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
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 6, 2026. Claims 1-12 are pending and currently examined.
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.
(Previous Rejection – Withdrawn) Claims 1-12 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and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.
This rejection is withdrawn in view of the amendment filed on Mar. 6, 2026.
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 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.
(Previous Rejection – Maintained) Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Oristo et al. (Journal of Applied Microbiology, 2018, 124: 1008-1016).
Claims 1-4 are directed to a sample pretreatment kit for detecting virus infectivity, comprising: a photoactivatable dye capable of intercalating into a nucleic acid; and a nuclease capable of degrading the nucleic acid, wherein the photoactivatable dye comprises PMA dye, PMAxx dye, EMA, platinum compounds, or palladium compounds.
Claims 5-12 are directed to a method for detecting virus infectivity, comprising steps of: (a) dividing a clinical sample into a test sample and a control sample; (b) treating the test sample with a photoactivatable dye and a nuclease, wherein the photoactivatable dye comprises PMA dye, PMAxx dye, EMA, platinum compounds, or palladium compounds; (c) exposing the test sample to a light for photoactivation; (d) amplifying a target nucleic acid in the test sample and the control sample; and (e) determining virus infectivity based on amplification results of the test sample and the control sample.
Oristo teaches a study on pre-RT-qPCR treatments to discriminate infectious human rotaviruses and noroviruses from heat-inactivated viruses using PMA/PMAxx, benzonase and RNase. Oristo teaches that detection/quantification of RNA viruses is mostly done by reverse transcriptase (RT)-(q)PCR, but it does not distinguish between infectious and noninfectious viruses. See Abstract. The aim of the study was to test how different pretreatments before RT-qPCR could eliminate positivity originated from external nucleic acids or genomes of damaged particles. Heat-inactivated (80°C for 10 min) rotavirus (RV) Wa strain and faecal samples containing rotavirus or norovirus were treated with PMA/PMAxx, benzonase or crude extract RNase prior to RT-qPCR. PMA/PMAxx pretreatments were not consistently efficient for rotavirus (RV), although they seemed to work to some extent for heat-inactivated norovirus. Benzonase and RNase provided consistently 2.2–2.8 log10 reductions in the titre of faecal rotavirus. It was concluded that all pretreatments need to be further validated for each virus separately, taking into account sample matrix and inactivation conditions. Although none of the pretreatments could completely render inactivated viruses undetectable, RNase worked most consistently for both rota- and norovirus. This study sheds light on capacity of the most common pre-RT-qPCR treatments to eliminate damaged, noninfectious rotaviruses and noroviruses after thermal treatment. See Abstract.
Oristo teaches the effects of PMA/PMAxx treatments on the RT-qPCR titres of infectious and inactivated viruses. It teaches that when infectious or heat-inactivated RV was treated with PMA or PMAxx, but not subjected to photoactivation, their titres did not differ significantly from the controls (-0.23 to 0.09 log10 gc; P > 0.05; data not shown); that, unexpectedly, however, PMA treatment with photoactivation reduced the titres of infectious (no thermal treatment) Wa and F_RV by 0.73 and 1.65 log10 gc, respectively (P < 0.05; Table 2, Fig. 1a, columns below xaxis); and that the same applied for PMAxx, with reductions of 1.63 and 2.02, respectively (P < 0.05; Table 2, Fig. 1b). See page 1012, left column, para 2-3. These teachings indicate that photoactivation is performed for samples treated with PMA or PMAxx in the PCR process of the study.
Accordingly, Oristo teaches a method for detecting virus infectivity (i.e., discriminating infectious from non-infectious viruses), comprising: (a) dividing a virus sample (a laboratory sample or clinical sample) into a test sample or control sample (e.g., heat-inactivated virus can be considered as a control sample), (b) treating the test sample with a photoactivatable dye OR a nuclease (i.e., Bezonase or crude RNase) wherein the photoactivatable dye comprises PMA/PMAxx dye, (c) exposing the test sample to a light for photoactivation; (d) amplifying a target nucleic acid in the test sample and the control sample; and (e) determining virus infectivity based on amplification results of the test sample and the control sample. However, the method of Oristo does not treat the test sample with both a photoactivatable dye AND a nuclease, as required by claims 5-12. Instead, in the assays of Oristo, the photoactivatable dye and the nucleases are tested separately.
