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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission dated 12/11/2025 has been entered pursuant to RCE filed on 12/11/2025.
Claims dated 12/11/2025 are acknowledged. Claims 1-21 are pending in the instant application and are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/US2020/038126 filed on 06/17/2020 and claims benefit provisional application 62/864,430 filed on 06/20/2019.
Withdrawn Rejections
Applicant’s amendment, filed on 12/11/2025, with respect to the rejection of claim 1-21 under 35 U.S.C. 103 as being unpatentable over Scorza et al (WO 2014/140211 A1, published 09/18/2014, PTO-892 dated 02/28/2025), and Braman et al. (WO 2007/149791 A1, published 12/27/2007, PTO-892 dated 02/28/2025), and as evidenced by Moreno et al. (J. of Res. Of the National Bureau of Standards, published November 1968, PTO-892 dated 08/11/2025), has been fully considered and is not persuasive. The rejection has been withdrawn in favor of the modified/new rejection below. The rejection is hereby withdrawn.
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.
Claims 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Scorza et al (WO 2014/140211 A1, published 09/18/2014, PTO-892 dated 02/28/2025), BioRad (Ceramic Hydroxyapatite Application Guide for Process Development and Scale-Up, published 10/04/2017, PTO-892), and Braman et al. (WO 2007/149791 A1, published 12/27/2007, PTO-892 dated 02/28/2025), and as evidenced by Moreno et al. (J. of Res. Of the National Bureau of Standards, published November 1968, PTO-892 dated 08/11/2025).
Scorza is drawn to methods for purifying RNA from a sample, comprising one or more steps including hydroxyapatite chromatography. The methods can purify RNA in a highly efficient manner without unduly comprising potency or stability, to provide compositions in which RNA is substantially cleared of contaminants (abstract). Scorza exemplifies RNA purification using hydroxyapatite chromatography (example 3, paragraph 000182). Scorza teaches that the preferred hydroxyapatite stationary phase is ceramic hydroxyapatite (paragraph 00071). Scorza teaches that hydroxyapatite chromatography involves hydroxyapatite as a stationary phase. Hydroxyapatite chromatography of nucleic acids is believed to exploit the charge interaction between
their negatively charged phosphate backbone and the positively charged calcium ions on the surface of the hydroxyapatite medium. Differential elution, such as DNA and undesired RNA species from desired RNA species, is accomplished by the application of an increasing phosphate gradient (paragraph 00067). Scorza exemplifies the use of a phosphate elution buffer (paragraph 000182). Scorza teaches that the method may be performed at room temperature (paragraph 00049). The method may be used to separate desired RNA species from unwanted RNA species and can be applied to either dsRNA or ssRNA, but preferably ssRNA (paragraphs 00025-00026). Scorza teaches that after purification the RNA is present in a purer form than before purification and that undesired constituents of RNA containing samples may be removed such as removing dsRNA vs ssRNA (paragraph 000157). Scorza teaches that mRNA can be bound and recovered from a hydroxyapatite column (paragraph 000182). The RNA may contain a modified nucleobase including pseudouridine or 5-methylcytosine residues (paragraph 00029). Scorza teaches that the method purifies the RNA sample to at least 99% purity (paragraph 00024). It would have been obvious to one of ordinary skill in the art at the effective filing date, that if the sample is at least 99% pure, then less than 1 % of the undesired product remains in the sample meeting the limitations of claims 2-7. Scorza teaches that the invention provides a method for purifying RNA from a sample, comprising one or more steps of tangential flow filtration, hydroxyapatite chromatography, core bead flow-through chromatography, or any combinations thereof (abstract). Scorza teaches that the step of either tangential flow filtration or core bead flow-through chronography may precede hydroxyapatite chromatograph (paragraphs 00012-00013). Scorza obtains the sample from an in vitro transcription (IVT) source, in an IVT buffer. The IVT buffer may be considered the loading buffer (paragraph 000182). A typical IVT buffer is Tris-based such as 50 mM Tris pH 8.0 (paragraph 00042). Scorza teaches that salt may be added to the sample prior to loading to the hydroxyapatite column and further teaches the salt may be sodium chloride at a final concentration of between 0-500 mM (paragraphs 00077-78). Scorza teaches that the elution buffer may be sodium phosphate or potassium phosphate (paragraph 00081). Scorza also teaches that the method may further comprise additional steps such as wash steps either before or during loading, eluting, and collecting steps (paragraph 00070).
