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
Election/Restrictions
Applicant's election without traverse of Group I in the reply filed on 10/14/2025 is acknowledged.
Status of the Application
Claims 199-214 and 219-222 are pending and are currently under examination.
Information Disclosure Statement
The submission of the Information Disclosure Statements on 09/25/2023 and 10/14/2025 is in compliance with 37 CFR 1.97. The information disclosure statements have been considered by the examiner and signed copies have been placed in the file.
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 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.
Claim(s) 199-207, 214 and 219 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Behlke, Mark A. ("Chemical modification of siRNAs for in vivo use." Oligonucleotides 18.4 (2008): 305-320).
The claims are interpreted as a double stranded RNA having two strands complementary to each other less than 100 nucleotides, comprises modified nucleotides and can have overhang regions. The preamble of and ADAR recruiting molecule is not accorded patentable weight because a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951).
Regarding claims 199-206, 214 and 219, Behlke et al. teach a double stranded RNA comprising two complementary strands less than 100 nucleotides in length where the strands comprise terminal base pairs between the complementary strands, overhang regions on at least one strand, phosphorothioate modifications, backbone modifications within 1-5 of a terminal nucleotide, 2’OMe modifications and base pair modifications (see Table 1).
Regarding claim 207, Behlke et al. teach the double stranded RNA can further comprising a moiety such as a alpha-tocopherol (vitamin-E) attached to the end of the strand.
Thus Behlke et al. anticipates the instant claims.
Claim(s) 199-210, 214 and 219-221 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Doudna et al. (US 20190276842 of record cited on IDS 09/25/2023).
Regarding claims 199, 200, 204 and 205, Doudna et al. discloses an adenosine deaminase acting on ribonucleic acid (RNA) (ADAR) recruiting molecule (para [0149] comprising two complementary stretches of nucleotides that hybridize to one another to form a double stranded RNA duplex [0129] wherein the RNA includes two complementary stretches of nucleotides that hybridize to one another to form a double stranded RNA duplex, comprises two strands of RNA of an equal number of nucleotides of 19 nt in length [0159]. This meets the limitation of a terminal base pair between complementary nucleotides of the two RNA strands. Doudna teach the two RNA strands are not connected to one another by means of a hairpin [0170] and at least one RNA strand of the double stranded RNA duplex comprises at least one nucleoside modification and/or at least one backbone modification [0241] and further teach in some cases, not all nucleotides of the duplex region are paired, and therefore the duplex forming region can include a bulge (e.g., see FIG. 6, panel c, and FIG. 7) (i.e. base pair mismatches).
Regarding claims 201 and 202, Doudna et al. teach suitable nucleic acid modifications include, but are not limited to 2-'O-o
7methyl modified nucleotides, 2' Fluoro modified nucleotides, locked nucleic acid (LNA) modified nucleotides, peptide nucleic acid (PNA) modified nucleotides, nucleotides with phosphorothioate linkages [0242].
Regarding claim 203, Doudna et al. teach the base modification can be placed anywhere except the 3’ end and thus encompasses positions with 1-5 of the terminal end [0245].
Regarding claim 206, the double stranded molecule can have an overhang on the 3’ end of a strand in the duplex [0493].
Regarding claim 207, Doudna et al. teach vectors can be used with the RNA [0225] and thus meets the limitations of “a moiety” as broadly claimed.
Regarding claims 208, 209, 214, the double stranded RNA duplex can be linked to a single stranded guide nucleic acid via a linker wherein the single stranded guide RNA can have a length of 3 to 100 ([0153] and Fig. 6).
Regarding claim 210, Doudna et al. do not teach the single guide RNA is modified so therefore it would have all consecutive non-modified nucleotides and would meet the limitations of the claim.
Regarding claim 219 and 220, Doudna et al. teach the double stranded RNA duplex comprises at least one base pair mismatch, wherein the mismatch is not positioned at either terminal nucleotide base pair of the double-stranded RNA duplex [0161].
Regarding claim 221, Doudna et al. teach a first double-stranded RNA duplex comprising two RNA strands, a second double-stranded RNA duplex comprising two RNA strands and a single-stranded guide nucleic acid [0149, 0416].
Regarding claim 222, Doudna et al. teach an RNA targeting molecule for use when targeting ssRNA target nucleic acids include RNA editing enzymes (e.g., RNA deaminases, e.g., adenosine deaminase acting on RNA (ADAR) comprising: a double-stranded RNA duplex comprising two RNA strands that hybridize to one another to form a double stranded RNA duplex (dsRNA duplex") and a first single-stranded guide nucleic acid a second single-stranded guide nucleic acid and a linker wherein the first single-stranded guide nucleic acid is connected to the second single-stranded guide nucleic acid via the linker (para [0149, 0153, 202 and 416]
Thus Doudna et al. anticipates the instant claims.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 211-213 is/are rejected under 35 U.S.C. 103 as being unpatentable over Doudna et al. (cited above) and Qu et al. ("Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs." Nature biotechnology 37.9 (2019): 1059-1069 cited on IDS 10/14/2025).
