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 .
Claims 1-17 are 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.
Claims 3, 6, 7-17 are 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.
Regarding claims 3, 6, 7, 9, 12-14, 16 and 17, the word “preferably” renders the claim indefinite because it is unclear whether the limiting following the word is part of the limitation.
Claims 8, 10, 11 and 15 are rejected for same reason because they depend on the above claims and do not remedy the indefiniteness.
Regarding claim 11, the recitation of “such as” and “e.g.” renders the claim indefinite because it is unclear whether the limitation following the word is part of the claim limitation.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of classifying a subject, monitoring efficacy of a therapeutic treatment or likely to die of the infection, infected with SARS-CoV-2 virus comprising measuring the quantity of circulating RNA of RNase P in a sample comprising blood, plasma or serum, between 8-13 days from the 1st day of symptoms of SARS-CoV-2 infection, does not reasonably provide enablement for such methods wherein the infection is due to other types of SARS corona virus, or when the circulating RNA of RNase P is measured at different time points during the infection, or prior to the development of a 1st symptom. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The nature of the invention
The claims are drawn to a method of classifying a subject, monitoring efficacy of a therapeutic treatment or likely to die of the infection, infected with SARS-CoV virus comprising measuring the quantity of circulating RNA of RNase P in a sample comprising blood, plasma or serum.
The breadth of the claim
The claim breadth is rather broad. The broadest claims 1, 12 and 14 encompasses classifying a subject, monitoring efficacy of a therapeutic treatment or likely to die infected with the family of corona virus comprising measuring the quantity of circulating RNA of RNase P in a sample comprising blood, plasma or serum.
The teaching from the specification and the presence of working examples
The specification teaches that “while the inventors were attempting to measure SARS-CoV-2 RNA in blood of patients, they used RNA of RNase P, that is a cellular housekeeping gene, as an internal control to measure. They were extremely surprised to find that the RNA of RNase P was dramatically increasing, reflecting severity of the disease.” (page 2, lines 3-5). The specification provides examples, a method of quantification of circulating RNase P by droplet based digital PCR in two cohorts, who were diagnosed with SARS-CoV-2 infection, wherein the sample was collected between 8-12, or 10-13 days following the 1st sign of viral infection. The two examples provides a correlation of copy numbers/ml of RNase P in the sample and the severity of SARS-CoV-2 infection, determined by admission to ICU, use of ventilation and death. However, there is no teaching in the specification whether this correlation extends to different types of coronavirus infection. The specification also fails to teach whether this correlation exists when the subject infected with SARS-CoV-2 is asymptomatic, and/or prior to the development of the first clinical sign of the infection. As such, the claimed scope exceeds the teaching from the instant specification.
The state of prior art and the level of predictability in the art
At the time of filing, coronaviruses are known as non-segmented positive RNA viruses belonging to the family of Coronaviridae and the order of Nidovirales and broadly distributed in humans and other mammals, and “the coronaviruses already identified might only be the tip of iceberg, with potentially more novel and severe zoonotic events to be revealed.” (page 497, 1st col., Huang et al., IDS) Prajapat et al. published a reference “molecular diagnosis of COVID-19 by targeting envelop, RdRp and RNase P genes,” (International Journal of Medical Science and Current Research, 2023, Vol.6, no.4, pages 294-299), in which RNase P genes is used as an internal control in multiplex RT-PCR for SARS-CoV-2 positive symptomatic and asymptomatic patients (page 295, 1st col., 3rd paragraph). Prajapat et al. demonstrates that the level of RNase P gene is consistent in all samples (Figure 1 and Figure 2). As such, the prior art and post filing art is silent on the claimed method of classifying a subject, monitoring efficacy of a therapeutic treatment or likely to die of the infection, infected with SARS-CoV virus comprising measuring the quantity of circulating RNA of RNase P in a sample comprising blood, plasma or serum.
The amount of experimentation required make/use the claimed invention
Due to the lack of teaching from the prior art, a skilled artisan would rely solely on guidance provided in the present specification to practice claimed invention. However, the present specification only teaches that circulating RNase P level in blood sample is correlated to the severity of the SARS-CoV-2 infection measured between day 8-12 or 10-13 after the 1st clinical sign of SARS-CoV-2 infection, whether RNase P level has such correlation at other time points of the infection such as before the development of the 1st sign, or in asymptomatic patients is unpredictable. Moreover, due to the large family of Coronaviridae, whether this correlation may be extended to other virus in this family in also unpredictable. The skilled artisan would have to engage in undue experimentation to practice the claimed method to its full scope. Therefore, the claimed method is only enabled to the scope as indicated above.
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.
