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 .
Application Status
The preliminary amendment filed September 1, 2023 is acknowledged. Claims 184-202 are pending and under examination.
Claim Objections
Claim 194 is objected to because of the following informalities:
Claim 194 recites an oligonucleotide comprising an antisense of SEQ ID NO: 1145 and further comprising a sense strand of SEQ ID NO: 1055, wherein: the antisense comprises [the exact structure of SEQ ID NO: 1145 as defined in the sequence listing] and the sense strand comprises [the exact structure of SEQ ID NO: 1055 as defined in the sequence listing]. Providing both the SEQ ID NO and the exact structure as defined in the sequence listing of the SEQ ID NO is repetitive. If is suggested that the sequence-structure be removed from the claim. If Applicant desires to have the exact sequence-structure recited in the claim, then it is suggested to move the SEQ ID NOs to end of the corresponding sequence-structure and placed in parentheses.
Appropriate correction is required.
Claim Rejections - 35 USC § 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 186-188, 190-191, 193 and 195-202 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 186-188 recite the oligonucleotide of claim 184 [186], where the sequence strand comprises at its 3’ end a stem-loop set forth as S1-L-S2 [wherein L is a tetraloop of GAAA], wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length. Claim 184 requires the sense strand to comprising SEQ ID NO: 875, which is aauuaucagcuuaaaauuaaGCAGCCgaaaGGCUGC. The underlined sequence meets the criteria of the S1-L-S2. The GAAA tetraloop is bolded. The six capitalized nucleotides on either side of the bolded tetraloop are an inverted repeat and thus are complementary to each other. Therefore, the sense oligonucleotide required in claim 184 already has the features recited in claims 186-188. It is not clear if claims 186-188 require an additional S1-L-S2 structure. If this is the case, claim 186 should recite “wherein the sense strand further comprises”. If claims 186-188 merely recite features that are already present in the sense oligonucleotide, then they would not further limit claim 186 (see § 112(d) rejection below).
Claims 190-191 recite oligonucleotide positions comprising modifications “preferably” at specific positions. The use of “preferably” renders the claim indefinite because it is unclear whether the limitation(s) that follow “preferably” are part of the claimed invention. See MPEP § 2173.05(d).
Claim 193 recites “The oligonucleotide of claim 184, where at least one nucleotide is conjugated to one or more targeting ligands, optionally, where the one or more targeting ligands is a saturated or unsaturated fatty acid moiety. Claim 184 already requires the oligonucleotide to comprise an C18 fatty acid to the 5’ end of the oligonucleotide. According to the Specification, fatty acids such as C18 function as a targeting ligand ([00319], Table 4). It is not clear if claim 193 requires an additional targeting ligand. If this is the case, claim 193 should recite “wherein the oligonucleotide further comprises at least one nucleotide conjugated…” or recite a targeting ligand other than a genus in which C18 falls under.
Claims 195-196, 199, and 202 recite “the oligonucleotide or oligonucleotide-lipid conjugate of claim 184”. Claim 184 recites an oligonucleotide… compris[ing] a saturated C18 hydrocarbon conjugated to the 5’ terminal nucleotide”. It is not clear which or both of “the oligonucleotide” and “oligonucleotide-lipid conjugate” are referring to the C18-siRNA oligonucleotide of claim 184. If claims 195-196, 199 and 202 are using both terminologies “the oligonucleotide” and “oligonucleotide-lipid conjugate” to refer to the same molecule, then it is very confusing as it is not clear why the claims would use both terminologies. If the claims 195-196, 199 and 202 are using “oligonucleotide-lipid conjugate” to refer to the C18-siRNA molecule and “the oligonucleotide” only to refer to the nucleic acid portion of the molecule (and not the C18 moiety) then the claims would not include all the limitations of the claim from which they depend (see § 112(d) rejection below).
Claims 197-198 and 200-201 are rejected for depending from claims 196 and 199 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(d)
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 186-188, 193 and 195-202 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.
As indicated above in the rejections under §112(b), claims 186-188, 193 and 195-202 recite subject matter that could be interpreted as already provided in claim 184 or not encompassed by claim 184. The following rejections are directed to those interpretations.
Claims 186-188 recite the oligonucleotide of claim 184 [186], where the sequence strand comprises at its 3’ end a step-loop set forth as S1-L-S2 [where in L is a tetraloop of GAAA], wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length. Claim 184 requires the sense strand to comprising SEQ ID NO: 875, which is aauuaucagcuuaaaauuaaGCAGCCgaaaGGCUGC. The underlined sequence meets the criteria of the S1-L-S2. The GAAA tetraloop is bolded. The six capitalized nucleotides on either side of the bolded tetraloop are an inverted repeat and thus are complementary to each other. Thus, claims 186-188 merely recite features that are already present in the sense oligonucleotide. As such, claims 186-188 do not further limit the subject matter of claim 186.
