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 Arguments
The Amendment filed 04/28/2026 in which claims 1 – 3, 5, 10, 11, and 13 – 15 were amended has been entered.
Claims 1 – 18 are under examination on the merits.
Claim Objections
(Previous objection, maintained and modified as to claim 1 in view of the amendment) Claim 1 objected to because of the following informalities: The formatting of “hsa-miR-576.5p, hsa -miR-143.3p, hsa -miR-185.5p, hsa -let-7b.5p, hsa -miR-23a.3p, hsa -miR-25.3p, hsa -miR-190b.5p, hsa -miR-145.5p, hsa -miR-181a.5p, hsa-miR-625.5p, hsa -miR-744.5p, and hsa -miR-206” is not commonly used and should be redrafted as “hsa-miR-576-5p, hsa-miR-143-3p, hsa-miR-185-5p, hsa-let-7b-5p, hsa-miR-23a-3p, hsa-miR-25-3p, hsa-miR-190b-5p, hsa-miR-145-5p, hsa-miR-181a-5p,hsa-miR-625-5p, hsa-miR-744.5p, and hsa-miR-206.”
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
(Previous rejection, withdrawn as to claim 1 in view of the amendment) Claims 1 – 18 were rejected under 35 U.S.C. 101 because the claimed invention was directed to judicial exception without significantly more. This judicial exception was not integrated into a practical application and the claim did not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Applicant’s amendment to claim 1 has overcome previous rejections to that claim and, subsequently, the dependent claims.
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 to claims 1 and 2 in view of the amendment) Claims 1 and 2 is rejected under 35 U.S.C. 103 as being unpatentable over Snoek et al. (International journal of cancer, 2019) hereinafter “Snoek”, and further in view of Ding et al. (Asian Pacific Journal of Cancer Prevention, 2014) hereinafter “Ding”, Honegger et al. (PLoS pathogens, 2015) hereinafter “Honegger”, Chen et al. (Diagnostic pathology, 2014) hereinafter “Chen”, Agrawal et al. (BMC genomics, 2014) hereinafter “Agrawal”, Ribeiro et al. (BioMed research international, 2015) hereinafter “Ribeiro”, Masadah et al. (Cancers, 2021) hereinafter “Masadah”, Zhao et al. (Aging, 2020) hereinafter “Zhao”, He et al. (Molecular Medicine Reports, 2020.) hereinafter “He”, Shen et al. (Cell Cycle, 2019). hereinafter “Shen”, Y Li et al. (Cell Biochemistry and Biophysics, 2020) hereinafter “Y Li”, ZH Li et al. (Identity, 2015) hereinafter “ZH Li”, Cui et al. (Oncology letters, 2018) hereinafter “Cui”, and Krayanak et al. (WO/2018/209322). hereinafter “Krayanak”.
Concerning claims 1 and 2, Snoek teaches using miRNA levels as a biomarker by evaluating one or more biological samples from a subject who has HPV type 16- or HPV type 18-related HSIL (Abstract) for the presence of hsa-let-7b-5p expression profile in HPV positive cervical cancer (Results, Quantitative RT-PCR, Para. 1, line 1), calculating normalized levels for each of the miRNAs and isomiRs (Materials and Methods, Data processing miRNA sequencing, Para. 2), and determining a miRNA signature based on normalized levels of the miRNAs and isomiRs (Materials and Methods, Data processing miRNA sequencing, Para. 2). Regarding claim 2, Snoek teaches the detection of miRNA through RNA sequencing (Abstract).
Snoek fails to teach a panel consisting of hsa-miR-143-3p, hsa-miR-185-5p, hsa-let-7b-5p, hsa-miR-23a-3p, hsa-miR-25-3p, hsa-miR-190b-5p, hsa-miR- 145-5p, hsa-miR-181a-5p, hsa-miR-625-5p, hsa-miR-744.5p, and hsa-miR-206. Snoek also fails to teach administering a therapeutically effective amount of VGX-3100 to said subject if the subject is categorized as biomarker positive.
