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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a double-stranded RNA molecule, in the reply filed on 01/19/2026 is acknowledged.
Claims 71-72, 179-181, 186, 188, 190 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/19/2026.
Applicant’s election without traverse of an antisense strand complementary to SEQ ID NO:1 and comprising SEQ ID NO:8, and of Formula I-1, in the reply filed on 01/19/2026 is acknowledged.
Claims Status
Claims 4-44, 46-67, 69-77, 80-82, 84, 86, 89-133, 135-156, 159-175, 177-191 is/are cancelled and claims 192-199 is/are newly added. Claims 1-3, 45, 68, 78-79, 83, 85, 87-88, 134, 157-158, 176, 192-199 is/are currently pending with claims 71-72, 179-181, 186, 188, 190 withdrawn. Claims 1-3, 45, 68, 78-79, 83, 85, 87-88, 134, 157-158, 176, 192-199 is/are under examination.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Figs. 1, 2, 3, 4, and 5 are color drawings.
Claim Rejections - 35 USC § 112
112(b):
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 1-3, 45, 68, 78-79, 83, 85, 87-88, 134, 157-158, 176, 192-199 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.
Claims 1-2, 87, 134, 157 recite sequences “substantially complementary” to an ATN1 nucleic acid and “sufficiently complementary” to direct target-specific silencing of ATN1 mRNA; claim 3 recites a sequence which “comprises complementarity” to at least 10 contiguous nucleotides of SEQ ID NOs:1-7. The claims do not recite any degree of complementarity required for a sequence to be considered to be “substantially” or “sufficiently” complementary, or “comprising complementarity”. The terms “substantially complementary”, “sufficient complementarity”, and “comprises complementarity” in claims 1-3, 87, 134, 157 are relative terms which render the claims indefinite. The terms “substantially”, “sufficiently”, “substantially complementary”, “sufficiently complementary”, “sufficient complementarity”, and “comprising complementarity” are 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. Because these terms are relative terms and are not sufficiently defined, they render the metes and bounds of the structures claimed by 1-3, 87, 134, and 157 unclear. Claims 45, 68, 78-79, 83, 85, 88, 158, 176, 192-199 depend on claims 1, 87, 134, and 157 but do not clarify this indefiniteness, and so are also rendered indefinite.
The term “about” in claims 192 and 194 is a relative term which renders the claim indefinite. The term “about” 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. There is no definition of the term “about” that is commonly accepted in the art, and as such, the term “about” must be defined by the applicant. Without a definition, the term “about” implies a range of acceptable error which is potentially limitless. Without a proper definition of this term, the metes and bounds of the acceptable error for a value modified by the term “about” cannot be determined.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 83 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 83 is drawn to a cell comprising a vector. The specification teaches that the claimed dsRNA may be administered to patients in need (paragraph [072]), which would encompass administration to humans. As such, the cell of claim 83 is interpreted to encompass cells in a human organism. As cells comprised in a human organism constitute part of the human organism, claim 83 is interpreted to encompass a human organism. Amendment of “A cell” to “An isolated cell” in the preamble of claim 83 would be remedial.
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) 1-3, 68, 192, 195-199 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hashimoto (WO2021153747A1, English translation of specification, claims, and abstract provided).
Regarding claims 1-3, 192, Hashimoto teaches a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence complementary to an ATN1 sequence comprised between nucleotides 5666 and 5715 of SEQ ID NO:2 (this sequence encompasses instant SEQ ID NOs:1 and 8, see alignment below), and wherein the antisense strand consists of 8-80 nucleotides (claim 6; paragraph [0146]).
Instant SEQ ID NO:8 (comprised within instant SEQ ID NO:1):
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Regarding claim 68, Hashimoto teaches a pharmaceutical composition comprising the dsRNA (claim 6; paragraph [0146]) which further comprises a pharmaceutically acceptable carrier (paragraph [1058]). Hashimoto teaches that the pharmaceutical composition has the purpose of inhibiting ATN1 expression in an organism (paragraphs [0005], [0161]).