For claims 1-4, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the current invention to put the agents used in the study of Oristo, including the photoactivable dyes PMA/PMAxx and nucleases (e.g., benzonase and crude RNase), together into a “kit” to facilitate storage or shipping/handling. The combination of the known elements would have predictable results to one of ordinary skill in the art since all the claimed elements would continue to operate in the same manner that is no more than the predictable use of prior-art elements according to their established functions. Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). See MPEP 2112.01 III.
For claims 5-12, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the current invention to combine the treatment agents PMA/PMAxx dye and a nuclease (i.e., benzonase or crude RNase), both of which are used for destroying virus nucleic acids in non-infectious virus particles, to evaluate the combined effect of the two agents in discriminating infectious and non-infectious viruses via PCR. Additionally, such a combination, or a substitution of one element for another known in the field to have the same function for the same purpose, is evidence that the claimed invention may be found obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06. Therefore, the instant invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
As to the claimed ranges of concentrations and incubation time, Oristo teaches that a final concentration of 100 umol/L PMA/PMAxx (Biotium, Hayward, CA) was used, and that PMA/PMAxx-treated samples underwent incubation in the dark for 60 min at 6°C, and photoactivation (performed with Biotium-Lite LED Photolysis device (Biotium)) for 15 min at room temperature. Oristo further teaches that Benzonase treatment was performed similarly to PMA treatment, but with 100 U of benzonase per sample, and incubation at 37°C for 1 hr. See page 1010, left column, paragraphs 3-4. One of skill in the art would have found it obvious to arrive at the claimed ranges from those disclosed in Oristo through routine experimental optimization, unless there is evidence that the claimed ranges are critical.
Response to Applicant’s Arguments
Applicant’s arguments filed on Mar. 6, 2026 have been fully considered and addressed as follows.
To the 103 rejection, Applicant makes the following arguments:
A. Referring to Examples 2-3 and Tables 5 and 7, Applicant argues that experimental data shows that RNase alone only achieves a 17.2% inhibition rate on dead cells, indicating RNase alone is virtually ineffective, and that there is no reasonable motivation or “reasonable expectation of success” to combine a reagent that is demonstrably ineffective (RNase) with a highly efficient reagent like PMAxx (which is already achieves 97.4%).
B. Applicant argues that when PMAxx alone reaches a 97.4% inhibition rate, the system is theoretically approaching a point of saturation, one of skill in the art would typically expect that adding further reagents to a 97.4% baseline would either result in no significant change or mere fluctuations within the margin of experimental error. Applicant argues that the combination of PMAxx and RNAse surprisingly boosted the rate to 99.7%, which is technically profound in the field of viral detection.
C. Applicant argues that RNase and PMAxx have different mechanisms, wherein RNase degrades exposed RNA, while PMAxx binds to nucleic acids of damaged cells or viral envelopes, thereby blocking PCR amplification. Applicant argues that the fact that RNase is nearly ineffective on its own but provides a significant boost in the presence of PMAxx is a classic indication of synergy, and the synergy between RNase and PMAxx stems from their distinct and complementary mechanisms.
Applicant’s arguments are not persuasive.
As to argument A, the current rejection is based on the teachings of the prior art Oristo et al., not on the instant disclosure. Therefore, Applicant’s argument that the experimental data disclosed in the instant application does not provide motivation to combine the two related reagents is not germane to the current rejection.
As to argument B, Applicant has not provided convincing evidence why a 17% difference caused by RNase is insignificant, while the 2.3% increase from the 97.4% to 99.7% caused by combining RNAse with PMAxx is. There is no evidence that the 2.3% difference is not also “no significant change or mere fluctuations within the margin of experimental error.” In this case, Appellant’s arguments are treated as arguments of counsel. Argument of counsel cannot take the place of evident in the record. MPEP 2145.
As to argument C, both RNase and PMAxx have the function of inhibiting PCR amplification for viral genome nucleic acid in dead (broken) virus particles for the same purpose of distinguishing infectious and non-infectious virus particles. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06. Additionally, indicated above, Applicant has not provided convincing evidence that the 2.3% difference is not also “no significant change or mere fluctuations within the margin of experimental error.”
Applicant appears to be arguing that the claimed invention produces unexpected results. As an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e).
Conclusion
No claims are allowed.
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 extension fee 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 NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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