Scorza does not teach the use of a C1-C5 alcohol or acetonitrile in the loading buffer, the wash buffer, or the elution buffer.
BioRad is an application guide for process development of ceramic hydroxyapatite. BioRad teaches that ceramic hydroxyapatite can be used to separate single-stranded from double-stranded DNA (page 10). BioRad teaches that ceramic hydroxyapatite is compatible with the following solutions at pH 6.5-14 in the presence of calcium and phosphate: 100% acetonitrile,100% ethanol/methanol, 6 M guanidine-HCl, 8 M urea, 4 M NaCl, 1 M potassium phosphate, and 0.5 M sodium phosphate (page 16).
Braman teaches the option of hydroxyapatite as a solid phase substrate capable of binding nucleic acids under suitable conditions (paragraph 048). Braman teaches that single-stranded and double-stranded nucleic acids can differentially bind to a mineral substrate in the presence of an organic solvent and chaotropic salts and can be used to preferentially separate single-stranded nucleic acids from double-stranded nucleic acids (paragraph 007). The method can be adjusted to selectively bind predominantly single-stranded nucleic acids or double-stranded nucleic acids (paragraph 118). Braman further specifies that the organic solvent could be ethanol or acetonitrile (paragraph 148) and that the chaotropes could include guanidine hydrochloride and urea (paragraph 056). Braman teaches that for nucleic acids, the organic solvent concentration may range from 0 to 100%, and when the target is RNA, the preferred concentration of the organic is about 45% to maximize binding of the RNA (paragraph 148). Braman teaches that the once at least one biological molecule has been absorbed to the mineral substrate, the substrate can be optionally washed with solution(s) that contain an organic solvent, such as ethanol (paragraph154). Braman teaches that one could add an organic solvent to the sample after prefiltration of the sample and that the organic solvent could be ethanol (paragraph 148).
Hydroxyapatite is a mineral substrate as evidenced by Moreno which teaches that the substrate has a formula of Ca5OH(PO4)4 (abstract).
It would have been prima facie obvious to combine Scorza, BioRad, and Braman before the effective filing date of the claimed invention by modifying the loading, wash and elution buffers taught by Scorza to contain ethanol and/or acetonitrile as taught by Braman to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the buffers to contain ethanol or acetonitrile because Braman teaches that ssRNA and dsRNA can be differentiated with mineral based substrates using organic solvents, teaches that hydroxyapatite is an appropriate solid phase and as evidenced by Moreno, hydroxyapatite is a mineral based substrate. Braman further teaches that appropriate organic solvents include ethanol and acetonitrile. One of ordinary skill in the art would have a reasonable expectation of success because Scorza teaches a method of separating ssRNA and dsRNA using hydroxyapatite, BioRad teaches that ceramic hydroxyapatite can be used to separate ssDNA from dsDNA and is compatible with acetonitrile in a phosphate buffer, and Braman teaches that ssRNA and dsRNA can be differentiated with mineral based substrates using organic solvents.
Regarding claim 18, it would have been prima facie obvious to combine Scorza, BioRad, and Braman before the effective filing date of the claimed invention by modifying the wash buffer taught by Scorza to contain 1-30% ethanol as taught by Braman to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the buffer to contain 10-30% ethanol because Braman teaches that ethanol may be used, the organic solvent concentration may range from 0 to 100%, and that the preferred concentration of the organic is about 45% to maximize binding of the RNA and BioRad teaches that ceramic hydroxyapatite can be used to separate ssDNA from dsDNA and is compatible with up to 100% ethanol in a phosphate buffer. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (MPEP § 2144.05(I)) Moreover, 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 233, 235 (CCPA 1955). (MPEP § 2144.05(II)) “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.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered, but they are not persuasive.