Claim 193 recites “The oligonucleotide of claim 184, where at least one nucleotide is conjugated to one or more targeting ligands, optionally, where the one or more targeting ligands is a saturated or unsaturated fatty acid moiety. Claim 184 already requires the oligonucleotide to comprise a saturated C18 fatty acid to the 5’ end of the oligonucleotide, which, according to the Specification, already functions as a targeting ligand ([00319], Table 4). Thus, claim 193 does not further limit the subject matter of claim 184, from which it depends.
Claims 195-196, 199, and 202 recite “the oligonucleotide or oligonucleotide-lipid conjugate of claim 184”. Claim 184 recite an oligonucleotide… compris[ing] a saturated C19 hydrocarbon conjugated to the 5’ terminal nucleotide”. Thus claim 184 requires a C18-siRNA lipid-nucleic acid conjugated. Under the interpretation that claims 195-196, 199 and 202 are using “oligonucleotide-lipid conjugate” to refer to the C18-siRNA molecule and “the oligonucleotide” only to refer to the nucleic acid portion of the molecule (and not the C18 moiety), the claims do not necessarily require the C18-siRNA lipid-nucleic acid conjugate. As such claims 195-202 do not require all the limitations claim 184, namely the C18-siRNA lipid-nucleic acid conjugated.
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 § 112(a)
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 196 and 199 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancers that have overexpressed or constitutively-activated STAT3, does not reasonably provide enablement for the treatment of any disorder or disease that is “associated with STAT3 expression”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use and/or practice the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of Claims
Claims 196 and 199 are drawn to a composition for use in methods of treatment, and a method for treatment of “a subject having a disease, disorder or condition associated with STAT3 expression”. The specification does not provide a limiting definition or description of “associated with STAT3 expression”, and is interpreted as being extremely broad, encompassing the range of no expression to overexpression of STAT3. A disease that has symptoms caused by reduced levels of STAT3 expression, would be considered by one skilled in the art “a disease associated with STAT3 expression.” Accordingly, enablement of the method requires one skilled in the art to be able to use the claimed STAT3 oligonucleotide to treat disorders that have both increased or decreased levels of STAT3 expression.
Guidance in the Specification
The specification teaches that STAT3 is an important transcription factor that is crucial for the maintenance of carcinogenesis and for chemoresistant to anticancer agents ([0012]). Specifically, activated STAT3 regulates the transcription of gene controlling cell survival and proliferation and is necessary for proliferation and survival of different cancers ([0011]). The specification lists various cancers that could be treated with STAT3-targeting siRNAs ([0011]) and cites to da Hora that teaches the inhibition of STAT-3 in different cancer types has been demonstrated to induce apoptosis and chemosensitization of cells ([0012]). As working examples, the Specification provides STAT3-inhibiting oligos to pancreatic tumors (Examples 8 and 9), in Huh7 cultured cells (example 11), and hepatocytes (Example 12).
Applicant does not attempt to treat any subjects with cancer with the claimed oligonucleotide or treat any other disease that can be interpreted as “associated with STAT3 expression” including diseases in which STAT3 is under expressed. Accordingly, in light of the specification, it is highly unpredictable how one skilled in the art would use the S TAT3-targeting oligos to treat the genus of diseases, disorders and conditions as claimed.
State of the Prior Art
The prior art provides ample evidence for using inhibitory RNAs like siRNAs for treating cancers in which STAT3 is overexpressed of constitutively activated. See e.g., Wang et al., MedComm (2022), 3(2): e124). However, there is no evidence in the art for using siRNAs for other non-cancer diseases that are associated with STAT3 expression.
Ott describes the state of the art of STAT3-associated diseases and treatments thereof approximately two years after the effective filing date of the claimed invention (Ott et al., Journal of Clinical Immunology (2023), 43: 1326-1359). Ott explains that STAT expression and activation balance is central to immune homeostasis: too much STAT signaling can lead to autoimmunity, whereas too little STAT signaling leads to immunodeficiency (Fig 2; page 1327, ¶4). STAT3 haploinsufficiency can cause invasive fungal infections (page 1329, ¶2). Patients with loss-of-function (LOF) mutations in ZNF341 significantly reduce STAT3 expression and cause hyper-IgE syndrome (HIES) which is characterized by pneumonia, recurrent staphylococcal infections and arthritis (page 1331 through ¶1 of page 1333). Importantly, Ott explains that no therapy for HIES exists (page 1333, ¶3).
Thus, in view of the prior art, it would be highly unpredictable how one skilled in the art would treat disorders caused by STAT3 haploinsufficiency or caused by mutations in other genes that are necessary for the expression of activation of STAT3.
Experimentation Required
In order to practice the invention, one skilled in the art would need to develop a means to bypass reduced STAT3 expression to activate expression of the genes that STAT3 normally activates. As the claimed oligonucleotides are directed to sequences specifically found in STAT3 transcripts it is entirely unknown what other steps or compositions would be needed to use a STAT3-inhibiting oligonucleotide to increase expression of genes that STAT3 normally activates. Thus, the experimentation needed to determine those steps/compositions is entirely undue.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of treating the genus of diseases with STAT3-targeting siRNAs, it is the conclusion that an undue experimentation would be required to make and use the invention across its entire claimed scope, which includes disease, disorders and conditions that do not have overexpressed or constitutively activated STAT3.
