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 .
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Brian Whiteman, Art Unit 1636.
Drawings
The drawings were received on 8/19/25. These drawings are acceptable.
Claim Objections
Claims 1, 43, and 118 are objected to because of the following informalities: deoxy is misspelled. Appropriate correction is required.
Response to Arguments
Applicant’s arguments, see pages 8-14, filed 8/19/25, with respect to the rejection(s) of claims 1, 2, 12, 13, 16, 38, 39, 43, 44, 54, 55, 85, 118 and 119 as being taught by Markelc (Gene Ther. 2012, 19:312-20) and claims 1, 11 and 120 under any rejection under 103 as being obvious based on Markelc (Gene Ther. 2012, 19:312-20), e.g., Markelc and Kellner et al. (Nat Chem Biol 2017 13:888-894) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn because of the amendment of the independent claims to limit the modified polynucleotide to a modification selected from a 3-hydroxyl group, 2’-O-methyl ribonucleotides, 2’-dexoy-2’-fluoro ribonucleotide, universal nucleotides, 5-C-methyl nucleotides, one or more modified internucleotide linkages, inverted deoxy abasic residue incorporation, one or more non-natural nucleic acids or combinations thereof. However, upon further consideration, a new ground(s) of rejection is made in view of an updated search of the prior art for administering a chemically modified polynucleotide comprising a RNA, DNA, a non-natural nucleic acid or a combination thereof.
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 3 and 38-39 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.
Claim 3 is rejected on the basis that it contains an improper Markush group set forth in the DNA is selected from the group consisting of circular plasmids, linear plasmids, vectors, single-stranded DNA, single-stranded oligonucleotides, double stranded oligonucleotides, a CRISPR system expression vector. See MPEP 2173.05(h). The group is limited to a group of DNA sequences, but vectors and oligonucleotides embrace RNA vectors and RNA oligonucleotides.
The term “a viable electroporation voltage level” in claim 38 is a relative term which renders the claim indefinite. The term “viable electroporation voltage” 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. The specification does not define the metes and bounds of the term so the skilled artisan would not understand what voltage level is considered higher than a viable electroporation voltage level. “However, electroporation settings, buffers, and equipment may vary among laboratories and may greatly influence electroporation results.” See Koojimans (Journal of Controlled Release 172, 2013, 229-238). Claim 39 is also rejected because it depends on claim 38.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 3, and 44 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 2 and 44 embrace RNA and DNA that are not limited to a modified RNA or DNA. The claims depend on a claim that limits that type of modified polynucleotide that is narrower than a DNA or RNA. Claim 3 embraces a modified polynucleotide comprising a circular plasmid, linear plasmid, vectors, and CRISPR system expression vectors, however, the claims depend on a claim that limits the modification to which after a search of the prior art do not appear to be found in these types of polynucleotides. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 12, 13, 16-18, 20, 43, 44, 54, 55, and 118-119 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Koojimans (Journal of Controlled Release 172, 2013, 229-238) as evident by Warner-Lambert Company (WO 00/09732 cited on an IDS).
Koojimans teach electroporation of Cy5 (far-red fluorescent dye) labelled-siRNA to extracellular vesicles (also known as exosomes) using the Cytomix electroporation buffer and Optiprep buffer. See pages 229-234.
Koojimans does not disclose the composition of Cytomix electroporation buffer.
However, ‘732 teaches Cytomix protects cells against osmotic rupture and has additional salts and other critical molecules, including antioxidants that help in the regeneration process during and following destabilization caused by electrical discharge through the cell (page 5). Cytomix has the following composition; 120 mM KC1, 0.15 mM CaCl2; 10 mM K2HPO4/KH2PO4, pH 7.6; 25 mM Hepes, pH 7.6; 2 mM EGTA, pH 7.6; 5 mM MgCl ; pH adjusted with KOH) with ATP (pH 7.6 adjusted with KOH 2 mM) and Glutathione (5 mM) added just before electroporation.
Thus, the method taught by Koojimans as evident by ‘732 would embrace the method steps recited in the instant claims. See MPEP 2112.02(I)Process Claims-prior art device anticipates a claimed process if the device carries out the process during normal operation
In addition, although Koojimans is silent with respect to the limitations in the preamble of the instant claims (a method of reducing nucleotide oxidation of a polynucleotide comprising an alteration during electroporation; a method of enhancing a transfection efficiency of a polynucleotide comprising an alteration during electroporation; a method of increasing an activity of a polynucleotide comprising an alteration after transfection into a recipient entity), Koojimans anticipates all of the claimed method steps and materials, so the functional effects of carrying out the methods steps in the claimed method are considered to be inherent property in the method steps made taught by Koojimans. See MPEP 2112.02(I)Process Claims-prior art device anticipates a claimed process if the device carries out the process during normal operation
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The limitation alteration (“modified polynucleotide”) recited in the independent claims reads on the modifications of the modified polynucleotide because the rest of the claimed method(s) is limited to using the modified polynucleotide and a free radical scavenger into a recipient entity and the alteration is directed to a chemical modification of the polynucleotide.
Claims 1-3, 12, 13, 16-18, 43, 44, 54, 55, and 118-119 are rejected under 35 U.S.C. 103 as being unpatentable over Rubius Therapeutics, Inc. (WO 2018009838, published on 1/11/18 and EFD 7/7/16) taken with Tothova et al. (Gene Therapy and Molecular Biology Vol. 14, pages 42-46, cited on an IDS).