However, in regards to a panel of miRNA and isomiR, in the context of HSIL and cervical cancer, Cui teaches the role of hsa-miR-206 in HPV positive cervical cancer cells (Results, Para. 1). ZH Li teaches the role of hsa-miR-744-5p in cervical carcinoma (Page 3 – 4, Implicated in, cervical carcinoma). Y Li teaches the expression profile of hsa-miR-625-5p in cervical cancer cells (Results). Shen teaches the expression profile of hsa-miR-181a-5p in cervical cancer cells (Abstract). He teaches the role of hsa-miR-145 in cervical carcinoma cells (Abstract).
Zhao teaches the role of long non-coding RNA TUSC8 in inhibiting cancer growth via hsa-miR-190b-5p (Abstract). Zhao further teaches TUSC8 role in cervical cancer cells (Introduction, Para. 3). Zhao demonstrates that hsa-miR-190b-5p correlates with TUSC8, which is directly involved in cervical cancer. Zhao’s findings form the nexus through which, one of ordinary skill in the art would readily understand that hsa-miR-190b-5p is reasonably involved in cervical cancers. Masadah teaches the role of hsa-miR-25-3p in cervical cancer (Table 1). Ribeiro teaches the hsa-miR-23a-3p expression profile in HPV positive infection and cervical cancer development (Section 2.3, HPV Status). Agrawal teaches hsa-miR-185-5p is down-regulated by hypoxia (Results, Paragraph 1) and that hypoxia is a negative prognostic factor for cervical cancer (Background, Paragraph 1). Honegger teaches hsa-miR-143-3p expression profile in HPV positive tumor cells (Abstract). Furthermore, Honegger teaches hsa-miR-23a-3p expression profile in HPV positive tumor cells (Abstract). While Chen teaches hsa-miR-143 expression profile in HPV16 linked cervical squamous cancer (Abstract). Ding teaches hsa-miR-576-5p expression profile in cervical squamous cell carcinoma (Table 2).
Taken together, the prior art evidences that the claimed miRNAs or isomiRs were all known to be involved in cervical cancer pathogenesis and can serve as useful biomarkers for the detection or characterization of the condition The prior art further establishes that the expression of these miRNA are aberrant in the context of cervical cancer with numerous prior art reporting upregulation or downregulation in cervical cancer tissue or cell lines. Accordingly, it was well recognized that altered miRNA expression profiles constitute molecular signatures characteristics of cervical cancer, supporting their use as diagnostic biomarkers. It would have been obvious to one of ordinary skill in the art to track the fluctuations of the miRNA and isomiR recited in the claim, either alone or in combination, in subjects suffering from cervical cancers given the well documented role of each individual miRNA and isomiR in its relation to cervical cancers.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified Snoek by including additional biomarkers into a panel to detect cervical related cancers as prior art has established the use of multiple biomarkers to confirm a diagnosis of HSIL. Increasing the number of different miRNAs used would advantageously allow broad detection of HSIL, thereby increasing the probability of identifying HSIL. Furthermore, in view of Krayanak, it would have been prima facie to someone of ordinary skill in the art before the effective filing date of the claimed invention to subsequently administer a therapeutically effective amount of VGX-3100 to said subject if the subject is categorized as biomarker positive
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 to claims 3-4, 6- 8, 10-15, and 17-18 in view of the amendment) Claims 3-4, 6- 8, 10-15, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak as applied to claims 1-2 above, and further in view of Trimble at al. (The Lancet, 2015) hereinafter “Trimble.”
