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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-7) in the reply filed on 06/09/2025 is acknowledged. Per the previous action, the requirement is deemed proper and is therefore made FINAL.
Claims Status
Claims 2 and 10 are canceled, claims 12-22 are newly added, claims 8, 9, 11 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1, 3-7 and 12-22 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 12/05/2025 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 09/10/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
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.
This is a new rejection due to the claim amendments
Regarding claims 6, 17 and 19: The claim recites “annealing temperatures for said PCR assay is independently…” and “said PCR assay comprises independently…”.
It is unclear how a single PCR assay can independently comprise annealing temperatures and cycles.
The claim is interpreted as “annealing temperatures for said PCR assay are
Appropriate correction is required
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 (i.e., changing from AIA to pre-AIA ) 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, 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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Brancaccio et al (Virology (2018) 520;1-10; cited previously) in view of Chen et al (Virology (2019) 516;1-43; cited previously).
This is a repeated rejection from the action posted 09/04/2025.
Regarding claim 1: Brancaccio teach detecting the presence of known and unknown HPV genotypes from a human sample (abstract). Brancaccio teach HPV types are organized into five major genera alpha, beta, gamma, mu and nu, and that some alpha types have a clear association with human carcinogenesis (p1 col1 para1).
Brancaccio disclose using PCR with novel primer sets to detect novel HPV genotypes (p8 col1 para4). Brancaccio detect 265 different papilloma virus genomes from skin samples and 161 different papilloma virus genomes from oral samples (p5 col1 para 4,6, Table S1 and S2). Brancaccio detect of 29 of the 65 claimed HPV genotypes (sup table 1 and sup table 2).
Brancaccio do not detect the entire 65 claimed HPV genotypes as recited in claim 1.
Chen et al (Virology (2019) 516;1-43) teach that of there are 65 genital HPV types and it is unclear why only a limited set of HPV viruses progress to cancer (p11 para4). The 65 human HPV types disclosed by Chen are identical to the 65 HPV genomes recited in the instant claim 1. Chen discloses the 65 papillomavirus types from humans were identified in the study of Chen, from previous studies and a search for HPV genomes in GenBank, and genomes represent the 13 human Alphapapillomavirus species groups (Figure 1, p13 para1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Brancaccio drawn to detecting the presence of HPV genomes from a human sample by including the 65 human HPV genomes taught by Chen. Chen disclose it is still unclear why only a small proportion of oncogenic HPV infections progress to precancer and cancer (p2 para2). Chen teach HPV classification will facilitate understanding of the clinical and biological roles the sequence variations play (p19 research highlights) and foster studies on the associations of HPV variants with cancer risk (abstract).
Accordingly, one of ordinary skill in the art would have been motivated to identify the 65 human HPV genomes as disclosed by Chen using the method taught by Brancaccio for the purposes of better understanding the role of HPV in disease. One would have had a reasonable expectation of success in adapting the method of Brancaccio to identify the 65 genomes taught by Chen because the method of Brancaccio successfully identifies ~45% of the 65 genomes.
Claims 3, 7 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Brancaccio et al (Virology (2018) 520;1-10; cited previously) in view of Chen et al (Virology (2019) 516;1-43; cited previously) as applied to claim 1 above, and as discussed below.
This is a new rejection due to the claim amendments, however relies on previously cited art.
Regarding claims 3 and 7: The teachings of Brancaccio are described supra. Brancaccio also teach 1) obtaining DNA from a sample; “after DNA extraction, all samples were analyzed” (p2 col2 para2). DNA is necessarily extracted from a sample. The sample of Brancaccio is an ex vivo sample, as Brancaccio discloses viral DNA was detected from skin swabs and oral rinses (p2 col1 ¶5). One of ordinary skill in the art would understand both skin swabs and oral rinses would comprise cells and secretions.
Brancaccio teach 2) reacting the DNA with each primer pair; Table 1 discloses the primer sets used (p2 col2 para3). Finally, Brancaccio teach 3) detecting the presence of HPV in said sample according to results of PCR assays; analysis of the PCR data revealed a total of 265 different papilloma virus types identified from the skin DNA samples (p5 col1 para 4).
Brancaccio do not teach detection of the 65 genotypes as recited in claim 1.