Claim Rejections - 35 USC § 103
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.
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.
Claims 184, 186-191, 193, 195-202 are rejected under 35 U.S.C. 103 as being unpatentable over Schutz (Schutz et al., Translational Oncology (2015), 8: 97-105) as evidenced by GPP Web Portal (Construct: shRNA TRCN0000071456, GPP Web Portal, Broad Institute, https://portals.broadinstitute.org/gpp/public/clone/details?cloneId= TRCN0000071456) in view of Gatta (Gatta et al., Expert Opinion on Drug Discovery (2018), 13: 709-725), Brown (US 20170306332 A1), Kubo (Kubo et al., ACS Chemical Biology (2020), 16: 150-164), Zhou (Zhou et al., Molecular Therapy-Nucleic Acids (2012), 1, e17), and Genbank (NM_001369512.1, STAT3 transcript variant 4, mRNA, https://www.ncbi.nlm.nih.gov/nuccore/1610577039, [retrieved April 20, 2026]).
Regarding claim 184, Schutz teaches an shRNA called TRCN0000071456 (i.e., an oligonucleotide) that successfully reduces STAT3 expression (page 98, ¶8; Fig. SA). Schutz teaches that STAT3 is "constitutively activated in the majority of lung cancer" (Abstract; see also Discussion). Schutz teaches that STAT3 should be further evaluated as a potential target for individualized tumor treatment (pg. 104, ¶1-2). Schutz is silent as to the sequence of the shRNA targeting STAT3. GPP Web Portal teaches the sequence of Schutz's shRNA (i.e., TRCN0000071456) is 5'-CCGG-CCTGAGTTGAATTATCAGCTT-CTCGAG-AAGCTGATAATTCAACTCAGG-TTTTTG-3' (page 4).
Schutz does not teach an siRNA duplex with sequences of SEQ ID NO 965 and 875, which could be modified at the 5’ terminal nucleotide of the sense strand with a lipid moiety, a 3’ overhand dinucleotide, and comprising modified nucleotides and modified antinucleotide linkages.
Gatta teaches that for therapeutic purposes, siRNA is preferred over shRNAs as "the shRNA has to be cloned into a viral vector ... [and] [t]here are vector-related toxicity issues" [and] [t]he shRNA could trigger IFN responses and it is less specific" (Section 9). Gatta teaches the structures of siRNAs and means to prepare siRNAs were well known (see at least pg. 709-710; Tables 1-2). Gatta teaches the following criteria are recommended for designing siRNAs 25-27 nt, asymmetric, where antisense strand is 27 nt and sense strand is 25nt with a 2 nt 3’ overhang on the antisense strand (Section 10, ¶4). Gatta teaches that an oligonucleotide’s target site influences its’ effectivity (Section 3.3). Gatta teaches various software to identify secondary structure in an mRNA and algorithms for designing siRNAs are publicly available (Sections 3.3 and 3.4). Gatta teaches algorithms for designing siRNAs including for incorporating dinucleotide overhangs at the 3’ ends (Table 2). Gatta teaches including 2’-O-methyl and 2’-O-fluoro modifications (i.e., 2’-modified nucleotides) and phosphorothioate linkages (i.e., modified internucleotide linkages) to avoid immune stimulation and enhance stability (Section 10, ¶5).
Brown teaches the function of tetraloops in the context of a dsRNA is to stabilize the RNA duplex to which it is attached by increasing the melting temperature higher than expected ([0152]). Brown teaches siRNA oligonucleotides comprising a tetraloop with the sequence cagccgaaaggcugc (Fig 7A). Brown teaches that tetraloop-containing siRNAs demonstrate “robust knockdown properties in vivo across” three different targets even at extremely low concentrations ([0626]). Brown teaches the tetraloop-containing siRNAs tolerated all modification patterns ([0626]). Brown teaches the tetraloop-containing siRNAs also conjugated to GalNac moieties and tested for in vivo efficacy, which showed ~ 50% knockdown efficiencies ([0628]).
Kubo and Gatta teach that cell membrane permeability and intracellular localization are challenges facing siRNA-based therapeutics (Kubo, pg. 150-151; Gatta, at least Abstract and section 4.3). Both Kubo and Gatta teach that conjugation to lipid moieties enhances delivery (Kubo, page 151, Gatta, Table 5). Indeed, Kubo teaches siRNAs comprising lipid moieties conjugated to the 5' -terminal nucleotide of the sense strand (Fig 1 and legend), which show high membrane permeability (page 154; ¶2-3; Fig. 6), and efficient cytoplasmic localization (page 161, ¶1-4). Kubo teaches that C18 fatty acids in particular, e.g., stearic acid ("C18-siCAT") showed a "showed a high membrane permeability" amongst lipid-siRNA conjugates, with "strong RNAi effect after incubation for 96 h," suggesting these could be "promising molecules for clinical applications due to their strong and long-term RNAi activity" (page 161, left col.).