Rubius Therapeutics tested several different conditions for delivering exogenous modified and unmodified RNA to cells using electroporation. See pages 96-105. The exogenous modified RNA contained pseudo-uridine and 5-methyl cytosine.
Rubius Therapeutics does not specifically teach using a free radical scavenger (e.g., ascorbic acid (also knowns as Vitamin C), L-Methionine, glutathione, L-cysteine, and combinations thereof) in the method.
However, Tothova studied the effects of antioxidative additives on gene transfer electroporation efficacy and observed that Vitamin C and E and melatonin improved the efficacy of a plasmid into E. coli cells, if they were applied directly into the electroporation buffer (abstract).
Tothova does not specifically teach using chemically modified polynucleotides in the method.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Tothova taken with Rubius Therapeutics to study if Vitamin C (ascorbic acid) can increase the expression of modified polynucleotides taught by Rubius Therapeutics, namely to arrive at the claimed invention. See MPEP 2143(I)(C) and (G). The limitation ‘wherein the free radical scavenger reduces electroporation-induced oxidation of the modified polynucleotide’ recited in the instant claims is considered an inherent function of carrying out the method steps using Vitamin C because Vitamin C is an antioxidant and its effect would result in the limitation. With respect to the possibility that the limitation is considered an unexpected result of carrying out the claimed method. See MPEP 2145.
Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) (“the record establish[ed] such a strong case of obviousness” that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) (“given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion” of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988).
This is the case here since the combination of Rubuis Therapeutics and Tothova provide motivation to try Vitamin C in the electroporation of a modified polynucleotide taught by Rubuis Therapeutics.
In addition, although Tothova and Rubius Therapeutics are silent with respect to the limitations in the preamble of the instant claims (a method of reducing nucleotide oxidation of a polynucleotide comprising an alteration during electroporation; a method of enhancing a transfection efficiency of a polynucleotide comprising an alteration during electroporation; a method of increasing an activity of a polynucleotide comprising an alteration after transfection into a recipient entity), Tothova and Rubius Therapeutics make obvious all of the claimed method steps and materials, so the functional effects of carrying out the methods steps in the claimed method are considered to be inherent in the method steps made obvious by Tothova and Rubius Therapeutics. See MPEP 2112.02(I)Process Claims-prior art device anticipates a claimed process if the device carries out the process during normal operation
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Rubius Therapeutics and Tothova as applied to claims 1-3, 12, 13, 16-18, 43, 44, 54, 55, and 118-119 above, and further in view of Kamerkar et al. Nature 2017, 546:498-503, cited on an IDS.
Rubuis Therapeutics and Tothova do not specifically teach delivering the chemically modified polynucleotide to an exosome.
However, Kamerkar teach using electroporation of tagged siRNA into exosomes (page 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Rubuis Therapeutics and Tothova taken with Kamerkar to study transfection efficiency of the tagged siRNA in exosomes using an electroporation buffer comprising Vitamin C.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 20, 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Rubuis Therapeutics and Tothova as applied to claims 1-3, 12, 13, 16-18, 43, 44, 54, 55, and 118-119 above, and further in view of Cornell University (WO 2018049284, published on 3/15/18 and EFD 9/9/16).
Tothova and Rubuis Therapeutics do not specifically teach the electroporating step comprises a voltage level higher than a viable electroporation voltage level in the absence of the free radical scavenger.
Note: in view of the 112(b) for the limitation in instant claim 38 there are metes and bounds to the limitation The electroporation voltage level could embrace a method step when one of ordinary skill in the art used different amounts to study any parameter of electroporation delivery (e.g., transfection efficiency, expression of the polynucleotide).
However, ‘284 studied various electroporation voltage of siRNA into vesicular bodies and it was found that siRNA loaded vesicles (exosomes) transfected the cells at greater efficiency at higher voltage and less efficiency at lower voltages (page 69, Figure 13).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Rubuis Therapeutics and Tothova taken with ‘284 to determine the optimal voltage for delivery the labelled siRNA to an exosomes, namely to arrive at the claimed invention. See MPEP 2144.05(II) Routine Optimization. The limitation recited in instant claim 39 would read on one of ordinary skill in art using different voltages levels, including wherein one level is a higher voltage level compared to another voltage level
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Koojimans (Journal of Controlled Release 172, 2013, 229-238) as evident by Warner-Lambert Company (WO 00/09732 cited on an IDS) as applied to claims 1-3, 12, 13, 16-18, 20, 43, 44, 54, 55, and 118-119 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by above, and further in view of Cornell University (WO 2018049284, published on 3/15/18 and EFD 9/9/16).
Koojimans does not specifically teach the electroporating step comprising a voltage level higher than a viable electroporation voltage level in the absence of the free radical scavenger.
Note: in view of the 112(b) for the limitation in instant claim 38 there are metes and bounds to the limitation The electroporation voltage level could embrace a method step when one of ordinary skill in the art used different amounts to study any parameter of electroporation delivery (e.g., transfection efficiency, expression of the polynucleotide).
However, ‘284 studied various electroporation voltage of siRNA into vesicular bodies and it was found that siRNA loaded vesicles transfected the cells at greater efficiency at higher voltage and less efficiency at lower voltages (page 69, Figure 13).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Koojimans taken with ‘284 to try different voltage level to optimize delivery to the modified polynucleotide to a cell, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine the teaching to determine the optimal voltage for delivering a siRNA to a cell. See MPEP 2144.05(II) Routine Optimization. The limitation recited in instant claim 39 would read on one of ordinary skill in art using different voltages levels, including wherein one level is a higher voltage level compared to another voltage level
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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