Claims 6, 11, 14 and 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more. The claim(s) recite(s) “wherein a quantity of circulating RNA of RNase P of 4,5log10 copies/ml or more is indicative a severe case (6), likely develop cute pulmonary failure (11), high risk of death (14).” This judicial exception is not integrated into a practical application because the claims do not recite an application of the law. The only step in the above claims is measuring the quantity of circulating RNA of RNase P in a sample of the subject, which is a data gathering step in order to determine the quantity of circulating RNase P in the sample. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there no other active steps recited in the claims following the data gathering step. Therefore, claims 6, 11, 14 and 15 are not eligible under 101.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2 and 7 is/are rejected under 35 U.S.C. 102(a1) as being anticipated by Liu et al (CN111057797A, published on 2020-04-24).
Liu teaches a kit for real time detection of coronavirus 2019 including primers and probe having a fully defined sequence, and gene Rnase P specific primers, and a process for detecting COVID 19 in a sample (abstract). Since claim 1, 2 and 7 only comprise a single step of measuring RNase P, the teaching from Liu anticipates the claimed invention.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3-5, 8-10 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu, in view of Huang et al (IDS).
The teaching from Liu has been discussed above. However, Liu does not teach which day the measurements takes place following viral infection.
Huang teaches clinical features of patients infected with 2019-nCoV (SARS-CoV-2) (title). Huang teaches the median duration from illness onset to hospital admission was 7 (4-8) days, to shortness of breath (hypoxemia) was 8 (5-13) days, to ARDS was 9 (8-14) days and to ICU admission was 10.5 (8-17) days (page 501, 1st col., 1st paragraph, and Figure 2 and legend).
It would have been obvious to an ordinary skilled in the art that patients suffering from early symptom such as shortness of breadth should be subject to diagnostic screening with the SARS-CoV-2 detection kits that includes RNase P measurement taught by Liu et al. based on the clinical feature taught by Huang. The ordinary skilled in the art would recognize the patients with 1st symptom should be tested right away, or at most between 4-8 days when admitted into hospital (hypoxemia) so that appropriate therapy may be administered. The ordinary skilled in the art would have reasonable expectation of success to measure viral load and circulating RNase P in patient sample following combined teaching from Liu and Huang. Therefore, the claimed invention of claims 3, 5, 9 and 10 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claims 4 and 8, it would have been obvious to an ordinary skilled in the art to continuously monitoring the viral load in the patient because for patients that develop ARD is between 8-14 days. It would have been obvious to an ordinary skilled in the art that hospitalized patients should be closely monitored for viral load between 8-14 days to determine whether there is a difference between patients who develop ARD vs. patients who do not develop ARD.
Huang further teaches treatment for the patients comprises mechanical ventilation, and all patient received antibiotic treatment, and 93% patients received antiviral therapy, and 22% patients were given systematic corticosteroids (page 501, 2nd col., 1st paragraph).
It would have been obvious to an ordinary skilled in the art to continuously monitor hospital admitted patients continuously following different types of therapy as described by Huang. The ordinary skilled in the art would have been motivated to so to determine whether those therapy changes the viral load in patients as well as improve in symptoms of SARS-CoV-2 infection. Therefore, the claimed invention of claim 12 would have been prima facie obvious to an ordinary skilled in the art at the time this application was filed.
Claim(s) 13 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu, in view Persson (International Journal of Food microbiology, 2018, Vol. 284, pages 73-83).
The teaching from Liu has been discussed above. However, Liu do not teach a digital probe based RT-PCR such as digital droplet RT-PCR (ddRT-PCR).
Persson teaches a comparison for precise quantification of norovirus RNA between ddRT-PCR and real-time PCR, wherein two methods both 95% limits of detection, but ddRT-PCR generally showed greater precision in quantification (page 77, 2nd col., 4th paragraph).
It would have been obvious to an ordinary skilled in the art to use ddRT-PCR method for detecting SARS-CoV-2 viral load in patient sample based on combined teaching from Liu and Persson. The ordinary skilled in the art would be motivated to use ddRT-PCR because Persson teaches it shows greater precision in quantification. Since ddRT-PCR is a prior known method for determining viral load in sample and optimization this method for detecting SARS-CoV-2 would have been within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claims 13 and 16 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu and Huang, as applied to claim 12 above, and further in view of Persson.
The teaching from Liu and Huang and the reason for measuring SARS-CoV-2 viral load in patient sample following therapy has been discussed above.
However, neither reference teaches a digital probe based RT-PCR such as digital droplet RT-PCR (ddRT-PCR).
The teaching from Persson has been discussed above.
It would have been obvious to an ordinary skilled in the art to use ddRT-PCR method for detecting SARS-CoV-2 viral load in patient sample based on combined teaching from Liu, Huang and Persson. The ordinary skilled in the art would be motivated to use ddRT-PCR because Persson teaches it shows greater precision in quantification. Since ddRT-PCR is a prior known method for determining viral load in sample and optimization this method for detecting SARS-CoV-2 would have been within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 17 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Note: the above art rejection is applied to the active method step, which is a single step of measuring circulating RNase P in patient sample.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637