Genbank teaches the sequence of STAT3 mRNA (pages 6-7).
Zhou teaches Dicer-substrate siRNAs (DsiRNAs) with asymmetric structure having a two-base overhang on the antisense strand can be rationally designed to obtain greater efficacy (Abstract). Zhou teaches testing asymmetric siRNAs with a 3’ overhang, including a GG overhang (Table 1; “25 (gc)/27 (GG)”). Zhou teaches the GG-overhang version resulted in higher knockdown efficiency over original 21-mer blunt ended siRNA (Figure 6). Zhou teaches of all the dinucleotide combinations GG has one of the highest RNAi potencies when attached to the antisense strand (Table 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the structure of Schutz's STAT3-targeting RNAi oligonucleotide, i.e., an shRNA, for a STAT3-targeting siRNA comprising a tetraloop on the 3’ end of the sense strand, a two-nucleotide 3’ overhang on the antisense strand, at least one 2’ modified nucleotide and one phosophorothioate linkage, and conjugated to the C18 moiety. It would have amounted to a simple substitution of two known RNAi oligonucleotide structures, trying a finite number of possible targeting sites, and designing the siRNAs by known siRNA design parameters by known means to yield predictable results. Shultz’s shRNA sequence, the Genbank STAT3 mRNA sequence, and the claimed sense and antisense oligonucleotides are aligned below and indicated as follows: for SEQ ID NO 875, the tetraloop sequence taught in Brown is underlined, the STAT3-targeting sequence is bolded, and the claimed place of attachment for C18 is indicated. For SEQ ID NO 965, a GG dinucleotide at the 3’ end is capitalized and bolded.
Genbank: 5’-CCTGAGTTGAATTATCAGCTTAAAATTAAA
Shultz (sense): 5’-CCTGAGTTGAATTATCAGCTT
SEQ 875 (sense): C18-5'-aauuaucagcuuaaaauuaagcagccgaaaggcugc
SEQ 965 (antisense): 3'-GGuuaauagucgaauuuuaauu
Shultz (antisense): 3'-GGACTCAACTTAATAGTCGAA
Regarding the substitution of shRNA for siRNA and the target site of the STAT3 mRNA, the skilled artisan would have had a reasonable expectation of success in substituting the structures because GPP provides the exact sequence and structure of Schutz's functional shRNA, and the structures of siRNAs and means to prepare siRNAs were well known as evidenced by Gatta. The skilled artisan would have been motivated to substitute the structures because Gatta teaches that siRNA is a preferred structure for the purposes of RNAi-based therapy, which Schutz teaches should be explored for STAT3. Additionally, it would have bene obvious to try the targeting sequence of the claimed sense and antisense strand because there are a finite number of predictable solutions for targeting sequences. Genbank teaches STAT3 mRNA is only 4900 nucleotides in length. Thus, there is only 4880 predictable targeting sequences with 100% identity/complementarity to the target sequence. The skilled artisan would have been motivated to specifically choose to try the claimed sense/antisense strand because it is only shifted 9-nucleotides down from the Shultz’s shRNA construct that functioned to knockdown STAT3 in vivo, indicating that it likely targeted the STAT3 mRNA in an unstructured area, as suggested by Gatta.
Regarding the addition of the tetraloop sequence gcagccgaaaggcugc to the obvious sense stranded rendered obvious above, it would have amounted to a simple combination of an obvious siRNA sense targeting sequence and a known tetraloop sequence, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in including the tetraloop onto the 3’ end of the sense strand in the siRNA because Brown demonstrates the inclusion in a similar siRNA molecule targeted to a different gene. The skilled artisan would have been motivated to include the tetraloop because Brown indicates that a tetraloop sequence stabilizes the siRNA duplex and enables high knockdown efficiency at very low concentrations.
Regarding the addition of the GG dinucleotide to the 3’ end of the antisense strand sequence rendered obvious, it would have amounted to a simple combination of an obvious siRNA sense targeting sequence and a known dinucleotide overhang, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in including the dinucleotide onto the 3’ end of the antisense strand in the siRNA because Zhou demonstrates the inclusion of GG at the 3’ end in siRNA molecules targeted to a different gene. The skilled artisan would have been motivated to include the dinucleotide because Zhou teaches including the GG sequence increases the potency of the siRNA and the efficiency of knockdown by siRNAs in cells.