As discussed above, claims 1-2 were rendered prima facie obvious by the teachings of Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak. The references do not teach wherein the biological sample is a plasma sample, wherein the plasma sample is isolated from the subject prior to administration of VGX-3100, wherein VGX-3100 is administered to the subject by intramuscular injection followed by electroporation, wherein VGX-3100 is administered to the subject at a dose of 6 mg, wherein VGX-3100 is administered to the subject three times over the course of 12 weeks, wherein administration of VGX-3100 results in virologic clearance of HPV-16 and/or HPV-18 and histopathologic regression of cervical HSIL, wherein administration of VGX-3100 results in histopathologic regression of cervical HSIL, wherein administration of VGX-3100 results in virologic clearance of HPV-16 and/or HPV-18, wherein administration of VGX-3100 results in complete histopathologic regression of cervical HSIL to normal, wherein administration of VGX-3100 results in complete histopathologic regression of cervical HSIL to normal and virologic clearance of HPV-16 and/or HPV-18, wherein administration of VGX-3100 results in histopathologic nonprogression, wherein administration of VGX-3100 results in improved humoral and cellular immune response to VGX-3100 following a third administration of VGX-3100 and at 36 weeks following administration of VGX-3100 as assessed relative to baseline, or wherein the result of VGX-3100 administration is evaluated at 36 weeks following administration of VGX-3100.
However, Trimble teaches a method of treating HPV-16 and HPV-18 related HSIL contingent on proper identification of the condition. To this end, Trimble teaches collecting a sample of whole blood prior to the administration of VGX-3100 (Procedures, Para. 6). The collected whole blood can be used to isolate plasma. Trimble also teaches the administration of VGX-3100 by intramuscular injection followed by electroporation at a dosage of 6 mg (Procedures, Para. 1), three times over the course of 12 weeks (Randomisation and masking, Para. 1). Trimble further teaches that this treatment course results in positive outcomes ranging from histological nonprogression to complete virologic clearance of HPV-16 and/or HPV-18 and histopathologic regression of cervical HSIL (Results, Fig. 2 and Discussion, Para. 5). Importantly, the results of the treatment include varying degrees of histological regression and virologic clearance of HPV-16 and/or HPV-18 as well as an improvement of humoral and cellular immune response (Procedures, Para. 6). Trimble also teaches the evaluation of the VGX-3100 regiment at 36 weeks after the initial treatment 3100 (Procedures, Para. 7).
It would have been prima facie obvious before the effective filing date of the claimed invention to advantageously utilize the art-recognized method for treating HSIL taught by Trimble in the method taught by Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak. Specifically, with regards to claims 3 and 4, Trimble teaches collection of blood, including plasma before administration of VGX3100. One of ordinary skill in the art would have reasonably determined that plasma alone can be used to detect miRNA because miRNA detection with plasma alone has been well established, well known, successfully demonstrated, and commonly used before the effective filing date of the claimed invention. With regards to claims 6 to 8, 10 to 15, and 17 to 18, one of ordinary skill in the would have had a reasonable expectation of success at least because Trimble establishes successful treatment of HPV related HSIL using VGX-3100.
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 to claims 5 in view of the amendment) Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak as applied to claim 1 above, and further in view of Bhuyan et al. (Hum Vaccin Immunother, 2020) hereinafter “Bhuyan.”
As discussed above, claims 1-2 were rendered prima facie obvious by the teachings of Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak. The references do not teach that the HPV-16 or HPV-18 related HSIL is determined by a biopsy.
However, Bhuyan teaches long-term efficacy of VGX-3100 treatment of HPV-16 or HPV-18 positive HSIL partially enabled by collecting cervical cells and performing pap tests (Results, Pap test assessments). Bhuyan further teaches administration of VGX-3100 to treat the detected HSIL. It would have prima facie obvious before the effective filing date of the claimed invention to advantageously utilize the art-recognized method for treating HSIL taught by Bhuyan in the method taught by Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak with a reasonable expectation of success because cervical swabs are a routine and cost effective method of confirming HPV-16 or HPV-18 and will give a better understanding if treatment with VGX-3100 is appropriate.
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 to claims 9 and 16 in view of the amendment) Claims 9 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak as applied to claim 1 above, and further in view of Hollenberg et al. (Hum Vaccin Immunother, 2019) hereinafter “Hollenberg.”
