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 .
Claim Objections
1. 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.5Sp, hsa.miR. 145.5Sp, hsa.miR. 181 a.5Sp, hsa.miR. 625.5p, hsa.miR. 744.5Sp, and has.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.”
The terms “hsa.miR. 190b.5Sp”, “hsa.miR. 145.5Sp”, “hsa.miR. 181 a.5Sp”, and “hsa.miR. 744.5Sp” should be amend to recite hsa-miR. 190b-5p, hsa-miR-145.5p, hsa-miR-181a-5p, and hsa-miR-744.5p.
The term"has.miR.206" should be amended to recite "hsa-miR-206" as written in the specification (Para. 175).
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.
2. Claims 1 – 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. This judicial exception is not integrated into a practical application and the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because for the reasons set forth below. See MPEP § 2106 for analysis parameters.
The instant claims are drawn to a method of diagnosing high grade squamous intraepithelial lesions (HSIL) in a subject and in some embodiments treating subjects diagnosed with HSIL, which is a statutory category of invention (Step 1: YES).
The instant claims are directed to the natural correlation 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 levels to matching the signature of HSIL biomarker positive or negative and then classifying the subject as biomarker positive or biomarker negative based on the natural correlation followed deciding by VGX-3100 administration if biomarker positive. As such the instant claims recite judicial exceptions (JE) in the form of a law of nature and abstract idea (STEP 2A, Prong One: YES).
While in some embodiments, a VGX-3100 treatment is given to a subject who is identified as positive for HSIL biomarkers, in other embodiment the subject is identified as negative for HSIL biomarkers and no treatment is given. In such embodiments, the claimed method is limited to appreciation of the natural correlation to make a decision, i.e., do not administer VGX-3100 to a subject, based on gathered biomarker data. As such, these embodiments do not integrate the JE into a practical application (STEP 2A, Prong Two: NO).
As discussed in detail below, it was well-understood, routine, and conventional (WURC) at the time of filing to identify an altered miRNA and isomiR profile in a subject’s biological sample, including those recited in claim 1, and correlate the expression profiles to diagnose HSIL. In the instance claims where no treatment is given after identifying a subject’s negative biomarker status, the claims are limited to only recite WURC data-gathering steps, which does not reasonably provide an inventive concept. As such the instant claims do not recite significantly more than JE (STEP2B: NO).
In view of the foregoing, the instant claims do not constitute patent eligible subject matter under 35 U.S.C 101.
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.
3. Regarding claim 1, “HSIL” in claim 1 is used by the claim to mean “high grade cervical intraepithelial lesion.” However, in the specification, the acronym HSIL is used to refer to both “high grade cervical intraepithelial lesion” and “high grade squamous intraepithelial lesion.” Accordingly, consistent with the specification and prior art, the examiner interprets HSIL to mean both high grade squamous intraepithelial lesion and high grade cervical intraepithelial lesion.
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). 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 known to be involved in cervical cancer pathogenesis and can serve as useful biomarkers for the detection or characterization of the condition. Given the well documented role of each individual miRNA in its relation to cervical cancers, the prior art forms the nexus that each miRNA and isomiR recited in the claim as a diagnostic biomarker, either alone or in combination with other miRNA or isomiRs, was known to be related to cervical cancer before the effective filing date of the claimed invention. 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 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.
4. 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.
5. . 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.
6. 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.
Conclusion
NO CLAIMS ARE ALLOWED
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANYAL HASSAN ALAM whose telephone number is (571)272-1102. The examiner can normally be reached Reg.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672