Regarding the addition of the C18-targeting moiety to the obvious sense stranded rendered obvious above, it would have amounted to a simple combination of an obvious siRNA with a known lipid moiety, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in conjugating the 5' -terminal nucleotide of the sense strand in the siRNA with a lipid moiety of Kubo because Gatta teaches that siRNAs may be conjugated to various moieties, and Kubo teaches the means to conjugate a lipid moiety to a siRNA, and demonstrates that the lipid-siRNA conjugates are functional. The skilled artisan would have been motivated to conjugate the siRNA to a lipid of Kubo, particularly a fully saturated 18 carbon fatty acid, because as evidenced by
Kubo i) lipid-siRNA conjugates show higher cellular uptake efficacies, and ii) 16-18 carbon fatty acids in particular "showed a high membrane permeability" amongst lipid-siRNA conjugates with "strong RNAi effect after incubation for 96 h," suggesting these could be "promising molecules for clinical applications due to their strong and long-term RNAi activity."
Regarding including nucleotide and internucleotide modifications, it would have been obvious to include at least one 2’-O-methyl or 2’-O-fluoro modification and at least one phosphorothioate linkage in the STAT3-targeting C18-siRNA rendered obvious above because both Gatta and Brown teach inclusion of the 2’ modifications and linkages increases the stability of siRNAs in vivo. It would have been entirely predictable to include the modified nucleotide and linkages because both Gatta and Brown demonstrate the production and use of such modified siRNAs.
Regarding claims 186-188, the tetraloop sequence taught by Brown, GCAGCCgaaaGGCUGC, and whose addition is rendered obvious for claim 184 has the structural features recited in claims 186-188 as follows: the GAAA loop (L) is bolded. The six capitalized nucleotides on either side of the bolded tetraloop (i.e., S1 and S2) are an inverted repeat and thus are complementary to each other.
Regarding claims 189-191, the siRNA molecule rendered obvious above for claim 184 comprises 36 nucleotides in the sense strand and 22 nucleotides in the antisense strand. G-atta also teaches that degradation of siRNA by nucleases occurs from the 3’ end, and so the 3’ end of the siRNA should resist the attack by nucleases (Section 5, ¶1). Brown teaches the second strand (i.e., the antisense strand) comprising modified nucleotides, including 2’-O-methyl modifications at the terminal 3’ nucleotides ([0064], [0320]). Brown teaches tetraloop-comprising siRNAs wherein the terminal 3’ nucleotide of the tetraloop is modified with 2’-OMe (Fig 7A).
It would have been obvious to include a 2’-O-methyl modification at the 3’-most nucleotides in each of the sense and antisense strands, which is position 36 in the sense strand and position 22 in the antisense strand. It would have amounted to placing the known and obvious 2’-O-methyl modifications at known positions according to the direction provided in Gatta. The skilled artisan would have a reasonable expectation that the 3’ most nucleotide could be modified with 2’-O-methyl and been motivated to have done so because Gatta suggests such a placement and Brown demonstrates siRNAs comprising tetraloops having modified 2’-O-methyl nucleotides at the 3’ ends.
Regarding claim 193, the STAT3-targeting C18-siRNA-tetraloop siRNA molecule rendered obvious above for claim 184 includes the C18 saturated targeting ligand.
Regarding claims 195, Schutz teaches a pharmaceutical composition comprising the oligonucleotide in Dulbecco's modified Eagle's medium (i.e., a pharmaceutically acceptable carrier, delivery agent, or excipient (page 101, right col.). Gatta teaches various formulations for delivery of siRNAs including polymers and nanoparticles (i.e., pharmaceutically acceptable carriers) (Section 6). Brown teaches various pharmaceutical carriers and excipients ([0198]).
Regarding claims 196-198, MPEP 2112.01 states that "when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent." In the instant case, the product rendered obvious above has a substantially identical structure to that of the claims, and therefore the intended use of "for use in treating a disorder of condition associated with STAT3 expression in a patient in need thereof” is presumed to be inherent to the obvious product.
Regarding claims 199-201, the C18-siRNA conjugate of claim 184 is as rendered obvious above. Schutz also teaches that aberrant STAT3 activity in lung cancer cells is linked to malignant tumor progression (Abstract). Schutz also suggests evaluating both STAT3 and MMP-1 as potential targets for NSCLC tumor (i.e., lung carcinoma) treatment (page 104). Brown teaches using siRNA with tetraloops in methods for treating cancer ([0096]). Gatta teaches siRNA delivery modalities for treatment of cancer (Sections 6 and 9).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the C18-conjugated, STAT3-targeting, tetraloop-comprising siRNA rendered obvious for claim 184 in a method of treating lung carcinoma. It would have amounted to using the obvious siRNA in known methods by known means to yield predictable results. The skilled artisan would have predicted that the obvious siRNA could be used to treat lung carcinoma, and been motivated to have done so, because Schutz teaches STAT3 activation is required for malignant progression. As such, one would have predicted that inhibiting expression using the STAT3-targeting siRNA would reduce malignant transformation in lung carcinoma. Additionally, both Gatta and Brown teach using siRNAs to treat cancer.
