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 the Claims
Claims 1-6 and 8-16 are pending and under examination. This Office action is responsive to communication(s) filed on August 21, 2025.
Withdrawn Rejections
The rejection Claim 11 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s claim amendments.
The rejection of Claim(s) 1-6 and 8-14 under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Farmer et al. (US 2014/0093882 A1; published April 3, 2014) is withdrawn in view of Applicant’s claim amendments.
The rejection of Claim(s) 1-5, 8-10, 12, and 13 under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Kuersten et al. (US 2020/0199572 A1; published June 25, 2020) is withdrawn in view of Applicant’s claim amendments.
Claim Rejections - 35 USC § 103 – New Grounds
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) 1-6 and 8-14 are rejected under 35 U.S.C. 103 as being unpatentable over Farmer et al. (US 2014/0093882 A1; published April 3, 2014) published June 25, 2020), in view of Kuersten et al. (US 2020/0199572 A1; published June 25, 2020), and in further view of Church et al. (WO 2018045181 A1; published March 8, 2018), and in further view of Schliep et al. (2007). Efficient Computational Design of Tiling Arrays Using a Shortest Path Approach. In: Giancarlo, R., Hannenhalli, S. (eds) Algorithms in Bioinformatics. WABI 2007.
Regarding Claim 1, Farmer et al. teaches a method for depleting a target RNA molecule in a sample, the method comprising: forming DNA/RNA heteroduplexes by contacting a plurality of DNA oligos with the target RNA molecule, and digesting RNA in the formed DNA/RNA heteroduplexes (see Fig. 1, [0021], [0031], [0037]).
Oligos w/ a Predicted Melting Temperature in a Predetermined Range
Farmer et al. teach designing oligonucleotide probes, in part, with the assistance of algorithms and advanced models to predict the melting temperature of potential duplexes (see [0031]) as well as BLAST algorithms to generate optimal specificity of probes ([0032]).
Farmer et al. inherently teaches a “predetermined range” of melting temperatures as any oligonucleotides within a set will necessarily possess the melting temperature characteristic. Furthermore, Farmer et al. teach consideration of oligonucleotide hybridization temperature ranges ([0034]).
Further Algorithmic Selection Methods
Farmer does not appear to teach assigning a cost function to each of the candidate sequences based at least in part on a match score to reference off-target RNAs; and selecting a set of the candidate sequences that minimizes the cost function, inter-position gaps, and overlap as claimed.
Kuersten et al., who teaches a similar RNA depletion method to that of Farmer et al. (see Fig 1, [0005]-[0013], [0034], [0035]), notes that optimal gapping provides efficient hybridization of probes, and abutting or overlapping probe alignments may be avoided in some instances ([0051]).
Church et al. teach that using BLAST algorithms to assess potential off-target binding for probe candidates was a well-known strategy for optimizing probe specificity ([00142).
Schliep et al. teach generating tiling probe set candidates to a target sequence using an algorithmic cost function that considers various parameters including melting temperature, cross-hybridization potential, and other relevant parameters (pg. 386-390, Minimal Cost Tiling Paths). Schliep et al. notes that their methods can produce high-quality oligonucleotide probes with low cross-hybridization potential (pg. 392, Application & Discussion).
Obviousness Rationale
Absent a secondary consideration, it would have been prima facie obvious to a skilled artisan at the time of filing to implement the algorithmic means discussed in Chruch et al. and Schliep et al. into the probe selection methods of Farmer et al. because both Farmer et al. and Keursten et al. emphasize the importance of considering structural probe parameters when designing a successful RNA depletion method. Such artisan would have had expected successful implementation of the probe generation algorithmic means because Church et al. and Schliep et al. demonstrate that use of such computational means result in successful probe coverage optimization.
For example, a skilled artisan wanting to increase the likelihood of successful probe function within the range of melting temperatures within a group of probes that have a desired predicted melting temperature (methodology clearly contemplated by Farmer et al.), would have been motivated include additional computational means to consider additional relevant probe parameters (e.g. cross-hybridization potential, gapping, etc.). Keursten et al., in particular, notes the importance of optimal probe gapping. Church et al. and Schliep et al. provide the means the computational means to consider such additional factors such that high-quality probe selection is more likely.
Further Teachings
Regarding Claims 2-6, 12, and 13, Farmer et al. teaches a wide variety of probe designs including non-uniformity, tiling, minimal spacing, optimized melting temperature, and length ranges that cover about 18 to 44 bases [0029]-[0033]).
Regarding Claim 8, Farmer et al. teaches ribosomal RNA, globin transcripts, and mitochondrial RNA ([0024]).
Regarding Claim 9, Farmer et al. teaches RNase H ([0038]).
Regarding Claim 10, Farmer et al. teaches target mRNA, thereby increasing ratio of poly(a)-tailed RNA ([0024]).
