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 .
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.
This office action is a response to applicant’s communication submitted June 21, 2023, wherein claims 1-14 were canceled, and claims 15-30 were added.
Claims 15-30 are pending in this application.
Priority
This application is a 371 of PCT/EP2021/066861 filed June 21, 2021 and claims foreign priority to EP 20181010.8 filed June 19, 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been received.
Information Disclosure Statement
Regarding the information disclosure statement filed March 30, 2023, no legible
copy of foreign patent document (“EP 3445850”) has been provided. The Examiner obtained the
foreign patent document and it has been placed in the application file. Accordingly, the information disclosure statement has been considered by the examiner.
The information disclosure statement filed March 4, 2025 has been considered by the Examiner.
Drawings
The drawings are objected to because:
Figure 1 X labels are cutoff (i.e. the words end in triple period).
Figures 1-4 use commas instead of periods in Y labels (i.e. 20,00%).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
On page 3 of the specification, sometimes there are spaces between a number and unit, and sometimes there are not, “5 mM and 2M”, “5 mM and 500mM”, “100mM to 1M”, and “30kD to 300kD” (paras. 0012, 0014). The same issue occurs on pages 10 (para. 0070), 11 (para. 0073), 21 (paras. 0107-0109), 23 (paras. 0118, 0121-0122), 26 (paras. 0133-0134, 0138-0141), 27 (paras. 0142-0146, 0150).
On page 27 of the specification, the phrase “Error! Reference source not found.” is written (para. 0149).
Appropriate correction is required.
Claim Objections
Claims 23 and 25 are objected to because of the following informalities:
In claim 23, the phrase “5 nM” should read “5 mM”. This is based on page 3 of the instant specification (para. 0012).
In claim 25, there should be a space between 500 and mM, “500 mM”.
Appropriate correction is required.
Claim Interpretation
The broadest reasonable interpretation of the phrase “a filter” is a device that separates impurities or solid particles from a liquid or gas. This includes chromatography columns.
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.
Claim 22 is 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 claim 22: Claim 22 recites inter alia, “wherein the sample is applied to the filter in (b) by tangential flow filtration, diafiltration, dead-end filtration….”. It is unclear whether the limitations are meant to describe the filtration technique or filter utilized or is describing a technique in which the sample is applied to the filter. For example, according to the instant specification “tangential flow filtration” and “diafiltration” are techniques that use a filter as part of the technique (pg. 9, paras. 0064-0065). Particularly the phrase “wherein the sample is applied” causes a lack of clarity in the claim. For example, is the claim saying that the filter/filtration technique used is diafiltration, or diafiltration is used to apply the sample to a filter that is separate from the one used in diafiltration.
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.
Claim 30 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
The claim is directed towards a ssRNA molecule obtained by the method according to claim 15. According to Lal (Viruses, 2022, cited on PTO-892) ssRNA are natural products, the genome of viruses (pg. 1, para. 1). This judicial exception is not integrated into a practical application because the ssRNA are not different from ssRNA found in nature (See MPEP 2106 (b)). Without the inclusion of manipulation/method steps (i.e. A method of separating) recited by instant claim 15, claim 30 does not integrate these elements into a practical application. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim is directed to a natural product. Since the claims are product claims, they do not transform the nature of the claim to claim more than the judicial exception. Moreover, there is no evidence in the specification that the mere purification of ssRNA has markedly different characteristics from its natural state.
Claim Rejections - 35 USC § 102
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.
Claims 15-20, 23-24, and 29-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Levanova (Journal of Chromatography A, 2018, cited on PTO-892). The supporting information of Levanova has been provided.
Regarding claims 15-20, 23-24, and 29-30: Levanova teaches the use of CIM monolithic columns to separate dsRNA from ssRNAs of the same length (abstract). Levanova teaches loading a sample of dsRNA and ssRNA in a 0.8 M NaCl and 13% PEG-6000 (an alcohol) onto a column for separation (supporting information, pg. 2, figure S2). The ssRNA isolated by Levanova does not differ in structure compared to ssRNA obtained by the claimed method, absent evidence to the contrary, and thereby anticipates the claim.
Claim 30 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Baiersdorfer (WO 2017/182524, IDS filed March 30, 2023).