Regarding claim 202, the specification does not provide a special definition for the term "kit”, thus "kit" is interpreted as merely the sum of its contents. The C18-siRNA conjugate of claim 184 is as rendered obvious above. MPEP 2111.05 states
USPTO personnel must consider all claim limitations when determining patentability of an invention over the prior art. In re Gulack, 703 F.2d 1381, 1385, 217 USPQ 401, 403-04 (Fed. Cir. 1983). Since a claim must be read as a whole, USPTO personnel may not disregard claim limitations that include printed matter. See Id. at 1384, 217 USPQ at 403; see also Diamond v. Diehr, 450 U.S. 175, 191, 209 USPQ 1, 10 (1981). The first step of the printed matter analysis is the determination that the limitation in question is in fact directed toward printed matter… "[O]nce it is determined that the limitation is directed to printed matter, [the examiner] must then determine if the matter is functionally or structurally related to the associated physical substrate, and only if the answer is ‘no’ is the printed matter owed no patentable weight." Id. at 850, 117 USPQ2d at 1268.
In this case the “package insert comprising instructions for administration to a subject having a disease, disorder or condition associated with STAT3 expression” is not functionally or structurally related to the C18-siRNA(STAT3) and is not given patentable weight.
Claim 192 is rejected under 35 U.S.C. 103 as being unpatentable over Schutz (Schutz et al., Translational Oncology (2015), 8: 97-105) as evidenced by GPP (Construct: shRNA TRCN0000071456, GPP Web Portal, Broad Institute, https://portals.broadinstitute.org/gpp/public/clone/details?cloneId= TRCN0000071456), Gatta (Gatta et al., Expert Opinion on Drug Discovery (2018), 13: 709-725), Brown (US 20170306332 A1), Kubo (Kubo et al., ACS Chemical Biology (2020), 16: 150-164), Zhou (Zhou et al., Molecular Therapy-Nucleic Acids (2012), 1, e17), and Genbank (NM_001369512.1, STAT3 transcript variant 4, mRNA, https://www.ncbi.nlm.nih.gov/nuccore/1610577039, [retrieved April 20, 2026]) as applied to claims 184, 186-191, 193 and 195-202 above, and further in view of Hu (Hu et al., Signal Transduction and Targeted Therapy (2020), 5:101).
The teachings of Schutz, GPP, Gatta, Brown, Kubo, Zhou, and Genbank are recited above and applied as for claims 184, 186-191, 193, and 195-202. Brown also teaches that the dsRNAs can have phosphate backbone modifications including a phosphonate ([0081]). Gatta also teaches that siRNAs can have modified phosphonates in the backbone (page 718, ¶6).
Schutz, GPP, Gatta, Brown, Kubo, Zhou, and Genbank do not specifically teach a modified phosphonate attached to the 4’ carbon of the sugar on the 5’ nucleotide of the antisense strand.
Hu teaches the state of the art of therapeutic siRNAs (Title). Hu teaches various siRNA nucleotide modifications (Fig 2; page 4, right col.). Hu teaches 5-(E)-vinyl phosphonate (5′-(E)-VP), 5’-methylphosphonate (5’-MP) and (S)-5’-C-methyl with phosphate attached to the 4’ carbon on the 5’ end of the siRNAs (Fig 2; page 4, right col.). Hu teaches phosphonate modification with various analogs at the 5′-end of siRNA of single-stranded siRNA (ss-siRNA) is a newly developed but important decoration strategy to enhance siRNA activity… However, the natural 5′-phosphate can also be removed by dephosphorylation in cells… [R]esearchers have identified a series of analogs that have similar conformation and steroidal electronic properties to natural phosphates but are resistant to dephosphorylases... [including] 5′-methylphosphonate, (S)-5′-C-methyl with phosphate” (Fig. 2; page 4, right col.). Hu further teaches “the 5′-(E)-VP modification was further applied to double-stranded siRNA. Data have revealed that this modification improves siRNA accumulation and residence time in tissue and enhances siRNA potency in vivo by elevating Argonaute-2 binding” (page 4, right col.).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have further included an 5′-(E)-VP), 5’-MP or (S)-5’-C-methyl with phosphate at the 5’ end of the siRNA rendered obvious above. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in using the modified phosphonate at the 5' -terminal nucleotide of the antisense strand in the siRNA because Brown, Gatta and Hu all teach that siRNAs are amendable to incorporation of modified phosponates in their backbone. The skilled artisan would have been motivated to use the modified phosphonate on the 5’ end of the obvious siRNA because Hu teaches that they are resistant to nuclease activity and results in improved siRNA accumulation in tissues and enhances siRNA potency.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 184-202 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 96, 102, 104-106, 111-116 of copending Application No. 19210160. Claims 185 and 194 are rejected in view of Brown (US 20170306332 A1). Claims 199-201 are rejected in view of Lau (Lau et al., Cancers (2019), 11: 1681).
