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 with partial traverse of claims 1-7 and 9-19 with species election of SEQ ID NO:1, sgRNA, nanoparticle, and SEQ ID NO:16 in the reply filed on January 9, 2026 is acknowledged. The traversal is on the ground(s) that it would be “an unnecessary burden” on applicant and the Office to prosecute different SEQ ID NOs in separate applications as they all target ADAR1p110 and provide the same result. This is not found persuasive because the possibility that applicant needs to file separate applications for different SEQ ID NOs is not a criterion for restriction/election requirement under 371 in national stage applications. In addition, although SEQ ID NOs:14-36 and 100-107 may target the same gene, there is no evidence that the different SEQ ID NOs share the same, substantial nucleotide sequence that is responsible for providing the intended result. In fact, applicant’s elected SEQ ID NO:16 shares no sequence identity with SEQ ID NO:15 when the two 21-mer sequences are aligned from the 5’ end to the 3’ end. The two sequences do share a 6-mer sequence only when the alignment is shifted significantly such that nucleotide positions 14-19 of SEQ ID NO:16 match with nucleotide positions 7-12 of SEQ ID NO:15. Hence, the different SEQ ID NO species do not share the same technical feature, which is the same, core nucleotide sequence.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 1, 5-7, 9-17, 19, and 22-24 are currently pending in the instant application. Claims 22-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 1, 5-7, 9-17, and 19 are under examination on the merits in the instant application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application Nos. 63/129,878, 63/151,093, and 63/203,303, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The aforementioned provisional applications are deficient in adequately describing the instantly claimed aRNA having all structural limitations including but not limited to the complementary nucleotide lengths, target SEQ ID NOs, and/or the aRNA SEQ ID NOs. Since Application No. 63/285,311 appears to be first prior-filed application describing the aRNA being claimed in the instant application, the priority benefit for claims 1, 5-7, 9-17, and 19 is granted only to the ‘311 filing date, which is December 2, 2021.
Claim Rejections - Improper Markush Grouping
Claims 1, 5-7, 9-17, and 19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use.
Note that the instant rejection is judicially approved as set forth in “Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. 112 and for Treatment of Related Issues in Patent Applications” in Federal Register, Volume 76, Number 27, published on February 9, 2011, which expressly states the following:
“A Markush claim contains an “improper Markush grouping” if: (1) The species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use…When an examiner determines that the species of a Markush group do not share a single structural similarity or do not share a common use, then a rejection on the basis that the claim contains an “improper Markush grouping” is appropriate.” See page 7166, middle column.
Note that “the phrase "Markush claim” means any claim that recites a list of alternatively useable species regardless of format.” See MPEP §2173.05(h).
The three alternative target sequence species of SEQ ID NOs:1-3 recited in all claims under examination on the merits in the instant case are improper because the SEQ ID NOs:1-3 do not share any nucleotide sequence similarity. In fact, Table 3 of the instant specification makes it clear that all three sequences are those of distinct, non-overlapping regions of ADAR1 p110.
The alternative therapeutic RNA species of mRNA, miRNA, sgRNA, aRNA, iRNA, and ASO recited in claim 14 are improper because the different RNAs do not all share a single structural similarity, nor do they all share a single common function. For instance, an mRNA has a function of encoding a protein, whereas an ASO has a function of inhibiting an mRNA, thereby inhibiting the expression of a protein
The alternative delivery vehicle species of an antibody, a scFv, a peptide, GalNAc, an aptamer, and a nanoparticle recited in claim 16 do not share a single structural similarity as evidenced by the fact that an antibody comprises amino acids, whereas GalNAc is a sugar moiety.
The Markush grouping of antisense oligonucleotide sequence species of SEQ ID NOs:14-36 and 100-107 recited in claim 19 is improper because the alternatively recited different SEQ ID NOs do not share the same, substantial nucleotide sequence that is responsible for providing the intended result. For instance, applicant’s elected SEQ ID NO:16 shares no sequence identity with SEQ ID NO:15. In fact, Table 4a of the instant specification makes it clear that not all SEQ ID NOs recited in claim 19 are targeted to the same target region such that SEQ ID NO:16 is targeted to SEQ ID NO:1, whereas SEQ ID NO:15 is targeted to SEQ ID NO:3.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
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 1, 5-7, 9-17, and 19 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 instant claims recite “an antisense oligonucleotide sequence that is 19 to 30 nucleotides in length and that is complementary to 21 to 22 nucleotides in a target sequence”.