Doudna et al. is relied up as above but does not teach the guide RNA has at least one of the three consecutive non-modified nucleotide pairs with a nucleotide adjacent to a target adenosine or the nucleotide opposite the target adenosine comprising a cytosine.
Regarding clams 211-213, Qu et al. teach using endogenous ADAR recruiting RNAs for RNA editing in cells and teach the recruiting molecule comprises comprises sequences complementary to the target transcripts all contain a CCA opposite to the UAG codon so as to introduce a cytidine (C) mis-pairing with the adenosine (A) because adenosine deamination preferentially occurs in the A-C mismatch site (see page 1059 last para to page1060).
It would have been obvious to one of skill in the art to incorporate this sequence into the recruiting molecule taught by Doudna et al. given Qu et al. teach adenosine deamination preferentially occurs in the A-C mismatch. One of skill in the art would have been capable of incorporating this sequence into of the consecutive non-modified nucleotides as taught by Doudna et al.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
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 208, 209, 213, 221 and 222 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 pre-AIA the applicant regards as the invention.
Claim 208 recites "further comprising a linker". This limitation is indefinite because it is unclear what the linker is connecting or where the linker is attached to the RNA duplex. The claim is interpreted as found in the prior art above.
Claim 209 recites "further comprising a single-stranded guide nucleic acid". This limitation is indefinite because it depends from claim 199 and is unclear if the single stranded guide RNA is complementary to any strand of the RNA duplex. Claim 199 is drawn to just a RNA duplex and not a composition comprising the RNA duplex and thus it is unclear how a RNA duplex can further comprise a single stranded guide RNA. This claim is interpreted as it can be linked to the RNA duplex region.
Claim 213 is indefinite because it recites “a nucleotide opposite a target adenosine” and lacks antecedent basis because it depends from claim 212 which recites the nucleotide and the target adenosine. It is unclear if this claim recites a different nucleotide and target. The claim is interpreted as is the same nucleotide and target as in claim 212. The claim is also indefinite because the nucleotide opposite the target adenosine is the middle nucleotide of the three consecutive non-modified nucleotides and it is unclear how in step b) and c) the nucleotide can also be modified.
Claim 221 is indefinite because it is unclear how the additional double stranded duplex and single stranded guide RNA are configured with the double stranded RNA duplex of claim 199. It is unclear if they attached via an additional linker or complementary to each other. The claim is interpreted as found in the prior art above.
Claim 222 is indefinite because it is unclear how the first and second single-stranded guide RNA are configured with the double stranded RNA duplex of claim 199. It is unclear if they attached via an additional linker or complementary to each other. The claim is interpreted as found in the prior art above.
If Applicant presents a claim interpretation that is different than posited by the Examiner, that will not prevent the next Office Action from going Final if new claim rejections are necessary due to the new claim interpretation.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 199-214 and 219-222 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “…disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” Thus when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The claims are drawn to a genus of double stranded RNAs comprising backbone and sugar modifications, mismatched base pairs, overhang regions, linkers and attached single and double stranded guide RNAs with the function of editing any target gene.
The specification describes these double stranded duplexes recruit RNA editing enzymes such as ADAR and describe examples of double stranded RNA duplexes with base pair mismatches in Table A, and show in Table 1 editing efficiencies of oligo compositions targeted against a single GAPDH gene.
The specification and claims do not indicate what distinguishing characteristics of the oligo compositions in Table 1 are concisely shared by the members of the broad genus comprising backbones and sugar modifications, mismatched base pairs, overhang regions, linkers and attached single and double stranded guide RNAs that would convey to one of skill in the art that these RNA duplexes represent the entire genus that would be capable of editing any gene in a cell or subject. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination.
The prior art of Qu et al. ("Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs." Nature biotechnology 37.9 (2019): 1059-1069 cited on IDS 10/14/2025) describes exploiting endogenous ADAR for RNA editing by fusing the deaminase domain of the hyperactive E1008Q mutant ADAR1 (ADAR1DD)41 to the catalytic inactive LbuCas13 (dCas13a), a RNA guided RNA-targeting CRISPR effector42 (Supplementary Fig. 1a) and assessed the RNA editing efficiency EGFP gene (see page 1059 results – page 1060). Qu et al. teach the sequences complementary to the target transcripts all contain a CCA opposite to the UAG codon so as to introduce a cytidine (C) mis-pairing with the adenosine (A) (Supplementary Fig. 1b) because adenosine deamination preferentially occurs in the A-C mismatch site. The prior art does not describe using any double stranded RNA comprising modified backbones and sugar modifications, mismatched base pairs, overhang regions, linkers and attached single and double stranded guide RNAs, as claimed, that would be capable of exploiting endogenous ADAR and edit any target gene.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant comprising a vast number double stranded duplexes comprising modified backbones and sugar modifications, mismatched base pairs, overhang regions, linkers and attached single and double stranded guide RNAs, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Further, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every double stranded duplex comprising any modified backbones and sugar modifications, mismatched base pairs, overhang regions, linkers and attached single and double stranded guide RNAs with the function of recruiting endogenous ADAR and editing any target gene.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636