Copending claim 1 recites An oligonucleotide for reducing STAT3 expression, the oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length and a sense strand comprising the sequence set forth in SEQ ID NO: 1222, wherein the sense strand and antisense strand form a duplex region and the antisense strand has a region of complementarity to a target sequence of STAT3 as set forth in SEQ ID NO: 140. Copending claim 96 recites wherein the antisense strand comprises a sequence as set forth in SEQ ID NO: 965, which is identical to SEQ ID NO 965 of the examined application. Copending clam 102 recites wherein the antisense strand comprises the sequence set forth in SEQ ID NO: 1145, which appears to be identical in sequence and modifications to SEQ ID NO 1145 of the examined application. Copending claim 112 recites A pharmaceutical composition comprising the oligonucleotide of claim 104, and a pharmaceutically acceptable carrier, delivery agent, or excipient. The difference between SEQ ID NO 1222 in the copending application and the claimed siRNA with SEQ ID NOs 875 and 1055 in the examined application is as follows, bold = 2’-O-methyl, underlined = 2’-O-fluoro; capitalized = GalNac conjugated
SECQ 1222: C18-aattatcagcttaaaattaagcagccgaaaggctgc
Claimed SEQ 1055: C18-aattatcagcttaaaattaagcagccgAAAggctgc
Thus, the copending siRNA anticipates examined claims 184, 186-188, 189-193, 195-198 and 202.
The difference between the siRNA sense strand in the instant and copending claims is including of GalNac conjugation to the tetraloop. The copending claims do not recite methods for using the siRNAs to treat cancer.
Regarding claims 185 and 194, Brown teaches siRNAs comprising an antisense strand and a sense strand comprising a tetraloop (Fig 7A; Example 6 [0625]-[0630]). Brown teaches the loop portion of the tetraloop portion is GAAA (Fig 7A). Brown teaches the nucleotides in the tetraloop were conjugated to GalNAc moieties (i.e., [ademA-GalNAc]) ([0628]-[0630]). Brown teaches the siRNAs conjugated to GalNAc in the tetraloop were highly active and had higher efficacy than unconjugated forms ([0629]).
It would have been obvious to one skilled in the art to have modified the copending sense strand by including GalNAc conjugates to the nucleotides in the tetraloop to arrive at an siRNA sense strand with SEQ ID NO 1055. It would have amounted to the simple combination of known elements my known means to yield predictable results. The skilled artisan would have a reasonable expectation that GalNAc could be conjugated to the three adenosines in the tetraloop because Brown teaches the GAAA tetraloop nucleotides conjugated to GalNAc. The skilled artisan would have been motivated to do so based on the improved efficacy of siRNA-GalNAc conjugates as demonstrated by Brown.
Regarding claims 199-201, Lau teaches Signal transducer and activator of t transcription 3 (STAT3) is a transcription factor that is overexpressed and/or hyperactivated in multiple human cancers, where it enhances tumor cell survival and invasion through transcription of anti-apoptotic and pro-proliferative genes (page 1, ¶1). Lau teaches antisense molecules comprising 2’-O-methyl moieties, including siRNAs, have been used to downmodulate STAT3 expression and treat cancer in clinical trials (Section 1.6).
It would have been obvious to use the copending STAT3 siRNAs in methods of treating cancers, including carcinomas, sarcomas, melanomas and lymphomas. It would have amounted to using the copending STAT3 siRNAs in known methods to yield predictable results. The skilled artisan would have a reasonable expectation that the copending siRNAs could be used in methods, and been motivated to have used them, because Lau teaches antisense nucleic acid therapies for downregulating STAT3 for such treatments.
This is a provisional nonstatutory double patenting rejection.
Claims 184-202 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-159 of copending Application No. 18846890. Claims 184-193 and 195-202 are rejected in view of Kubo (Kubo et al., ACS Chemical Biology (2020), 16: 150-164).
Copending claims 1 and 3 recite A method of treating a disease, disorder or condition [associated with activated STAT3 expression], comprising administering to a subject in need thereof an RNAi oligonucleotide… wherein the oligonucleotide comprises an antisense strand of 15 to 30 nucleotides in length and a sense strand of 15 to 40 nucleotides in length, wherein the antisense and sense strands form a duplex region, wherein the antisense strand comprises a region of complementarity to a STAT3 mRNA target sequence, and wherein the region of complementarity is at least 15 contiguous nucleotides in length, thereby treating cancer in the subject. Claims 4-5 recite wherein the disease, disorder, or condition associated with activated STAT3 expression is a cancer, including carcinoma, sarcoma, melanoma, lymphoma, and leukemia, prostate cancer, breast cancer, hepatocellular carcinoma (HCC), colorectal cancer, pancreatic cancer and glioblastoma. Copending claims 47/51/53 recite The method of any one of claims 1-46, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands, wherein the targeting ligand is a saturated fatty acid moiety that ranges in size from C10 to C24 long, wherein the targeting ligand is a C18 saturated fatty acid moiety. Copending claim 76 recites The method of any one of claims 1-57, wherein the sense strand comprises the nucleotide sequence of SEQ ID NO: 1055 and the antisense strand comprises the nucleotide sequence of SEQ ID NO: 1145, which are 100% identical with the same modified nucleotides as SEQ ID NOs 1145 and 1055, respectively, of the examined application. Claims 82-161 recite kits with the oligonucleotides recited in claims 1-81. Thus, the copending claims anticipate examined claim 194.
