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 .
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 4, 22-23, 25-27, and 35-36 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.
The term ''substantially free'' in claims 4 and 23 is a relative term that renders the claim indefinite. The term ''substantially free'' is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 22 and dependent claims thereof, the phrase “under denaturing conditions” renders claims reading upon said phrase indefinite as the metes and bounds of the term are not clearly defined. For example, polyribonucleotides may be denatured at high temperatures as due to hydrogen bond disruption. It is unclear when the denaturing condition is high temperatures if applicant intends for the invention to be limited to a composition at said high temperatures or if the invention includes a composition that has been cooled below a temperature where denaturation occurs.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 23 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kahvejian et al. WO 2020/181013 A1 (Kahvejian).
Kahvejian relates generally to pharmaceutical compositions and preparations of circular polyribonucleotides and uses thereof (Abstract). Kahvejian found that linear polyribonucleotide molecules in circular polyribonucleotide pharmaceutical compositions or preparations should be detected, monitored and/or controlled, e.g., reduced or purified from the circular polyribonucleotide pharmaceutical compositions or preparations [0003].
In an aspect, Kahvejian teaches a pharmaceutical preparation of circular polyribonucleotide molecules comprises at least 30% (w/w), 40% (w/w), 50% (w/w), 60% (w/w), 70% (w/w), 80% (w/w), 85% (w/w), 90% (w/w), 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96% (w/w), 97% (w/w), 98% (w/w), 99% (w/w), 99.1% (w/w), 99.2% (w/w), 99.3% (w/w), 99.4% (w/w), 99.5% (w/w), 99.6% (w/w), 99.7% (w/w), 99.8% (w/w), 99.9% (w/w), or 100% (w/w) circular polyribonucleotide molecules relative to the total ribonucleotide molecules in the pharmaceutical preparation [0006]. In another aspect, Kahvejian teaches a pharmaceutical preparation of circular polyribonucleotide molecules has a level of linear polyribonucleotide molecules that is reduced by at least 30% (w/w), at least 40% (w/w), at least 50% (w/w), at least 60% (w/w), at least 70% (w/w), at least 80% (w/w), at least 90% (w/w), or at least 95% (w/w) after a purification step (e.g., after one or a plurality of purification steps) compared to the level of linear polyribonucleotide molecules in the preparation prior to the purification step(s) [0007].
In some embodiments, Kahvejian teaches the level of linear polyribonucleotide molecules in a pharmaceutical preparation of circular polyribonucleotide molecules may be measured by any suitable method, including microscopy, spectrophotometry, fluorometry, denaturing urea polyacrylamide gel electrophoresis imaging, UV-Vis spectrophotometery, RNA electrophoresis, RNAse H analysis, UV spectroscopic or fluorescence detectors, light scattering techniques, surface plasmon resonance (SPR) with or without the use of methods of separation including HPLC, by HPLC, chip or gel based electrophoresis with or without using either pre- or post- separation derivatization methodologies, using methods of detection that use silver or dye stains or radioactive decay for detection of linear polyribonucleotide molecules, or methods that utilize microscopy, visual methods or a spectrophotometer, or any combination thereof [0012]. In some embodiments, Kahvejian teaches that the pharmaceutical preparation is further substantially free of a pharmaceutical impurity or contaminant [0015].
In another aspect, Kahvejian teaches a method of making a pharmaceutical composition comprising: a) providing a preparation of circular polyribonucleotide molecules, b) processing the preparation to reduce the amount of linear polyribonucleotide molecules, c) optionally evaluating the amount of linear polyribonucleotide molecules in the preparation before, during, and/or after the processing step, and d) further processing the preparation to produce a pharmaceutical composition for pharmaceutical use [0022]. In some embodiments, the further processing of step d) comprises one or more of: i) processing the preparation to substantially remove DNA and/or protein (e.g., a cell protein such as a host cell protein) and/or endotoxin; ii) evaluating the amount of DNA and/or protein (e.g., a cell protein such as a host cell protein) and/or endotoxin in the preparation; iii) formulating the preparation with a pharmaceutical excipient; and iv) optionally, concentrating the preparation.
