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 .
Status of Claims
The amended claims filed 11/13//2005 are acknowledged and entered.
Claims 1, 4, 11, 14 have been amended
Claims 2 and 12 are cancelled
Claims 1, 3-11, and 13-20 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Objections
Specification - Withdrawn
The disclosure is objected to because of the following informalities:
a) The use of the term(s), which are a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, and/or ® following the term.
Applicant has corrected the informalities in the substitute specification and the objection is withdrawn.
Claim Rejections - 35 USC § 103 withdrawn
3. The rejections of claims 1-7, 10, 11-16 and 19-20 under 35 U.S.C. 103 as being unpatentable over Xu (CN 104131006 published November 05, 2014. IDS 04/21/2023 citation 7. English translation provided) in view of Schoenbrunner (US20180100205A1 published April 12, 2018) are withdrawn in view of Applicant’s amendments to 1, 4, 11, 14 and cancellation of claims 2 and 12.
4. The rejections of claims 1, 7-9, 11 and 16-18 under 35 U.S.C. 103 as being unpatentable over Xu Schoenbrunner in view of Poon (Journal of Clinical Virology 30 (2004) 214–217) and Gorbalenya (Nature Microbiology | Vol 5; March 2020 536–544; online publication date: Mar 2 2020).are withdrawn in view of Applicant’s amendments to 1 and 11.
New Rejections Based on Amendments
Claim Rejections - 35 USC § 103
The amended Claims 1, 3-7, 10, 11, 13-16 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Xu in view of Schoenbrunnen).
Xu teaches a method for extracting adenovirus DNA (as required by the amended instant claim 1 and instant claim 7) with a extracting solution comprising 50 mM Tris-HCl at pH 8, 10 mM EDTA at pH 8, 10 mM NaCl and 1% SDS (RNAse inhibitor) (Xu claim 1) (pretreatment solution/nucleic acid release agent (extracting) as required in amended instant claims 1 and 4 and instant claims 3), a method for detecting human adenovirus by PCR (Xu claim 2), including quantitative PCR technology (qPCR) ([0034] and [0053]) and the PCR reaction solution [0012] as required in amended instant claim 1 and instant claim 6. Xu also teaches the use of an antibiotic when collecting the sample [0005] as required in amended instant claim 1 and instant claim 5. Xu further teaches the composition of the extracting solution (50 mM Tris-HCl at pH 8, 10 mM EDTA at pH 8, 10 mM NaCl and 1% SDS (RNAse inhibitor) and an antibiotic) for a DNA virus (pretreatment solution as required in amended instant claims 11 and 14 and instant claims 13 and 15 and DNA virus as required by instant claim 16) and a kit for detecting adenovirus DNA including the extracting solution (pretreatment solution as required in instant claim 19) and/or PCR reaction solution (as required in instant claim 20) ([0020], [0021], [0022], [0023] and Xu claim 5). The concentrations and pH of Tris and EDTA in the extracting solution taught by Xu are within the range of concentrations recited in the pretreatment solution of amended instant claim 1 and 11.
Xu does not teach the type of antibiotic and its concentration as required in amended instant claims 1 and 11 and instant claims 5 and 15 or the origin of the sample (instant claim 10) to be analyzed.
Schoenbrunner teaches a composition comprising Phi6 (bacteriophage) suspended in a buffer suitable for a nucleic acid amplification reaction (PCR) at a pH between 7-9, including a preservative selected from sodium azide (NaN3) and ProClin 300 (Schoenbrunner claims 1 and 6), wherein NaN3 is found at a 0.05% concentration (Schoenbrunner claim 7), as required in amended instant claims 1 and 11 (same concentration range) and instant claims 5 and 15. This composition with 0.05% NaN3 (amended instant claim 11 and instant claim 15) can be used in methods and kits for nucleic acid amplification (abstract) as required in amended instant claim 1 and instant claims 5 and 19-20). Schoenbrunner further teaches that the sample to be analyzed comprises plasma, whole blood, urine, fecal material, mucus, mucosal swabs and cell cultures ([0028] and Schoenbrunner claim 13) as required by instant claim 10.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Xu with Schoenbrunner to develop a solution comprising Tris-HCl pH 8, EDTA pH 8, NaCl, SDS (RNAse inhibitor) (Xu’s solution) with a preservative/antibiotic (such as NaN3 or ProClin) as taught by Schoenbrunner, wherein this solution can be used as a pretreatment solution as required by the instant application. One of ordinary skill would have been motivated to do so because the ingredients of the solutions taught by Xu and by Schoenbrunner are also comprised in most commonly used solutions and/or buffers including solutions and buffers for sample (pre)treatment and PCR. It would further be obvious to develop a method to use the pretreatment solution in combination with a nucleic acid release agent (the extract solution taught by Xu) with the preservative/antibiotic (as taught by Schoenbrunner) and a qPCR amplification reagent (PCR reagent solution for qPCR as taught by Xu) to perform a qPCR test to detect a viral nucleic acid. One of ordinary skill would have been motivated to do so because both Xu and Schoenbrunner disclose viral detection by PCR. It would also be obvious to incorporate these solutions in a kit as taught by Xu.