The copending claims do not recite that the C18 targeting lipid is specifically attached to the 5’ end of the sense strand.
Kubo and teaches that cell membrane permeability and intracellular localization are challenges facing siRNA-based therapeutics (pages 150-151). Kubo teaches that conjugation to lipid moieties enhances delivery (page 151). Indeed, Kubo teaches siRNAs comprising lipid moieties conjugated to the 5' -terminal nucleotide of the sense strand (Fig 1 and legend), which show high membrane permeability (page 154; ¶2-3; Fig. 6), and efficient cytoplasmic localization (page 161, ¶1-4). Kubo teaches that C18 fatty acids in particular, e.g., stearic acid ("C18-siCAT") showed a "showed a high membrane permeability" amongst lipid-siRNA conjugates, with "strong RNAi effect after incubation for 96 h," suggesting these could be "promising molecules for clinical applications due to their strong and long-term RNAi activity" (page 161, left col.).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have specifically attached the copending C18 ligand to the 5’ end of the sense strand in the copending siRNA oligonucleotides. It would have amounted to a simple combination of an obvious siRNA with a known lipid moiety, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in conjugating the 5' -terminal nucleotide of the sense strand in the siRNA with the C18 lipid moiety because Kubo teaches the means to conjugate a lipid moiety to the 5’ end of an siRNA, and demonstrates that the lipid-siRNA conjugates are functional. The skilled artisan would have been motivated to conjugate the siRNA to a lipid of Kubo, particularly a fully saturated 18 carbon fatty acid, because as evidenced by Kubo i) lipid-siRNA conjugates show higher cellular uptake efficacies, and ii) 16-18 carbon fatty acids in particular "showed a high membrane permeability" amongst lipid-siRNA conjugates with "strong RNAi effect after incubation for 96 h," suggesting these could be "promising molecules for clinical applications due to their strong and long-term RNAi activity."
Allowable subject matter
Claims 185 and 194 are free of the prior art. Claims 185 and 194 require a specific STAT3-targeting sequence and a specific modification pattern in the sense and antisense strands. In order to arrive at the claimed invention based on the prior art, the skilled artisan would need to I) select the specific target sequence in STAT3 mRNA to which SEQ ID NO: 1055 and 1145 is designed, II) apply a tetraloop structure to the selected sequence, with (claim 194) or without (claim 185) GalNAc modifications, Ill) apply the specific pattern of 2'-fluoro and 2'-O-Me modifications to the resulting sense strand and antisense strands, and IV) include a 3’ dinucleotide overhang on the antisense strand, and V) modify the 5' end of the sense strand with a C18 moiety.
As described in the §103 rejections above, the skilled artisan could have arrived at a double-stranded oligonucleotide targeting a sequence adjacent to Schutz's successful oligonucleotide, and therefore, the target sequence in SEQ ID NO: 1145 and 1055. The prior art provides motivation to arrive at such a sequence, because there was motivation in the prior art to develop therapeutics targeting STAT3 (see Schutz, page 104, left col.), and the prior art teaches that an oligonucleotide's target site influences its effectivity (see Gatta, pg. 713, left col.). A search of the prior art did uncover guidance to construct tetraloop-comprising, GalNAc-conjugated oligonucleotides (see Brown’s teachings above), the suggestion of 5'-lipid conjugated oligonucleotides (see Kubo’s teachings above), and motivation to include a GG dinucleotide overhang to the antisense strand.
However, taking all the parameters together, the skilled artisan would essentially have to vary every parameter of the relevant prior art in order to arrive at the instantly claimed oligonucleotide; the target sequence of SEQ ID NO: 1055 and 1145 was not uncovered in the search and/or combined with the sequence with the tetraloop structure set forth in SEQ ID NOs: 1045/1145, and the specific pattern of 2'-fluoro and 2'-OMe modified nucleotides. MPEP 2143(I)(E) provides that obviousness cannot apply in such a situation (i.e., "when what would have been "obvious to try" would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of the many possible choices is likely to be successful"). Accordingly, the instantly claimed oligonucleotides comprising the sequence set forth in SEQ ID NO: 1045/1145, and pharmaceutical compositions comprising the oligonucleotides are free of the prior art considered during examination.
It is noted that claims 185 and 194 are rejected for nonstatutory double patenting (NSDP) because claims in two different copending applications recite siRNAs with the specific STAT3-targeting sequence and 2’-O-methyl and 2’-O-fluoro patterns to which the addition of a C18 moiety and/or GalNAc conjugates in the tetraloop would have been obvious in view of the prior art.
Conclusion
No claims are allowed.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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