It is unclear how a 19-mer can possibly be complementary to 21-22-mer target sequence. That is, the minimum length of the target sequence that can be complementary to a 19-mer antisense oligonucleotide is 19 nucleotides. As such, the claims recite conflicting structural limitations that are impossible and incompatible with each other, thereby rendering the metes and bounds of the claimed antisense oligonucleotide indefinite.
Claim 6 recites the limitation "the antisense sequence" in line 1. There is insufficient antecedent basis for this limitation in the claim.
In addition, claim 6 recites that “the antisense sequence is at least 80% complementary to a target sequence.” It is noted that claim 6 inherently recites all limitations of claim 1 by virtue of claim dependency, thereby inherently requiring that “the antisense sequence” (interpreted as the “antisense oligonucleotide sequence”) should be “complementary to 21 to 22 nucleotides in a target sequence”. It is further noted that the term “complementary” in claim 1 is not recited with any complementarity percentages less than 100% hence, the phrase “complementary to 21 to 22 nucleotides in a target sequence” inherently implies a perfect target sequence complementarity level. Hence, claim 6 recites structurally conflicting limitations (fully complementary vs. at least 80% complementary) regarding the complementarity levels between the antisense oligonucleotide sequence and the target sequence, thereby rendering the claim indefinite.
For examination purpose, the complementarity level will be interpreted as that the antisense oligonucleotide of at least 19 nucleotides being fully complementary to 19-22 nucleotides in length in the target sequence.
Claim 14 recites that the aRNA of claim 1 is linked to a therapeutic RNA that is “aRNA”. As currently written, it is unclear whether the additional “aRNA” in claim 14 should be the same or different from the aRNA of claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claims 1, 5-7, 9-17, and 19 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the interest of compact prosecution, the intended use/function recited in the product claims pertaining to “upregulates expression of ADAR” is given full patentable weight.
The instant claims are broadly drawn to an activating RNA (aRNA) that “upregulates expression of ADAR”, wherein the aRNA has the structure of nucleotide sequence complementarity to SEQ ID NO:1, wherein the aRNA is up to 30 nucleotides in length and is complementary to 19-22 nucleotides in SEQ ID NO:1.
It is noted that the instant specification at best discloses single-stranded antisense oligonucleotides of 21 nucleotides in length, wherein only the first 19-mer is fully complementary to the target sequence with the 2-nt 3’-overhang sequence of UU at positions 20-21. See Tables 4a-4b. Regarding a double-stranded aRNA structure, the specification at best discloses duplexes targeting “ADARp150” regions of SEQ ID NOs:4-7, which are distinct from the instantly claimed target “ADARp110”, especially SEQ ID NO:1 elected by applicant. Hence, pertaining to the instantly claimed genus targeting ADARp110, the instant specification at best discloses single-stranded 21-mer antisense RNAs comprising 2-nt 3’-overhang sequence of UU at positions 20-21, wherein the RNAs are SEQ ID NOs:14-37 and 100-107. This limited number of nucleotide sequence species of the same length is not representative of the entire genus of aRNA oligonucleotides that are claimed to be up to “30 nucleotides”, nor is the single-stranded structure representative of a double-stranded aRNA structure encompassed by the claims, wherein the aRNA is required to upregulate ADAR expression because the recited function of undisclosed aRNA species cannot be extrapolated from the disclosed aRNAs of SEQ ID NOs:14-37 and 100-107 in view of the art-recognized unpredictability of aRNA, also known as saRNA. For instance, Wagner et al. (WO 2016/170349 A1) demonstrate that only a few saRNAs show a statistically significant, scientifically meaningful upregulation of the target, CEBPA, mRNA expression when actually tested in vitro in DU145 cells compared to the negative control of “scramble”. See Figure 6A. See also Wu et al. (International Journal of Oncology, 2016, 49:1620-1628) demonstrating that double-stranded saRNAs designed to be complementary to an E-cadherin target sequence do not all provide E-cadherin mRNA expression upregulation. In fact, Wu shows that when four different saRNAs targeting four different regions of the target sequence were experimentally tested, only one saRNA showed target mRNA upregulated compared to negative controls (“Mock” and “dsCon”) in two cell lines in vitro. See Figure 1B. Similarly, Li et al. (International Journal of Oncology, 2018, 52:1815-1826) show that when dsRNAs targeting two regions