Applicant argues that Scorza in combination with Braman fails to disclose all elements of the methods of claim 1 because none of the cited references, either alone or in combination, teaches or suggests use of an organic solvent in the elution buffer. The argument is unpersuasive. Scorza teaches using a loading, washing, and eluting buffer with hydroxyapatite to separate nucleic acids. Braman teaches that organic solvents such as acetonitrile and ethanol may be added to a buffer to differentiate the interaction of single-stranded vs double-stranded nucleic acids on hydroxyapatite. BioRad teaches that ceramic hydroxyapatite can be used to separate ssDNA from dsDNA and is compatible with acetonitrile and ethanol in a phosphate buffer. Therefore, it would have been obvious to add an organic solvent such as acetonitrile or ethanol as taught by Braman to the buffers taught by Scorza to further differentiate the interaction of the single-stranded and double-stranded nucleic acids with the hydroxyapatite to improve separation because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Applicant argues that there is no motivation to combine or select the specific elements of Scorza and Braman to arrive at the pending claims. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The MPEP also states that “the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves” (see MPEP 2411 II). The cited reference Braman addresses that both salt, chaotropic salts, and organic solvents can differentiate between dsRNA and ssRNA binding with hydroxyapatite and provides additional options for improving the separation of the dsRNA and ssRNA when combined with Scorza’s method and BioRad teaches that ceramic hydroxyapatite can be used to separate ssDNA from dsDNA and is compatible with acetonitrile or ethanol in a phosphate buffer. It would have been obvious to one of ordinary skill in the art to seek alternative solutions to overcome any separation resolutions problems and improve the yield and/or process. Since it was known that the addition of organic solvents and chaotropic salts can differentiate the interactions between dsRNA and ssRNA with hydroxyapatite, it would have been obvious to add an organic solvent such as ethanol or acetonitrile and a chaotropic salt as taught by Braman because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that even if Scorza is combined with Braman, Scorza teaches away from the use of organic solvents. The argument is unpersuasive. Scorza does not teach away from the use of organic solvents. Scorza teaches that “organic solvents… should ideally be avoided” and may have “potential detrimental effects on RNA stability and potency” (emphasis added by examiner) (paragraph 006). The phrase “ideally” is preferential language and indicates that “ideally” the separation of single-stranded nucleic acids from double-stranded nucleic acids would be accomplished without organic solvents. Further, the phrase “potential” is not a definitive teaching that an organic solvent would result in RNA instability and lack of potency. Ultimately, Scorza does not teach that organic solvents would prevent the separation of single-stranded from double-stranded nucleic acids and therefore does not teach away from using an organic solvent to improve the separation if needed. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
Applicant argues that using an organic solvent in the elution buffer would be contrary to the teachings of Braman because Braman teaches the removal of the organic solvent. Further, the applicant argues that Braman does not teach how to separate dsRNA and ssRNA with any mineral support using organic solvents, much less teach or suggest how to separate dsRNA and ssRNA with hydroxyapatite using acetonitrile or an alcohol. The teachings of Braman relate to a separation device and do not include data involving the purity of the RNA species. The argument is unpersuasive. Braman is relied upon to teach that organic solvents such as acetonitrile and ethanol may be used to further differentiate the separation of single-stranded and double-stranded nucleic acids on hydroxyapatite and BioRad further supports that CHT is compatible with both acetonitrile and ethanol. Braman’s method of isolating the bound nucleic acid was specific to the automated device which is not relevant to the instant invention. In response to applicant's arguments against the references 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).
Applicant argues that there was no motivation to choose ethanol or acetonitrile for removing dsRNA from ssRNA as Braman describes several organic solvents. The argument is unpersuasive. Braman teaches a finite list of organic solvents that could be used to distinguish dsRNA from ssRNA on a mineral substrate and BioRad teaches that both ethanol and acetonitrile may be used with CHT. Therefore, as all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Applicant argues that the methods of present claim 1 lead to unexpected technical results. The argument is unpersuasive. Applicant exemplifies the separation of dsRNA from ssRNA and compares the results over several gradient conditions. In example 1 (instant specification, page 13), applicant exemplified the separation of ssRNA and dsRNA using a NaPi gradient. In example 2 (instant specification page 14), applicant exemplified the separation of ssRNA and dsRNA using a NaPi gradient and 15% ethanol with a 55% ssRNA recovery. The applicant then exemplified a NaPi gradient, 15% ethanol and 100 mM NaCl with a 70% ssRNA recovery. In example 3 (instant specification page 15, applicant exemplified the separation of ssRNA and dsRNA using a NaPi gradient and 4% acetonitrile, repeating a second time with the addition of 100 mM NaCl, but applicant did not report the ssRNA recovery. While the results show improved separation between ssRNA and dsRNA with the addition of the organic solvents, this would be expected based on the combined teachings of Scorza, BioRad, and Braman. Thus, there is no significant difference between the results to describe the instantly claimed invention as having unexpected results.
Conclusion
No claims are allowed.
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/S.L.S./ Examiner, Art Unit 1693
/SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693
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