In some embodiments, Kahvejian teaches that a circular polyribonucleotide is purified by utilizing a structural feature of the circular polyribonucleotide to separate it from a linear RNA or an impurity [0179]. In some embodiments, the circular polyribonucleotide is purified by utilizing a structural feature (e.g., a lack of free ends) such as described in Example 9. For example, circular RNA is enriched from a preparation comprising a mixed pool of circular RNA and linear RNA counterpart containing the same nucleotide sequences using polyadenylation of the linear RNA counterpart or fragments thereof. The 3’ end of the linear RNA counterpart or fragments thereof can be polyadenylated using poly(A) polymerase, resulting in the addition of a 3’ polyadenine tail.
To purify the circular RNAs, Kahvejian teaches that ligation mixtures were resolved on 4% denaturing PAGE and RNA bands corresponding to each of the circular RNAs were excised. Excised RNA gel fragments were crushed, and RNA was eluted with gel elution buffer (0.5M NaOAc, ImM EDTA and 0.1% SDS) for an hour at 37°C. Supernatant was harvested, and RNA was eluted once again by adding gel elution buffer to the crushed gel and incubated for an hour. Gel debris was removed by centrifuge filters and RNA was precipitated with ethanol. Eluted circular RNA was analyzed by 6% denaturing PAGE.
Raw electropherograms are analyzed using a primary fragment analysis tool (e.g. PeakScanner Applied Bio- systems) [0513]. The peaks at each position in the electropherogram are then integrated. For each RNA analyzed, y axis scaling to correct for loading error is performed so that the background for each primer extension reaction is normalized to that of a negative-control reaction performed on RNA that is not treated with BzCN. A signal decay correction is applied to the data for each reaction. The peaks are aligned to a ladder created from two sequencing reactions. At each position, the peak area of the negative control is subtracted from the peak area in BzCN- treated samples; these values are then converted to normalized SHAPE reactivities by dividing the subtracted peak areas by the average of the highest 2% to 10% of the subtracted peak areas.
Thus, Kahvejian teaches a composition comprising an enriched population of circRNA, wherein: (a) the composition is obtained from a sample comprising a population of polyribonucleotides comprising circRNA and IinRNA; (b) the composition has been exposed to one or more denaturing conditions; and (c) the composition is substantially free of one or more impurities or by-products. Thus, claim 23 is anticipated.
Claim(s) 37 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kahvejian et al. WO 2020/181013 A1 (Kahvejian) as applied to claim 23 above.
Thus, Kahvejian teaches a method of determining the purity of a circRNA comprising (a) providing a sample comprising a population of polyribonucleotides comprising circRNA and linRNA; (b) separating the circRNA from the IinRNA under denaturing conditions by chromatography; (c) collecting a chromatogram of the sample comprising a peak for the circRNA and a peak for the IinRNA; and (d) calculating the area under each peak to determine the purity of the circRNA in the sample. Thus, claim 37 is anticipated.
Conclusion
Claims 1-7, 15, 19-23, 25-27, and 35-38 are pending. Claims 4, 22-23, 25-27, and 35-37 are rejected. Claim 38 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claims 1-3, 5-7, 15, and 19-21 are allowed.
The following is a statement of reasons for the indication of allowable subject matter: Kahvejian et al. WO 2020/181013 A1 (Kahvejian) is representative of prior art. Kahvejian does not teach or suggest a method of separating circRNA from the linRNA under denaturing conditions that do not comprise the use of gel electrophoresis. Kahvejian does not teach or suggest a composition comprising circRNA and linRNA wherein the composition is in solution under denaturing conditions (e.g., Kahvejian teaches a gel vs. a solution).
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/
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