Chen et al (Virology (2019) 516;1-43) teach that of there are 65 genital HPV types and it is unclear why only a limited set of HPV viruses progress to cancer (p11 para4). The 65 human HPV types disclosed by Chen are identical to the 65 HPV genomes recited in the instant claim 1. Chen discloses the 65 papillomavirus types from humans were identified in the study of Chen, from previous studies and a search for HPV genomes in GenBank, and genomes represent the 13 human Alphapapillomavirus species groups (Figure 1, p13 para1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Brancaccio drawn to detecting the presence of HPV genomes from a human sample by including the 65 human HPV genomes taught by Chen. Chen disclose it is still unclear why only a small proportion of oncogenic HPV infections progress to precancer and cancer (p2 para2). Chen teach HPV classification will facilitate understanding of the clinical and biological roles the sequence variations play (p19 research highlights) and foster studies on the associations of HPV variants with cancer risk (abstract). Furthermore, Brancaccio teach the detection of multiple HPV types using primer panel of 11 specific primers and 4 degenerate primers, with additional degenerate primers, to detect 265 PV types from skin samples (p4 col2 ¶8-9; p5 col1 ¶4). Thus a specific primer panel which could amplify a large number of HPV genomes was known in the art at the time of the instant disclosure. Brancaccio further teach primers were designed by aligning HPV sequences using the HPV sequence database compendia (p4 col2 ¶) and therefore the tools to develop additional primers to known genomes were also available for one of ordinary skill in the art at the time of the invention.
Accordingly, one of ordinary skill in the art would have been motivated to identify the 65 human HPV genomes as disclosed by Chen using the method taught by Brancaccio for the purposes of better understanding the role of HPV in disease.
One would have had a reasonable expectation of success in adapting the method of Brancaccio to identify the 65 genomes taught by Chen because the method of Brancaccio successfully identifies ~45% of the 65 genomes of the instant disclosure and discloses methods for primer design to HPV genomes.
Regarding claim 12: The teachings of Brancaccio are discussed supra. Brancaccio also teach degenerate primers to amplify genomic HPV sequences (p2 col1 ¶5).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Brancaccio et al (Virology (2018) 520;1-10; cited previously) in view of Chen et al (Virology (2019) 516;1-43; cited previously) as applied to claims 1, 3, 7 and 12 above, and further in view of Seaman et al (Virology Journal (2010)7;1-17, cited previously) and Livak et al (Methods (2001) 25;1-7).
This is a new rejection as required by the claim amendments, however relies upon art of record.
Regarding claim 4: The teachings of Brancaccio are described supra. Brancaccio do not teach a reference Ct for which a measured Ct is less than a reference is positive and a Ct greater than or equal to said reference is negative.
Seaman teach detection and quantitation of HPV by real time PCR (title). Seaman disclose real time PCR reactions were performed to target HPV, and a reference was also used (p3 col1 para1). Seaman further disclose the Ct values and cycle numbers were quantified for the reference (p4 col1 para2). Table 3 teaches HPV quantitation by qPCR from samples.
Seaman does not teach a measured Ct is less than a reference is positive and a Ct greater than or equal to said reference is negative.
Livak teach one of the two most commonly used methods to analyze data from real-time quantitative PCR is relative quantification in which the PCR signal of the target transcript in one group is described relative a reference (abstract). Table 1 teaches Ct change is measured by subtracting a measured Ct (gene of interest; e.g. c-myc) from a reference gene (e.g. GAPDH) (p4). This reads on the instant claim because one of ordinary skill in the art would understand the basic principle of qPCR is that higher Ct values relate to lower sample input and lower Ct values relate to higher sample input.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Brancaccio drawn to detecting the presence of HPV genomes from a human sample by quantifying the HPV signal using qPCR and comparing the experimental signal to a reference signal as taught by Seaman and Livak.
One of ordinary skill in the art would have been motivated to modify the method of Brancaccio with the teaching of Seaman and Livak because Seaman teach an increase in HPV viral loads has been correlated with disease progression in cervical cancer, and thus quantifying viral load (compared with simply detecting) would provide important information about a patients potential for disease progression.
One would have been motivated to use a reference signal as taught by Livak because Livak teach relative quantification may be easier to perform because it does not require the use of standard curves (p7 col2 ¶1).
One would have had a reasonable expectation of success in adapting the method of Brancaccio to quantify HPV genomes as taught by Seaman and Livak because Livak teach using relative quantification in which an experimental sample is compared with a reference sample is one of the most widely used methods to analyze data from real-time quantitative PCR.
Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Seaman et al (Virology Journal (2010)7;1-17, cited previously) and Livak et al (Methods (2001) 25;1-7) as applied to claim 4 above, and further in view of Schmittgen et al (Nature Protocol (2008) 3:6;1-8).
This is a new rejection as required by the claim amendments.
Regarding claims 13-16: The teachings of Brancaccio and Livak are discussed supra. Brancaccio and Livak do not teach the specific Ct ranges for the reference sequence.