Regarding claims 195-199, Hashimoto teaches that the oligonucleotide comprises at least one phosphorothioate internucleotide linkage (“preferably all phosphorothioate linkages” in the central 5-30 nucleotides) and at least one of a: 2’-O-Me, 2’-fluoro, LNA, morpholino, phosphoramidate (paragraphs [0094]-[0095], [0032], [0068], [0165], [0091], [0089]; claims 15-27; see also for example, Tables 2-3).
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-3, 45, 68, 192-199 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hashimoto (WO2021153747A1), in view of Khvorova (2017).
Regarding claims 1-3, 192, Hashimoto teaches a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence complementary to an ATN1 sequence comprised between nucleotides 5666 and 5715 of SEQ ID NO:2 (this sequence encompasses instant SEQ ID NOs:1 and 8, see alignment below), and wherein the antisense strand consists of 8-80 nucleotides (claim 6; paragraph [0146]).
Instant SEQ ID NO:8 (comprised within instant SEQ ID NO:1):
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Regarding claim 68, Hashimoto teaches a pharmaceutical composition comprising the dsRNA (claim 6; paragraph [0146]) which further comprises a pharmaceutically acceptable carrier (paragraph [1058]). Hashimoto teaches that the pharmaceutical composition has the purpose of inhibiting ATN1 expression in an organism (paragraphs [0005], [0161]).
Regarding claims 195-199, Hashimoto teaches that the oligonucleotide comprises at least one phosphorothioate internucleotide linkage (“preferably all phosphorothioate linkages” in the central 5-30 nucleotides) and at least one of a: 2’-O-Me, 2’-fluoro, LNA, morpholino, phosphoramidate (paragraphs [0094]-[0095], [0032], [0068], [0165], [0091], [0089]; claims 15-27; see also for example, Tables 2-3).
However, Hashimoto does not teach the specific modification pattern required by instant claim 45, nor that the dsRNA comprises an overhang.
Khvorova teaches modifications of dsRNA which enhance clinical efficacy.
Regarding claim 45, Khvorova teaches that siRNA comprising alternating 2’-O-Me and 2’-fluoro modifications in both strands, and phosphorothioate linkages between the 2-9 3’ and 5’ terminal nucleotides of both strands, have enhanced efficacy and nuclease stability (Fig. 3; page 243).
Regarding claims 193-194, Khvorova teaches that siRNA molecules may comprise a 2-6 nucleotide overhang (Fig. 3).
Khvorova teaches siRNA (dsRNA) modifications which enhance clinical efficacy and nuclease stability in vivo. It would have been obvious to an artisan at the time of filing to modify a double-stranded RNA molecule of Hashimoto with the modification patterns taught by Khvorova, in order to enhance the efficiency of ATN1 knockdown and protect the dsRNA from nuclease degradation.
Claim(s) 78-79, 83 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hashimoto (WO2021153747A1) and Khvorova (2017) as applied to claim 1 above, and further in view of Kaemmerer (US20040162255A1).
The teachings of Hashimoto and Khvorova can be combined to render obvious the limitations of claim 1, as described above.
Regarding claim 79, a reduction of ATN1 gene expression by at least 30% resulting from introduction of an RNA molecule comprising an antisense strand comprising SEQ ID NO:8 (which composition is taught by Hashimoto) is taught by the instant specification to be an inherent quality of this RNA molecule (see Fig. 2, wherein siRNA “241” comprises an antisense strand of SEQ ID NO:8, see page 125).2
However, neither Hashimoto nor Khvorova teach that an siRNA may be delivered in a vector, including a viral vector.
Kaemmerer teaches an siRNA targeting the ATN1 gene, which is delivered to cells packaged in a delivery vector.
Kaemmerer teaches an siRNA (a double-stranded RNA) targeting the atrophin1 (ATN1) gene (claims 1, 22-23).
Regarding claims 78-79 and 83, Kaemmerer teaches that such an siRNA targeting the ATN1 gene can be delivered to target cells by packaging the siRNA in a delivery vector, including an rAAV vector (claims 60-65).
Both Kaemmerer and Hashimoto teach dsRNA targeting the ATN1 gene. The teachings of Kaemmerer would have rendered obvious to an artisan that dsRNA targeting and reducing expression of the ATN1 gene can be packaged and delivered, in a vector (including viral vectors), to cells in which reduced expression of the ATN1 gene may be desired. It thus would have been obvious to said artisan that delivery of the dsRNA of Hashimoto to cells may be facilitated by packaging the dsRNA in a delivery vector, as in Kaemmerer.