Regarding Claim 11, due to the ambiguity of the phrase “mathematically random, and in the interest of compact prosecution, such phrase will be interpreted to encompass spacing between any probe set heteroduplexes developed with the use of algorithmic means. Farmer et al. teaches development of probe set heteroduplexes through use of algorithmic means ([0032]).
Regarding Claim 14, Farmer et al. teaches independent concentrations for each probe ([0030]).
Response to Arguments
Applicant argues that none of the prior art when combined disclose or suggest a method for depleting a target RNA molecule in a sample, the method comprising: “... (i) generating a set of candidate sequences complementary to the target RNA molecule, wherein the candidate sequences have a predicted melting temperature within a predetermined range;...” or selecting “... DNA oligos that minimize...(C) overlap of sequences in the target RNA complementary to the candidate sequences” as in the amended claims.
These arguments are not persuasive. Farmer et al. clearly contemplate predicting oligonucleotide probe melting temperatures while also considering hybridization ranges (see 103 rejection above). Also, Farmer et al. inherently teaches a “predetermined range” of melting temperatures as any oligonucleotides within a set will necessarily possess the melting temperature characteristic. Furthermore, Keursten et al. in conjunction with Schliep et al. suggest that minimizing cost functions, gapping, and overlap of probe sequences are all critical considerations when designing optimal probe structures for given depletion targets, experimental conditions, and/or desired experimental outcomes.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Farmer et al. (US 2014/0093882 A1; published April 3, 2014) published June 25, 2020), in view of Kuersten et al. (US 2020/0199572 A1; published June 25, 2020), and in further view of Church et al. (WO 2018045181 A1; published March 8, 2018), and in further view of Schliep et al. (2007). Efficient Computational Design of Tiling Arrays Using a Shortest Path Approach. In: Giancarlo, R., Hannenhalli, S. (eds) Algorithms in Bioinformatics. WABI 2007 as applied to Claim 9 above, and further in view of Lemieux et al. (US 2013/0203057 A1; published August 8, 2013.
Farmer et al. teaches that a variety of nucleases may be used in the methods ([0038]). Farmer et al. does not expressly teach that the DNA oligos and the RNAse H are added
together in a single tube before the hybridization and digestion is carried out.
Lemieux et al. teach a nucleic acid detection assay that utilizes detection probes with a thermostable RNAse H enzyme ([0016]-[0017]). Lemieux et al. recognizes that a thermostable RNAse HII enzyme can perform over a range of melting temperatures, allowing hybridization and digestion of multiple different probes in the presence of the enzyme [0027]).
It would have been prima facie obvious to a skilled artisan at the time of filing to utilize a thermostable RNAse enzyme within the methods of Farmer et al. in order to increase the efficiency of such methods. A skilled artisan would have recognized that the method steps of Farmer et al. could have been combined into a single reaction with use of a thermostable RNAse enzyme as is claimed. A skilled artisan would have expected such combination to function successfully because Lemieux recognized that hybridization and digestion of multiple different probes in the presence of the enzyme.
Claim(s) 16 is rejected under 35 U.S.C. 103 as being unpatentable over Farmer et al. (US 2014/0093882 A1; published April 3, 2014) published June 25, 2020), in view of Kuersten et al. (US 2020/0199572 A1; published June 25, 2020), and in further view of Church et al. (WO 2018045181 A1; published March 8, 2018), and in further view of Schliep et al. (2007). Efficient Computational Design of Tiling Arrays Using a Shortest Path Approach. In: Giancarlo, R., Hannenhalli, S. (eds) Algorithms in Bioinformatics. WABI 2007 as applied to Claim 1 above, and further in view of Bobrow et al. (US 2006/0228735 A1; published October 12, 2006).
Farmer et al. teach that hybridization of oligonucleotides may occur at any suitable temperature, including ranges across 10-degree and 5-degree intervals ([0034]). Farmer et al. do not expressly teach that each DNA oligo has a melting temperature within 3.0 degrees of an initial melting temperature.
Bobrow et al. teaches that the melting temperatures within a collection of oligonucleotide probes may be optimized such that they will all hybridize within a narrow range of conditions (e.g. within 5, 4, or 3 degrees) (see [0062]).
Absent a secondary consideration, selection of the claimed melting temperature range would have been prima facie obvious to a skilled artisan at the time of filing through routine and conventional optimization procedures. A skilled artisan would have been motivated to optimize the melting temperatures of the oligonucleotide set to fall within a desired or necessary range (e.g., within 10 degrees, 5 degrees) because Farmer et al. suggests doing so to increase the likelihood of successful application of their RNA depletion method. A skilled artisan would have had a reasonable expectation of success in selecting the claimed range because Bobrow et al. suggests that one can successfully create oligonucleotide probes with narrow ranges of melting temperatures (e.g. within 3 degrees) that will function within narrow hybridization conditions. Thus, the claimed invention as a whole would have been obvious to a skilled artisan at the time of filing. See MPEP § 2144.05 II.
Conclusion
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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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633