of the E-cadherin promoter sequence, wherein the two regions are not tested by Wu, only one dsRNA provided upregulated in E-cadherin mRNA expression in T24 and 5637 cell lines. See Figures 1A-1B. See also Zeng et al. (Urolithiasis, 2018, 46:271-278) showing that only one saRNA is shown to upregulate target protein expression level compared to the negative control (“ds-NC”) when a total of five saRNAs were synthesized and tested. See Figure 1B. See also page 273 disclosing that “saRNA ds-320 could significantly increase the expression of TRPV5 whereas the other dsRNAs had no obvious effect on TPRV5 expression.” Indeed, the prior art knowledge disclosed by and gleaned from Wagner, Wu, and Li has remained unchanged for years as evidenced by Tan et al. (US 2024/0175033 A1) demonstrating the same or similar findings as disclosed by Wagner, Wu, Li, and Zeng such that the target-specific saRNA activity in upregulating target expression cannot be predicted unless actually tested in cells. See Figure 2 showing that only a few saRNAs upregulated the target, TMEM173, mRNA expression in HepG2 cells in vitro. As broadly written, the claimed aRNA reads on a 30-mer sequence that is fully complementary to only a 19-mer in SEQ ID NO:1 (see the claim interpretation in §112(b)), thereby having only about 63% sequence complementarity with SEQ ID NO:1. Since the actual function of target upregulation by aRNAs was not deemed predictable merely based on the nucleotide sequence as evidenced by Wagner, Wu, Li, Zeng, and Tan as explained above, the ADAR expression upregulation function recited in the claims would not have been reasonably extrapolated for a 30-mer comprising SEQ ID NO:16, applicant’s elected species, wherein the 30-mer has only about 63% sequence complementarity with SEQ ID NO:1. That is, the instant specification fails to describe the requisite structure-function correlation for the entire genus of aRNAs encompassing the recited length range.
In view of the foregoing, it is concluded that the instant specification fails to adequately describe the entire genus encompassing a myriad of structurally diverse aRNAs as now claimed in such a manner to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought or granted in the instant application.
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.
A person shall be entitled to a patent unless –
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 1, 5-7, 9-12, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by MacLachlan et al. (US 2014/0161894 A1).
See the claim interpretation set forth in the §112(b) rejection.
MacLachlan discloses a 23-mer RNA of SEQ ID NO:14479 comprising at least 19 nucleotides complementary to nucleotide positions 66-87 of SEQ ID NO:1 claimed in the instant case. See MacLachlan’s SEQ ID NO:14479 as reproduced below, which is obtained by following the instructions provided at page 29.
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Although the sequence of SEQ ID NO:14479 is shown as DNA, it is prima facie apparent that the 23-mer sequence is to represent an “RNA” sequence as evidenced by the fact that the sequence is identified as an “siRNA” sequence in “OTHER INFORMATION”.
MacLachlan teaches making a double-stranded siRNA comprising SEQ ID NO:14479, wherein each strand can be 19-21 nucleotides comprising a modified nucleotides (e.g., 2’-O-methyl ribonucleotide”) with 3’-overhang sequences of 2 nucleotides in length. See paragraphs 0017 and 0026.
MacLachlan teaches that the siRNA can be in “lipid nanoparticle formulation” or in “liposomes” and can be conjugated to a peptide or a dye. See paragraphs 0130, 0191, and 0338.
Since the RNA sequence corresponding to MacLachlan’s SEQ ID NO:14479 or 19-21 fragments thereof fully satisfies all of the structural limitations set forth in the instant claims, it necessarily follows that MacLachlan’s RNA either in the single-stranded form or the double-stranded form is deemed to possess the function/activity of an “ADAR aRNA”, absent objective evidence to the contrary.
“[T]he patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure.” Catalina Mkt. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002). That is, “[f]rom the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing.” In re Papesch, 315 F.2d 381, 391 (CCPA 1963).
Accordingly, claims 1, 5-7, 9-12, and 15-17 are described by MacLachlan et al.
Claims 1, 5-7, 9-10, 12, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brown et al. (US 2013/0109740 A1).
Brown discloses a 27-mer RNA oligonucleotide of SEQ ID NO:7374, which is reproduced below, which is obtained by following the instructions provided at page 436.
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It is noted that Brown’s SEQ ID NO:7374 is complementary to 22 nucleotides within positions 11-36 of SEQ ID NO:1 claimed in the instant case.