Regarding claim 30: Baiersdorfer teaches methods for obtaining single-stranded RNA (ssRNA, abstract). Baiersdorfer teaches a method of purifying ssRNA from dsRNA comprising providing a sample of dsRNA and ssRNA and binding it to a cellulose material and filtering the sample (pg. 3, lines 9-26, pg. 4, lines 8-25). The RNA sample is provided as a liquid comprising a buffer comprising 14 to 16% (v/v) ethanol and a salt in a concentration of 20 to 60 mM (pg. 3, lines 9-15). The sample can also comprise a buffering substance that can be TRIS and/or EDTA (pg. 3, lines 15-17). The ssRNA isolated by Baiersdorfer does not differ in structure compared to ssRNA obtained by the claimed method, absent evidence to the contrary, and thereby anticipates the claim.
Claim 30 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Voloudakis (Plant Virology Protocols. Methods in Molecular Biology, 2015, IDS filed March 30, 2023).
Regarding claim 30: Voloudakis teaches a method of separating ssRNA and dsRNA via precipitation using 8M LiCl followed by centrifugation (pg. 269, para. 3). The ssRNA isolated by Voloudakis does not differ in structure compared to ssRNA obtained by the claimed method, absent evidence to the contrary, and thereby anticipates the claim.
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 15-29 are rejected under 35 U.S.C. 103 as being unpatentable over Baiersdorfer (WO 2017/182524, IDS filed March 30, 2023) as applied to claim 30 above in view of Funkner (WO 2016/193206, cited on PTO-892).
Regarding claims 15-29: Baiersdorfer teaches methods for obtaining single-stranded RNA (ssRNA, abstract). Baiersdorfer teaches a method of purifying ssRNA from dsRNA comprising providing a sample of dsRNA and ssRNA and binding it to a cellulose material and filtering the sample by applying gravity, centrifugal force, pressure, or vacuum to the spin column or filter device such that the liquid and solid phases are separated (pg. 3, lines 9-26, pg. 4, lines 8-25). According to the instant specification, this is an example of dead-end filtration (pg. 9, para. 0066). The RNA sample is provided as a liquid comprising a buffer comprising 14 to 16% (v/v) ethanol and a salt in a concentration of 20 to 60 mM (pg. 3, lines 9-15). The salt is preferably sodium chloride (pg. 14, lines 16-25). The sample can also comprise a buffering substance that can be TRIS and/or EDTA (pg. 3, lines 15-17, pg. 14, lines 28-30). Baiersdorfer teaches ssRNA is stable and can be stored in 10mM TRIS and 1 mM EDTA (pg. 21, lines 4-5). The pH of the buffer can range from 6.5 to 8.0 (pg. 14, lines 30-35, pg. 24, lines 1-10). The appropriate pH can be selected by adding hydrochloric acid to the corresponding base TRIS (i.e. Tris-HCl, pg. 24, lines 1-9). The concentration of the buffering substance is 10 to 15 mM (pg. 14, lines 30-32). Baiersdorfer teaches a buffer to be used for purification procedures comprises 10 mM TRIS, pH 7.0, 50 mM NaCl, 20 mM EDTA (pg. 66, lines 15-18).
Baiersdorfer does not teach a method that is free of cellulose or cellulose chromatography steps.