As discussed above, claims 1 -2 were rendered prima facie obvious by the teachings of Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak. The references do not teach wherein VGX-3100 is formulated at a concentration of 6 mg/ml in 150 mM sodium chloride and 15 mM sodium citrate nor wherein administration of VGX-3100 results in clearance of HPV-16 and/or HPV-18 infection from noncervical anatomic locations.
However, Hollenberg teaches effective and safe formulations of VGX-3100 in healthy populations including formulating VGX-3100 at a concentration of 6mg/ml in saline sodium citrate (SSC) buffer (Methods, Trial design, drug material, and participants, Paragraph 1), which was well known, successfully demonstrated, and commonly used in the art at concentrations resulting in 150mM sodium chloride and 15 mM sodium citrate. Hollenberg also teaches the use of VGX-3100 in the clearance of HPV-16 and/or HPV-18 infection from noncervical anatomic locations such as the anus and vulva (Discussion, Para. 4).
It would have prima facie obvious before the effective filing date of the claimed invention to advantageously utilize the art-recognized concentrations of SSC buffer and the method for treating HSIL in noncervical anatomical locations taught by Hollenberg in the method taught by Snoek, Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Krayanak. One of ordinary skill in the art would have had a reasonable expectation of success at least because Hollenberg establishes using a dosage formulation of VGX-3100 for the treatment of HPV related HSIL.
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
Applicant's arguments filed 04/28/2026 have been fully considered but they are not persuasive.
Applicant contends on page 5 of the Remarks: Claim 1 is amended to replace “’has.miR’ with ‘has-miR-‘“
In response: The formatting remains objectionable. Please amend claim 1 with “-“ and no “.” i.e. “hsa-miR-576-5p” not “hsa-miR-576.5p”. As discussed above and previously, the use of “-“ is standard in the field.
Applicant contends on page 5 of the Remarks: Claims 1 – 18 were amended to administer treatment in subjects that are categorized as biomarker positive for HPV based on a miRNA signature.
In response: The 35 U.S.C. § 101 rejection to claims 1 – 18 has been withdrawn.
Applicant contends on page 5 of the Remarks: Applicant states, regarding claims 1 and 3, that “none of the cited references, taken alone or in combination, teaches or suggests any baseline miRNA profile associated with responsiveness of HPV-16- or HPV-18- related cervical high grade squamous intraepithelial lesion to treatment with VGX3100, much less the specific miRNA profile recited by the solicited claims. Kraynyak also fails to disclose any baseline patient profile - miRNA or otherwise - associated with responsiveness of HPV-16- or HPV-18-related cervical high grade squamous intraepithelial lesion to treatment with VGX3100.”
And:
“Snoek identified a panel of 9 miRNAs related to development of cervical intraepithelial neoplasia grade 3 (CIN3), not histopathological regression in response to treatment with VGX3100. The miRNA panel identified by Snoek thus has no relevance to the solicited claims.”
“Zhao concludes that IncRNA tumor suppressor candidate 8 (TUSC8) functions as a "molecular sponge" for miR-190b-5p to inhibit breast cancer growth and metastasis. Zhao, abstract. Notably, Zhao makes no mention of the role of miR-190b-5p in cervical cancer. Given the complexity of the pathways involved in cancer cell proliferation, particularly across cancer cell types, one skilled in the art would not have extrapolated the role of miR-190b-5p deduced by Zhao in breast cancer to cervical cancer.”
“Ribeiro discloses that there is no difference in miR-23a distribution between normal HPV-negative samples, normal HPV-positive samples, LSIL samples, HSIL samples, and ICC samples. Ribeiro, section 3.2 and Table 1. “
“Agrawal discloses that hypoxia has been shown to be a negative prognostic factor in cervical cancer but is silent regarding the role, if any, of miR-185-5p in cervical cancer.”