Schmittgen teach the threshold cycle (Ct) of real-time PCR is defined as the PCR cycle at which the fluorescent signal of the reporter dye crosses an arbitrarily placed threshold (p2 col1 ¶2).
Therefore, selection of a Ct value for a reference would have been a matter of routine optimization based on the samples being analyzed, the primers used and methods known in the art.
Claims 6 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Brancaccio et al (Virology (2018) 520;1-10; cited previously) in view of Chen et al (Virology (2019) 516;1-43; cited previously) as applied to claims 1, 3, 7 and 12 above, and further in view of Genaxxon (Optimization of Annealing Temperature and other PCR Parameters [online]. Genaxxon [retrieved on 04/29/2026]. Retrieved from the Internet: <https://www.genaxxon.com/shop/en/blog/optimization-of-annealing-temperature-and-other-pcr-parameters) and as evidenced by Forslund et al (Journal of General Virology (1999)80;1-7).
This is a new rejection as required by the amendments, however relies upon art of record.
Regarding claims 6, 17 and 19: The teachings of Brancaccio are described supra. Brancaccio disclose the PCR protocols were run as described in Forslund (p2 col2 para3). Forslund disclose PCR conditions comprising an annealing temperature of 50°C and 45 cycles (p2 col2 para1).
MPEP 2131.03 reads “[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art."
Therefore the teaching of Brancaccio, an annealing temperature of 50ºC and 45 PCR cycles reads on the PCR parameters of the instant claims.
Regarding claims 18 and 20: The teachings of Brancaccio are described supra. Brancaccio do not disclose the specific annealing temperature of 55°C and does not explicitly disclose 40 PCR cycles.
Genaxxon teach that it is critical that a PCR protocol be systematically tested and optimized to identify optimum annealing temperature in a given set of conditions and that testing will reveal parameters that will minimize the incidence of spurious artifacts (p1). Genaxxon teach typical annealing temperatures are 5°C below primer Tm and often fall in the range of 50-60°C (p3). Genaxxon also teach 20-30 PCR cycles can detect approximately 104 copies of target DNA, and that fewer cycles are needed for high DNA concentrations (p2). Genaxxon further teach reactions using more than 30 cycles may require longer extension times (p3).
Therefore, as taught by Genaxxon, selection of annealing temperature and number PCR cycles for PCR reactions is dependent on the primers used and concentration of template DNA and thus would have been a matter of routine optimization based on the samples being analyzed, the primers used and methods known in the art.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Brancaccio et al (Virology (2018) 520;1-10; cited previously) in view of Chen et al (Virology (2019) 516;1-43; cited previously) as applied to claims 1, 3, 7 and 12, and further in view of Gaiffe et al (Plos ONE (2012) 7:5;1-10).
This is a new rejection as required by the amendments, however relies upon art of record.
Regarding claims 21-22: The teachings of Brancaccio are described supra. Brancaccio do not teach the sample comprises mesenchymal stem cells.
Gaiffe teach human mesenchymal cells take up apoptotic-derived cervical cancer cells and were able to be transformed (abstract). Gaiffe further teach a subset of cancer cells called cancer stem cells are likely initiated as a result of horizontal gene transfer and cause very aggressive cancers with a high propensity toward metastatic dissemination (p6 col1/2 ¶2/1). Gaiffe teach HPV-positive cervical cancer cells transfer viral DNA to promote growth and transformation of HPFs and represents a mechanism for cellular transformation (p3/4 col2/1 ¶2/1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Brancaccio drawn to detecting the presence of HPV genomes from a human sample by using a sample that comprises mesenchymal stem cells as taught by Gaiffe.
One of ordinary skill in the art would have been motivated to modify the method of Brancaccio with the teaching of Gaiffe to use a sample that comprises mesenchymal stem cells because Gaiffe teach horizontal gene transfer from infected apoptotic cells can transform other cells and that cancer stem cells have a high propensity toward metastatic dissemination. Thus one of ordinary skill in the art would have understood that understanding the HPV status of the mesenchymal stem cells and potential cancer stem cells could elucidate the role of HPV infection and horizontal gene transfer in the role of transformation of different cell types.
One would have had a reasonable expectation of success in adapting the method of Brancaccio to detect HPV from a sample comprising mesenchymal stem cells because one of ordinary skill in the art would understand that any cell type sample can be used as sample.
Allowable Subject Matter
Claim 5 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Regarding claim 5: As discussed supra, the specific HPV genomes and tools to make degenerate primers for amplification and detection of said genomes is known.