However, Funkner teaches general methods of purifying a solution of RNA using tangential flow filtration (TFF) (i.e. a filtration technique, abstract). Funkner teaches there is a need in the art to isolate a desired RNA species from undesired RNA species following manufacture of RNA (pg. 1, lines 19-28). Funkner teaches the method can be applied to the isolation of either single stranded or double stranded RNA (pg. 26, lines 26-29, pgs. 26-27, bridging para.). Funkner teaches the method comprises purifying transcribed RNA (i.e. single stranded), from a solution following the transcription of DNA using TFF (pg. 38, lines 23-33). Funkner teaches a transcription buffer can be 40 mM Tris with a pH of 7.5 (pg. 35, lines 24-25). The method can be utilized to remove contaminants, RNA fragments, DNA fragments, high and low molecular weight contaminants, reducing or abolishing the need to purify RNA via organic solvent extraction, alcohol precipitation, or salt precipitation (pg. 39, lines 1-7). Funkner teaches that either a cellulose-based membrane or a PES or mPES-based filter membrane with a molecular weight cutoff (MWCO) of 100 kDa can be used (pg. 41, lines 13-15). Funkner teaches the membrane may be selected depending on the size of the desired RNA molecule, wherein molecular weight cutoff of the filter can be optimized (pg. 41, lines 1-8). Funkner teaches the TFF method is performed using diafiltration solution or buffer which can comprise NaCl from about 0.2 to about 0.5 M NaCl (pg. 40, lines 33-35, lines 1-6, lines 18-20). Funkner teaches EDTA can be added to the solution which stabilizes RNA and reduces turbidity of the solution, allowing for faster flow rates during filtration (pgs. 53-54, bridging para.).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the cellulose material based method of Baiersdorfer with the tangential flow filtration method of Funkner, such as by replacing the cellulose material with a PES or mPES-based filter membrane with a molecular weight cutoff (MWCO) of 100 kDa. A person of ordinary skill would have had the motivation to do so with a reasonable expectation of success as the art establishes filtration as a general technique for the separation of single-stranded and double-stranded nucleic acids and that cellulose and PES or mPES materials are equivalents suitable for the same purpose (See MPEP 2144.6 (II)).
With respect to the claimed concentrations/conditions for filtration, the Examiner notes that, 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." (See MPEP 2144.05 (II)). Together the art establishes tolerable ranges for pHs (6.5 to 8.0), salt concentrations (20 mM to 500mM (0.5 M)), buffer concentrations (10 mM Tris, 20 mM EDTA), and alcohol concentrations (14 to 16% (v/v)) to be used in filtration techniques for the purification of RNA molecules. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 (I)). Baiersdorfer teaches ssRNA is stable and can be stored in 10mM TRIS and 1 mM EDTA (pg. 21, lines 4-5). Funkner teaches EDTA can be added to the solution which stabilizes RNA and reduces turbidity of the solution, allowing for faster flow rates during filtration (pgs. 53-54, bridging para.) and is thus an established result effecting variable. Thus, wherein the art establishes varying pH and component concentrations in filtering methods for purifying/isolating an RNA molecule, it would be well within the technical grasp of the skilled artisan to arrive at the claimed concentrations and pH value as recited by instant claim 28 through routine optimization.
Claims 15-18, 22-23, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Voloudakis (Plant Virology Protocols. Methods in Molecular Biology, 2015, IDS filed March 30, 2023) as applied to claim 30 above in view of Perlmutter (Perlmutter & Idea development, 2018 cited on PTO-892).
Regarding claims 15-18, 22-23, and 29: As discussed above, Voloudakis teaches a method of separating ssRNA and dsRNA via precipitation using 8M LiCl followed by centrifugation (pg. 269, para. 3). In another embodiment, Voloudakis teaches 2 M LiCl can be used to separate dsRNA from ssRNA (pg. 266, last para.).
Voloudakis does not teach wherein the sample is applied to a filter.
However, Perlmutter teaches filtration and centrifugation are known techniques in the art for separating solids from liquids (pg. 2, last two paras.). Perlmutter teaches filtration utilizes a filter in which fluids and small particles pass through a filter mesh under pressure, vacuum, or gravitational force, while large particles in a mixture are unable to pass through (para. 1). According to the instant specification, this is an example of dead-end filtration (pg. 9, para. 0066). Perlmutter establishes that the two techniques accomplish the same goal of separating solid particles from a liquid, albeit centrifugation is a faster and more efficient technique (pg. 3, paras. 1-2, last two paras.). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Voloudakis, such that filtration, rather than centrifugation, is utilized to separate the ssRNA and dsRNA as taught by Perlmutter. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success as filtration is a known techniques in the art for separating solid particles from a mixture. Wherein the techniques are known to accomplish the same goal, it is prima facie obvious to substitute equivalent techniques known for same purpose, absent a showing of unexpected results (See MPEP 2144.6 (II)).
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/S.L.G./Examiner, Art Unit 1693
/ERIC OLSON/Primary Examiner, Art Unit 1693