Brown teaches making a double-stranded RNA (dsRNA) comprising SEQ ID NO:7374 and a complementary sequence thereof. See paragraph 0046.
Brown teaches that the two strands of the dsRNA each comprise modified nucleotides such as 2’-O-methyl modified RNA with a 2-nt 3’-overhang. See paragraphs 0062-0063.
Brown teaches that the dsRNA is linked to “an effective delivery vehicle (e.g., an effective lipid nanoparticle formulation)” or linked/conjugated to a peptide or is encapsulated in polymeric “nanocapsules”. See paragraphs 0130, 0192, and 0338.
Since Brown’s SEQ ID NO:7374 or Brown’s dsRNA comprising SEQ ID NO:7374 fully satisfies all of the structural limitations set forth in the instant claims, it necessarily follows that Brown’s RNA either in the single-stranded form or the double-stranded form is deemed to possess the function/activity of an “ADAR aRNA”, absent objective evidence to the contrary.
Accordingly, claims 1, 5-7, 9-10, 12, and 15-17 are described by Brown et al.
Claims 1, 5-7, and 9-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Saetrom et al. (WO 2016/170348 A2, applicant’s citation).
Saetrom teaches making an saRNA that is targeted to the sequence upstream of the TSS of a target gene (e.g., ADAR1) and upregulates the expression of the target gene and the saRNA can comprises 3’ overhangs of 2 nucleotides and a thiophosphate linkage modification. See paragraphs 0059-0065, 0090, 0098-0101, and 00448; Table 1; claims 1, 29, and 33-36; FIG. 1.
Saetrom discloses a small activating RNA (saRNA) comprising SEQ ID NO:6284 (5’-UUUGGAAAGCUACGGAAUA) complementary to nucleotide positions 299-317 of SEQ ID NO:1 claimed and elected by applicant.
Saetrom teaches that the saRNA can be “double-stranded” and also discloses a sense strand sequence of SEQ ID NO:6285 (5’-UAUUCCGUAGCUUUCCAAA). See paragraphs 0018 and 0070-0072.
Saetrom teaches that the saRNA can be contiguously linked to “the sequence of a miRNA”. See paragraph 0092.
Saetrom teaches that the saRNA can be formulated and encapsulated in a “nanoparticle” comprising “lipids”. See paragraphs 00258-00267.
Accordingly, claims 1, 5-7, and 9-17 are described by Saetrom et al.
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 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a fragment of a product of nature without significantly more. The claim recites a single-stranded RNA sequence that is 19 nucleotides in length (see the claim interpretation in the §112(b) rejection), wherein the RNA sequence is not claimed to be artificially modified, thereby reciting a fragment of naturally occurring RNAs. It is noted that SEQ ID NO:16 elected by applicant is an antisense RNA sequence wherein the first 19-mer is complementary to a 19-mer sequence in SEQ ID NO:1. Now, Lee et al. (US 2017/0037396 A1) disclose a polycomb-associated long non-coding human RNA sequence of SEQ ID NO:622464, which comprises the entire first 19-mer sequence of SEQ ID NO:16 at positions 26616-26634. Further, Hatchwell et al. (US 2018/0223360 A1) disclose SEQ ID NO:1508 identified as a human ADAR gene transcript variant 1 mRNA sequence (NM_001111), which comprises the first 19-mer of SEQ ID NO:16 at positions 24606-24624. Hence, it is clear that a 19-mer RNA satisfying the claimed structural limitations in claim 1 is a part of naturally occurring RNAs, human lncRNA and human mRNA as evidenced by Lee and Hatchwell.
The instantly claimed judicial exception is not integrated into a practical application because there is no additional structural limitation that alters the naturally occurring RNA sequence into a non-naturally occurring RNA sequence. The recitation of the intended use/function in claim 1 for the claimed RNA is not sufficient to render the claimed structure as not being a fragment of a naturally occurring lncRNA or mRNA, and the claim does not include any additional structural elements that are sufficient to amount to significantly more than the judicial exception because claim 1 does not recite any significant structural modification introduced to the RNA of claim 1 so as to render the RNA of claim 1 significantly structurally different from a naturally occurring RNA or a fragment thereof.
See Univ. Of Utah Research Found. v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014) decided on December 17, 2014, wherein the Federal Circuit ruled that synthetic primers do not have a different structure from naturally occurring nucleic acids thus patent ineligible under §101. See also the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (June 13, 2013).
Accordingly, claim 1 is not found patent eligible under §101.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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