As discussed above and previously, the it would have been obvious to include additional biomarkers into a panel to detect cervical related cancers and that by including more biomarkers the probability of identifying HSIL would increase.
Snoek identified 9 miRNAs related to development of CIN3 and cervical cancer (“Since we set out to find a panel of miRNA markers that can be applied in cervical screening that should be able to detect both CIN3 and cervical cancer with high discriminatory power, we combined CIN3 and cervical cancer (CIN3+) for the analysis of the validation set.”). Because the biomarkers are effective at measuring the progression of the disease, it would have been obvious that the same biomarkers would be of use to identify the regression of the disease, including any regression caused by treatment.
As discussed previously and above, Zhao teaches that TUSC8 is involved in cervical cancer (“The lncRNA tumor suppressor candidate 8 (TUSC8), also named as XLOC_010588 and LINC01071, is located on chromosome 13q14.11 and is a non-protein coding transcript. Previous studies have shown that over-expression of TUSC8 could inhibit the invasion and migration of cervical cancer cells by up-regulating PTEN via miR-641. Low expression of long non-coding XLOC_010588 indicated a poor prognosis and it played a pivotal role in cervical cancer cell proliferation via decreasing c-Myc expression.”). Zhao teaches the role of long non-coding RNA TUSC8 in inhibiting cancer growth via hsa-miR-190b-5p (Abstract). Zhao further teaches TUSC8 role in cervical cancer cells (Introduction, Para. 3). Zhao demonstrates that hsa-miR-190b-5p correlates with TUSC8, which is directly involved in cervical cancer. Zhao’s findings form a nexus through which, one of ordinary skill in the art would readily understand that hsa-miR-190b-5p is reasonably involved in cervical cancers.
Riberio teaches that miR-23a can be used a normalize to understand the changes of other miRNA during HSIL. In addition, Honegger teaches that hsa-miR-23a-3p expression profile in HPV positive tumor cells and that miR23a-3p decreases when the HPV-positive tumor cells are treated (Abstract).
As discussed previously and above, Agrawal teaches hsa-miR-185-5p is down-regulated by hypoxia (“We also conducted miRNA microarray profiling of U87MG cells grown in normoxia (21% O2) or hypoxia (0.2% O2) for 48 h. A total of 10 microRNAs were found to be up regulated and 23 microRNAs were found to be down regulated in hypoxia [>0.6-fold (log base 2), p < 0.05] (Additional file 5). A comparison of both microarray and deep sequencing data found miR-210-3p and miR-1275 to be up-regulated and miR-10b-5p, miR-181a-2-3p and miR-185-5p to be down-regulated, according to both data sets.”) and that hypoxia is a negative prognostic factor for cervical cancer (“Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been shown to be a negative prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain.”) Agrawal’s findings form the nexus through which, one of ordinary skill in the art would readily understand that hsa-miR-185-5p is reasonably involved in cervical cancers.
As discussed above and previously, it would have been obvious to one of ordinary skill in the art to use miRNA that are dysregulated in HSIL, cervical cancers, and/or associated conditions as biomarkers for the development or regression of HSIL because biomarkers are known to be bidirectional, i.e. if a disease is identified by a biomarker at an elevated level then a biomarker at a decreased level would result in one of ordinary skill in the art to identify a regression or remission of the disease.
Applicant contends on page 8 of the Remarks: Applicant states that “none of Trimble, Bhuyan, and Hollenberg remedies the deficiencies of Snoek in view of Ding, Honegger, Chen, Agrawal, Ribeiro, Masadah, Zhao, He, Shen, Y Li, ZH Li, Cui, and Kraynyak as explained above.”
In response: Applicant’s arguments have been full considered but they are not persuasive. As discussed above, Applicant’s arguments were not persuasive for claims 1 and 2 and, as such, the previous rejection is maintained and modified in view of amendments.
Conclusion
NO CLAIMS ARE ALLOWED
THIS ACTION IS MADE FINAL. 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
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