Applicant states that a person of ordinary art would have “no reason to expect that a virus including a MUC 16 promoter nucleic acid at least 150 bp in length within a region from -1200 nucleic acid residues to -500 nucleic acid residues upstream of the MUC16 TSS could function as a conditionally replicative oncolytic virus”
As discussed previously and above, Zhang teaches a 191 bp MUC16 promoter and teaches that MUC16 promoter drives expression in MUC16 expressing cells i.e. conditional expression. Weichselbaum teaches a mucin promoter driven conditionally replicative adenovirus. It would have been obvious to one of ordinary skill in the art to use a conditionally active MUC16 promoter in an adenovirus to arrive at a conditionally replicative adenovirus.
d) Applicant states that a person having ordinary skill in the art would have no expectation or motivation to arrive at the claimed virus based on the teachings of the prior art
As discussed previously and above, based on the teachings of Zhang and Weichselbaum, one of ordinary skill in the art would have arrived at a MUC16 driven adenovirus wherein the MUC16 promoter was at least 150 bp. One of ordinary skill in the art would have readily understood that to improve the efficacy of an oncolytic adenovirus, one would include TRAIL, because as taught by Kuroki, an oncolytic adenovirus encoding TRAIL improves killing of ovarian cancer cells. One of ordinary skill in the art would have also readily understood that to improve the efficacy of an oncolytic adenovirus, one would include anti-CTLA-4 antibody, because as taught by Du, an oncolytic adenovirus encoding anti-CTLA-4 antibody improves killing of ovarian cancer cells.
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