However the combination of the 18 specific degenerate primer pairs as recited in claim 5 is considered non-obvious in view of the prior art because Seq ID No: 8 appears free of the art. Thus the combination of primers as recited in claim 5, comprising seq ID NO: 8, is also free of the art.
Response to Arguments
The responses are directed to the Arguments filed 12/05/2025.
Regarding the Drawings: The drawings filed 06/13/2022 are acknowledged and no objections are made.
Regarding priority: Acknowledgment is made of Applicant' s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from PCT CN2020/135565 filed on December 13, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received June 13, 2022. While a certified copy of the foreign patent application PCT CN2020/135565 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Regarding Sequence Disclosures:
The amendments to claim 5 overcome the objection over the sequence disclosure and the objection is withdrawn.
Regarding Arguments directed to 35 USC § 112:
The claim amendments overcome the rejections and the rejections from the action filed 09/10/2025 is withdrawn.
Regarding Arguments directed to 35 USC § 101:
The amendments to the claims overcome the rejections and the rejections from the action filed 09/10/2025 is withdrawn.
Regarding Arguments directed to 35 USC § 103:
Applicant argues Claim 1 and its dependent claims are patentably distinguishable over the cited references.
The rejections over claims 3-4 and 6-7 are withdrawn due to the claim amendments and thus rejections directed to the claims are moot.
Arguments regarding claim 1 are addressed below:
Regarding argument A: Brancaccio Does Not Teach or Suggest Designing Complete Primer Sets Covering All 65 HPV Genotypes
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).
Specifically, the combination of Brancaccio and Chen is relied upon and arguments against only Brancaccio are therefore unpersuasive.
Regarding argument B: Designing a Complete 65-Genotype Primer Panel Is Technically Non-Trivial and Not Taught by the Art
Applicant argues that one of ordinary skill in the art could not combine the disclosure of Chen with the method of Brancaccio to obtain the claimed 65-genotype panel.
As discussed in the instant rejection supra, Brancaccio teach primers were designed by aligning HPV sequences using the HPV sequence database compendia (p4 col2 ¶). Therefore the tools to develop additional primers to known genomes were available for use by one of ordinary skill in the art at the time of the invention. The argument is therefore considered unpersuasive.
Applicant asserts Brancaccio provides no guidance on cross-reactivity management across a large and diverse genotype panel and does not address designing multi-genotype degenerate primers with optimized degeneracy for broad coverage.
MPEP 2111.04 states “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.”
The only active stem in the instant claim 1 is “detecting the presence” and the 65 genomes are required to be detected. Thus, as discussed supra in the present rejection, based on the art at the time of filing, the method of claim 1 would have been obvious with a reasonable expectation of success, and one would have had reasonable motivation to do so.
Furthermore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., multi-genotype degenerate primers with optimized degeneracy for broad coverage) are not recited in the rejected claim 1. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding argument C: The Prior Art Provides No Motivation to Design Primers for Non-Pathogenic or Low Risk Genotypes
As discussed supra, Chen teach the 65 HPV genomes recited in the instant claim 1 are known genital HPV types and it is unknown why a limited set of HPV viruses progress to cancer (p11 ¶4). Chen further disclose it is still unclear why only a small proportion of oncogenic HPV infections progress to precancer and cancer (p2 para2). Chen teach HPV classification will facilitate understanding of the clinical and biological roles the sequence variations play (p19 research highlights) and foster studies on the associations of HPV variants with cancer risk (abstract).
Thus motivation to design primers to the 65 claimed HPV genomes was present at the time of the instant invention; as taught by Chen and discussed supra, one of ordinary skill in the art would have been motivated to generate a panel to detect all 65 HPV genomes to gain understanding in HPV biology which could shed light on why some viruses progress to cancer and others do not.
Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success because Brancaccio teach successful detection of ~45% the claimed HPV genomes and discloses methods for primer design that could be applied to additional HPV genomes.
Regarding argument D: The Claimed Primer Set Has a Non-Obvious Technical Structure Not Disclosed or Suggested by the Prior Art
The argument regarding the claimed primer is relevant only to claim 5, in which the claimed primer set is disclosed.
Claim 5 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Regarding claim 5: As discussed supra, the specific HPV genomes and tools to make degenerate primers for amplification and detection of said genomes is known.
However the combination of the 18 specific degenerate primer pairs as recited in claim 5 is considered non-obvious in view of the prior art because Seq ID No: 8 appears free of the art. Thus the combination of primers as recited in claim 5, comprising seq ID NO: 8, is also free of the art.
The arguments directed to claim 1 are unpersuasive and the rejection over Claim 1 is maintained.
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 ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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