It would further be obvious that the ingredient dosages in the solutions are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
There would be a reasonable expectation of success to make and use the claimed invention because the ingredients of the pretreatment solution are commonly found in the art and qPCR is a well validated technique for viral nucleic acid detection as demonstrated by Xu and Schoenbrunner.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the 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.
Claims 1, 7-9, 11 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Xu and Schoenbrunner, in view of Poon (Journal of Clinical Virology 30 (2004) 214–217) and Gorbalenya (Nature Microbiology | Vol 5; March 2020 536–544; online publication date: Mar 2 2020).
Xu and Schoenbrunner teachings have been discussed above and applied herein.
Xu and Schoenbrunner do not teach the detection of an RNA virus, a coronavirus or SARS-CoV-2 as required in instant claims 1, 7-9, 11 and 16-18.
Poon teaches a one-step quantitative RT-PCR for detection of SARS coronavirus (SARS-CoV) (title, entire article) as required in instant claims 1, 7-8, 11 and 16-17 but does not teach the detection of SARS-CoV-2 as required in claims 9 and 18.
Gorbalenya teaches the identification and phylogeny of SARS-CoV-2 within the Coronaviridae (entire article). SARS-CoV-2 clusters with SARS-CoV in trees of the species Severe acute respiratory syndrome-related coronavirus (figure 2b) and the genus Betacoronavirus (figure 2c). That is, any method develop for SARS-CoV will be applicable to SARS-CoV-2 as required by instant claims 9 and 18 because of their phylogeny.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Xu and Schoenbrunner with Poon and Gorbalenya and develop a pretreatment solution, a kit, and a method to use this pretreatment solution in combination with a nucleic acid release agent and a qPCR amplification reagent to perform the qPCR test as taught by Poon to detect RNA viruses from a sample such as SARS-CoV. The RNA viruses can include coronaviruses and also SARS-CoV-2 because SARS-CoV and SARS-CoV-2 are very closely related coronaviruses as taught by Gorbalenya. One of ordinary skill would have been motivated to do so because the reagents to detect viral nucleic acid by qPCR are not dependent on the type of virus found in the sample. Xu teaches the detection of Adenovirus which is a DNA virus, Schoenbrunner teaches the detection of Phi6 bacteriophage which is a double-stranded RNA virus infecting Pseudomonas, and Poon teaches the detection of SARS-CoV-1 which is a single stranded RNA virus. There would be a reasonable expectation of success to make and use the claimed invention because many types of PCRs are standard techniques run in commercial laboratories for virus diagnosis.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the 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.
Relevant arguments that apply to new claims
Applicant’s arguments are as follow:
- (a) The component concentrations of the adenovirus DNA extraction solution disclosed in Xu, specifically, the concentrations of EDTA and NaCl, are significantly different from the instant application range, and such differences directly determine the quality of detection results. They are not "routine selections" and confer unexpected technical effects.
Regarding EDTA, applicant argues that Xu's concentration at supposedly 100mM far exceeds the upper limit of the present application. Example 6 of the specification clearly verifies that when EDTA concentration is equal or above 200 mM, "no Ct value" is obtained for RNA virus detection.
Regarding NaCl, applicant argues that Xu's concentration is only 1/17 of the lower 342mM limit of the present application, which cannot maintain the osmotic pressure of virus particles (especially single-stranded RNA viruses). This concentration difference is a core design for "stable preservation of RNA viruses" and not routine optimization.
