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 1-4, 6-12, 16-19, 22-23, 26-27 and 31 are pending and are being examined on the merits.
Preliminary Amendment
The Preliminary Amendment filed May 3, 2023 has been entered.
Information Disclosure Statements
Each of the two Information Disclosure Statements submitted February 5, 2024 have been considered.
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.
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.
Claims 1-4, 6, 8-12 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung1 (US Patent App. Pub. No. 2011/0294674 A1) in view of McCown2 (Naturally occurring modified ribonucleosides, Wiley Interdisciplinary Reviews RNA, 11(5): 1-71, September 2020).
Regarding independent claim 1, Cheung teaches …
A method for preparing a DNA molecule from an RNA template via reverse
transcription, the method comprising reacting a reaction mixture comprising: (i) a thermostable enzyme that comprises RNA-dependent DNA polymerase activity, (ii) the RNA template, (iii) one or more oligonucleotide primers that hybridize to the RNA template, and (iv) reagents for performing reverse transcription of the RNA template (paras. 115, 118, 123, 131, 162, 165).
Cheung teaches that the RNA template may comprise a naturally-occurring molecule, while McCown teaches naturally occurring RNA templates comprising one or more modified ribonucleosides (abstract; p. 2, para. 2; p. 19, section 4.1).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Cheung method to incorporate the McCown RNA templates comprising modified ribonucleosides. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
Regarding dependent claim 2, Cheung does not teach the location of the primers relative to the modified ribonucleosides, however, it would be obvious to optimize the location.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above, to optimize the location of the primers relative to the modified ribonucleosides. It would have been obvious for the ordinary artisan to customize the assay through routine experimentation to optimize the primers for the particular assay. The ordinary artisan would have had an expectation of success as primer design is well-known in the art of nucleic acid assays.
Regarding dependent claims 3-4, Cheung additionally teaches that the reaction mixture is reacted for at least about 14 minutes or longer (para. 175: 30 min), as recited in claim 3, or, in the alternative, that the reaction mixture is reacted for no more than about 6 minutes or less (para. 133: approx. 4 min), as recited in claim 4.
Regarding dependent claims 6 and 8, Cheung additionally teaches that the thermostable enzyme additionally comprises DNA-dependent DNA polymerase activity (para. 115: Tth DNA polymerase), as recited in claim 6, and that the reaction mixture comprises an additional different enzyme that comprises DNA-dependent DNA polymerase activity (para. 115: Taq DNA polymerase), as recited in claim 8.
Regarding dependent claims 9 and 10, Cheung additionally teaches that the reaction mixture further comprises: (v) a forward primer and a reverse primer (i.e., a primer pair) that hybridize to the DNA molecule, and (vi) reagents for amplifying the prepared DNA molecule, and the method further comprises amplifying the prepared DNA molecule via performing a polymerase chain reaction (PCR) amplification (paras. 115, 118, 123, 131, 162, 165), as recited in claim 9, and that the method comprises performing an elongation step in which reverse transcription of the RNA template occurs and an amplification step during which amplification of the prepared DNA occurs (paras. 115, 131), as recited in claim 10.
Regarding dependent claims 11-12 and 16-19, McCown additionally teaches that the RNA template comprises ribosomal RNA (abstract; p. 2, para. 2), as recited in claim 12, that the modified ribonucleoside is a naturally occurring modified ribonucleoside (abstract; Fig. 2; p. 2, para. 2), as recited in claim 16, that the modified ribonucleoside comprises a methylated base or a methylated ribose (abstract; p. 2, para. 2; p. 19, section 4.1: N6-methyladenosine; Fig. 2) as recited in claims 17-18, and that the one or more modified ribonucleosides are selected from N6-methyladenosine (p. 19, section 4.1), as recited in claim 19. Regarding dependent claim 11, McCown suggests that the template is at least 200 nucleotides in length or longer, and the method prepares a DNA molecule corresponding to the full-length RNA template. Specifically, McCown teaches the importance of characterizing modified ribonucleosides in entire transcripts, such as tRNA, which is known to have such modifications throughout various loop portions of the molecule, and mRNA, which is known to have such modifications in 5’ UTRs, coding sequences, and 3’ UTRs (section 3). Thus, it would be obvious to prepare a DNA molecule corresponding to a full-length transcript, in order to completely characterize the types and locations of modified ribonucleases in the transcripts.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above to incorporate the McCown RNA templates of various lengths comprising modified ribonucleosides, including those with a methylated base or a methylated ribose. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides, including those with a methylated base or a methylated ribose, are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Cheung (US Patent App. Pub. No. 2011/0294674 A1) in view of McCown (Naturally occurring modified ribonucleosides, Wiley Interdisciplinary Reviews RNA, 11(5): 1-71, September 2020) as applied to claim 1 above, and further in view of Blauwkamp3 (WO 2018/191563 A1).
Regarding dependent claim 7, Blauwkamp teaches that the enzyme is RTX (para. 245).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above to incorporate the RTX enzyme. Cheung teaches that a variety of reverse transcriptases can be used in the method. Blaukamp teaches that RTX reverse transcriptase is useful in such methods. It would have been obvious for the ordinary artisan to customize the assay through routine experimentation to optimize the reverse transcriptase for the particular assay. In addition, as taught in Blauwkamp, RTX is known in the art for being suitable for that intended purpose. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute enzymes is well-known in the art.
Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung (US Patent App. Pub. No. 2011/0294674 A1) in view of McCown (Naturally occurring modified ribonucleosides, Wiley Interdisciplinary Reviews RNA, 11(5): 1-71, September 2020) and Rogozin (Theoretical analysis of mutation hotspots and their DNA sequence context specificity, Mutation Research, 544, 65-85, 2003).