Claim(s) 85, 87-88, 134, 157-158, 176 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hashimoto (WO2021153747A1) and Khvorova (2017) as applied to claim 1 above, and further in view of Alterman (WO2017132669A1, of record).
The teachings of Hashimoto and Khvorova can be combined to render obvious the limitations of claim 1, as described above.
Regarding claims 87-88, 134, 157, Hashimoto teaches a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence complementary to an ATN1 sequence comprised between nucleotides 5666 and 5715 of SEQ ID NO:2 (this sequence encompasses instant SEQ ID NOs:1 and 8, see alignment below), and wherein the antisense strand consists of 8-80 nucleotides (claim 6; paragraph [0146]). Hashimoto teaches that the oligonucleotide comprises at least one phosphorothioate internucleotide linkage (“preferably all phosphorothioate linkages” in the central 5-30 nucleotides) and at least one of a: 2’-O-Me, 2’-fluoro, LNA, morpholino, phosphoramidate (paragraphs [0094]-[0095], [0032], [0068], [0165], [0091], [0089]; claims 15-27; see also for example, Tables 2-3) (required by claim 157, which requires at least one or more chemical modifications in each of the sense and antisense strands).
Instant SEQ ID NO:8 (comprised within instant SEQ ID NO:1):
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Regarding claim 176, Hashimoto teaches a pharmaceutical composition comprising the dsRNA (claim 6; paragraph [0146]) which further comprises a pharmaceutically acceptable carrier (paragraph [1058]). Hashimoto teaches that the pharmaceutical composition has the purpose of inhibiting ATN1 expression in an organism (paragraphs [0005], [0161]).
However, Hashimoto does not teach the specific modification pattern required by instant claim 134, nor that the dsRNA comprises an overhang.
Khvorova teaches modifications of dsRNA which enhance clinical efficacy.
Regarding claim 134, Khvorova teaches that siRNA comprising alternating 2’-O-Me and 2’-fluoro modifications in both strands, and phosphorothioate linkages between the 2-9 3’ and 5’ terminal nucleotides of both strands, have enhanced efficacy and nuclease stability (Fig. 3; page 243).
Khvorova teaches siRNA (dsRNA) modifications which enhance clinical efficacy and nuclease stability in vivo. It would have been obvious to an artisan at the time of filing to modify a double-stranded RNA molecule of Hashimoto with the modification patterns taught by Khvorova, in order to enhance the efficiency of ATN1 knockdown and protect the dsRNA from nuclease degradation.
However, neither Hashimoto nor Khvorova teach a branched RNA compound.
Alterman teaches branched dsRNA compounds.
Regarding claims 85, 87-88, 134, and 176, Alterman teaches branched RNA compounds comprising dsRNA linked together by a linker, spacer, or branching point (claims 1, 7).
Regarding claim 157, Alterman teaches a compound of formula (I):
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“wherein L is selected from an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, and combinations thereof”, “N is an RNA duplex comprising a sense strand and an antisense strand, wherein the sense strand and antisense strand each independently comprise one or more chemical modifications; and n is 2, 3, 4, 5, 6, 7 or 8” (claim 18).
Regarding claim 158, Alterman teaches that the compound has structure selected from the following:
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wherein B is a branch point and S is a spacer (claims 18-19).
Alterman teaches that branched RNA structures are “essential for enhanced tissue distribution and tissue retention of modified oligo nucleotides”, compared to “a single non conjugated siRNA” (paragraphs [0179], [0171]). Alterman further teaches that “multiple adjacent branches (e.g., 2 or 3) allow each branch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release” (paragraph [084]). It would have been obvious to an artisan that the efficacy of an siRNA could be enhanced by replacing the single siRNA with a branched RNA compound comprising the siRNA, based on the teachings of Alterman. It thus would have been obvious to said artisan to use the branched RNA structures taught by Alterman instead of the single dsRNA of Hashimoto or Khvorova, designed such that the branched RNA structures comprise the dsRNA sequences of Hashimoto, in order to enhance the tissue distribution and retention, internalization, trafficking, and release properties of the dsRNA compositions of Hashimoto and Khvorova.
Conclusion
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636