Regarding an antibiotic, applicant argues that Xu fails to balance "long-term bacteriostasis" and "qPCR compatibility". Example 1 of the present application verifies that 0.04% Proclin 950 can inhibit microbial growth at room temperature for 72 hours without
affecting RT-PCR enzyme activity. This concentration selection is an exclusive optimization based on multiple sets of experiments, for which Xu provides no technical suggestion.
- (b) Experimental data confirmation: concentration differences confer unexpected effects of "improved DNA virus detection efficiency and achievable RNA virus detection":
- (b.1) Additional experiment 1. Rapid detection of two different pretreated adenovirus (ADV) oropharyngeal swab samples (DNA virus project).
- (b.2) Additional experiment 2. Rapid detection of two different pretreated Respiratory Syncytial virus (RSV) oropharyngeal swab samples (RNA virus project)
- (c) There is no motivation to combine Schoenbrunner with Xu, and the combination cannot adapt to the technical route of the amended claim 1. The internal control buffer disclosed in Schoenbrunner helps to monitor whether the PCR process is normal and improves the accuracy of qualitative and/or quantitative nucleic acid detection methods, it belongs to the backend monitoring step of detection which has no direct technical connection with frontend sample pretreatment (virus pretreatment). The forced combination of frontend extraction reagents (pretreatment solution) and backend quality control reagents (internal control nucleic acid) would not yield any technical benefit, and thus there is no motivation for combination.
- (d) Poon's "RNA Extraction + RT-PCR" differs from the present application's method in technical route, and cannot be combined with Xu to obtain the present application's solution. Gorbalenya only confirms that SARS-CoV and SARS-CoV-2 are closely related taxonomically (belonging to the same species). It does not mention the impact of pretreatment solution concentrations on detection, nor the compatibility of pretreatment solutions or detection reagents with different coronaviruses.
Applicant’s arguments have been considered but are not persuasive. In response to Applicant’s arguments:
- Regarding item (a):
Applicant argues that the EDTA concentration disclosed by Xu is 100mM (table page 8). However, the EDTA concentration disclosed by Xu is 10mM which is within the claimed EDTA range (Xu claim 1) and is less than 200 mM. Therefore, this argument is moot.
Applicant argues that the difference in NaCl concentration can affect the osmotic pressure of ssRNA viruses but there is no evidence demonstrating unexpected results for the different osmotic pressures for ssRNA viruses and there is no evidence demonstrating unexpected results about how NaCl concentration would affect DNA or dsRNA viruses. NaCl is commonly present in many types of buffers and solutions. Therefore, the amount of NaCl in a solution is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
Applicant argues that Xu fails to balance "long-term bacteriostasis" and "qPCR compatibility regarding the antibiotic concentration. Whereas Xu teaches the presence of an antibiotic, it is Schoenbrunner who teaches a preservative ((NaN3) and ProClin 300), wherein NaN3 is found at a 0.05% concentration (same concentration range as required by the instant application). 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). See discussion above for more details regarding the teachings of Xu, Schoenbrunner relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
A showing of unexpected results (technical effects) must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). MPEP § 2145. A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). MPEP 716.02 (a). The evidence relied * > upon < should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). MPEP 716.02 (b). Applicant must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). MPEP 716.02 (b). Applicant has failed to provide evidence of such clinical unexpected technical affects regarding the EDTA, NaCl and antibiotic concentrations.
- Regarding item (b), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
- Regarding item (c), In response to applicant's arguments against Xu and Schoenbrunner 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). Whereas Xu teaches the presence of an antibiotic, Schoenbrunner teaches a preservative ((NaN3) and ProClin 300), wherein NaN3 is found at a 0.05% concentration. Applicant has not sufficiently described why there is no prima facie case for obviousness. See discussion above for more details regarding the teachings of Xu, Schoenbrunner relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
- Regarding item (d), In response to applicant's arguments against Poon and Gorbalenya 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). Whereas Xu and Schoenbrunner do not teach the detection of an RNA virus, Coronavirus or SARS-CoV-2 virus. Poon teaches the detection of SARS-CoV and Gorbalenya teaches that both SARS-CoV and SARS-Cov-2 are related viruses. Applicant has not sufficiently described why there is no prima facie case for obviousness. See discussion above for more details regarding the teachings of Xu, Schoenbrunner, Poon and Gorbalenya relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
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.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671
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