Regarding independent claim 22, Cheung teaches …
A method for characterizing an RNA template, the method comprising: (a) preparing a DNA molecule from the RNA template via reverse transcription by reacting a reaction mixture comprising: (i) a thermostable enzyme that comprises RNA-dependent DNA polymerase activity, (ii) the RNA template, (iii) one or more oligonucleotide primers that hybridize to the RNA template, and (iv) reagents for performing reverse transcription of the RNA template comprising deoxyribonucleotides which optionally are labeled; and (b) identifying the incorporated deoxyribonucleotides in the DNA molecule, and (e) identifying the ribonucleoside in the RNA template at a position corresponding to the position in the DNA molecule (paras. 115, 118, 123, 131, 142, 162, 165).
Cheung teaches that the RNA template may comprise a naturally-occurring molecule, while McCown teaches naturally occurring RNA templates comprising one or more modified ribonucleosides, and teaches identifying the position of the modified ribonucleoside in the RNA template (abstract; p. 2, para. 2; p. 19, section 4.1; Fig. 4; Table 2).
Rogozin teaches (c) generating a mutation spectrum based on the incorporated deoxyribonucleotides at a position in the DNA molecule, (d) comparing the generated mutation spectrum to a reference mutation spectrum which is characteristic of the modified ribonucleoside (Fig. 1; Table 1; sections 1.1, 1.2, 1.4, 2.1, 4.7).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Cheung method to incorporate the McCown RNA templates comprising modified ribonucleosides. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. It would have been additionally obvious to incorporate the Rogozin mutation spectrum analysis into the modified Cheung method because the mutation spectrum analysis is also useful for detecting diseases. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
Regarding dependent claim 23, McCown teaches and that the modified ribonucleosides is selected from N6-methyladenosine (p. 19, section 4.1)
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above to incorporate the McCown RNA templates comprising modified ribonucleosides, including those with a methylated base or a methylated ribose. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides, including those with a methylated base or a methylated ribose, are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
Claims 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung (US Patent App. Pub. No. 2011/0294674 A1) in view of McCown (Naturally occurring modified ribonucleosides, Wiley Interdisciplinary Reviews RNA, 11(5): 1-71, September 2020).
Regarding independent claim 26, Cheung teaches …
A method for preparing a DNA molecule from an RNA template via reverse
transcription, the method comprising reacting a reaction mixture comprising: (i) a thermostable enzyme that comprises RNA-dependent DNA polymerase activity, (ii) the RNA template, (iii) one or more oligonucleotide primers that hybridize to the RNA template, and (iv) reagents for performing reverse transcription of the RNA template (paras. 115, 118, 123, 131, 162, 165).
Cheung teaches that the RNA template may comprise a naturally-occurring molecule, while McCown teaches naturally occurring RNA templates comprising one or more modified ribonucleosides (abstract; p. 2, para. 2; p. 19, section 4.1).
Cheung does not teach that the primers comprise at least one bridging oligonucleotide primer that hybridizes to a region of the RNA template spanning the one or more modified ribonucleosides, however, it would be obvious to optimize the location of the primers.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Cheung method to incorporate the McCown RNA templates comprising modified ribonucleosides. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
It would have been additionally obvious to further modify the modified Cheung method, discussed above, to optimize the location of the primers relative to the modified ribonucleosides. It would have been obvious for the ordinary artisan to customize the assay through routine experimentation to optimize the primers for the particular assay. The ordinary artisan would have had an expectation of success as primer design is well-known in the art of nucleic acid assays.
Regarding dependent claim 27, McCown teaches and that the modified ribonucleosides is selected from N6-methyladenosine (p. 19, section 4.1)
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above to incorporate the McCown RNA templates comprising modified ribonucleosides, including those with a methylated base or a methylated ribose. Cheung teaches a highly sensitive method that is useful for detecting RNA templates, and teaches that the method can be used to detect naturally occurring molecules. McCown teaches that naturally occurring RNA molecules comprising modified ribonucleosides, including those with a methylated base or a methylated ribose, are clinically important. Thus, it would have been obvious to try detecting the McCown template with the Cheung method, since the Cheung method is useful for detecting such molecules. The ordinary artisan would have had an expectation that doing so would result in the advantage of a highly sensitive method of detecting clinically-relevant templates. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute samples and templates is well-known in the art.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Cheung (US Patent App. Pub. No. 2011/0294674 A1) in view of McCown (Naturally occurring modified ribonucleosides, Wiley Interdisciplinary Reviews RNA, 11(5): 1-71, September 2020) as applied to claim 26 above, and further in view of Blauwkamp (WO 2018/191563 A1).
Regarding dependent claim 31, Blauwkamp teaches that the enzyme is RTX (para. 245).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Cheung method, discussed above to incorporate the RTX enzyme. Cheung teaches that a variety of reverse transcriptases can be used in the method. Blaukamp teaches that RTX reverse transcriptase is useful in such methods. It would have been obvious for the ordinary artisan to customize the assay through routine experimentation to optimize the reverse transcriptase for the particular assay. In addition, as taught in Blauwkamp, RTX is known in the art for being suitable for that intended purpose. The ordinary artisan would have had an expectation of success as modifying nucleic acid assays to substitute enzymes is well-known in the art.
Conclusion
Claims 1-4, 6-12, 16-19, 22-23, 26-27 and 31 are being examined and are rejected. No claims are allowed.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 Cheung was cited in the Information Disclosure Statement submitted February 5, 2024.
2 McCown was cited in the Information Disclosure Statement submitted February 5, 2024.
3 Blauwkamp was cited in the Information Disclosure Statement submitted February 5, 2024.