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
Claims 1-5, 11, 15, 16, and 25 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/4/25.
The elected species that was searched was antisense oligonucleotide (ASO) as the first domain and small molecule as the second domain, the third linker (see below) and polyethylene glycols (linkers 12 to 20 listed) in claim 31 and mRNA in claim 45.
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Claim 43 and the non-elected linkers in claim 31 and non-elected target sequences (lncRNA, pre-mRNA, microRNA, enhancer RNA, transcribed RNA, nascent RNA, chromosome-enriched RNA, ribosomal RNA, membrane enriched RNA and mitochondrial RNA) in claim 45 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/4/25.
(NOTE: the limitation ‘first domain is a small molecule’ in claim 26 was removed from the claim and claim 38 was cancelled).
Claim Objections
Claims 26-31, 33-37, 39-42, and 44-47 are objected to because of the following informalities: the claim recited a second small molecule, however, there is no first small molecule recited in claims 26 and 39 in view of the amendment to claim 26. It appears to be an apparent oversight and the second small molecule will be considered the first small molecule in view of the amendment to remove first small molecule.
Claim 30 is objected to because of the following informalities: the term “of” on line 2 should be “or”. The amendment filed on 8/4/25 changed the term from ‘or’ to ‘of’ and the Office missed the amendment to claim 30 and the status identifier did not indicate that claim 30 was amended.
Appropriate correction is required.
Response to Arguments
Applicant’s arguments, see pages 7-8, filed 2/6/26, with respect to 102 and 103 rejections over Salim et al; Juliano; and Behlke have been fully considered and are persuasive. The rejection of claims 26-30, 32, 33, 36-37, 39 and 44-45 has been withdrawn because of the amendment to the independent claims to exclude a bifunctional molecule containing a ligand that has affinity for a receptor on a target cell. However, upon further consideration a new rejection is required because of the amendment to claim 26 to exclude a ligand having an affinity for a receptor on a target cell and the addition of new claims 46-47.
The broadest reasonable interpretation of the claimed product embraces the bifunctional molecule does not comprise a ligand having an affinity for a receptor on a target cell or the first or second domain does not contain a ligand having an affinity for a receptor on a cell. The specification provides a positive recitation of a small molecule or aptamer binding a receptor (see paragraphs 139, 168, 177, 187, 244-249 and 257), and has written support for the new negative limitation recited in claim 26. See MPEP 2173.05(i). NOTE: An aptamer could work as a ligand and could result in an issue if the aptamer is rejoined with the elected species.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 26-30, 36, 37, 39-41 and 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Woolf (CA 2702028) taken with Tyler et al. (Science 256, 1397-1401, 2017, of record).
The term ‘an antisense oligonucleotide’ broadly reads on a single stranded or double stranded oligonucleotide comprising an antisense oligonucleotide. Pages 14-18 of the specification do not limit the antisense oligonucleotide to exclude double stranded oligonucleotides comprising an antisense strand.
The claims (e.g., claim 1) of ‘028 recites: An RNAi construct comprising:
(a) an RNAi core comprising a blunt-ended double-stranded RNA (dsRNA)
with or without a portion of said RNAi core substituted with a non-nucleic
acid based functional moiety, said RNAi core consisting of a sense strand
and an antisense strand, each strand being 25-30 nucleotides in length,
wherein said sense strand is chemically modified, and wherein said
antisense strand is at least partially complementary to and hybridizes with
a transcript from a target gene wherein the transcript is a protein-coding mRNA or non-protein coding RNA sequence, and,
(b) one or more terminal moieties, each independently selected from: a
bimodal partner, a carrier mimic, a membrane intercalator, a lipophilic
molecule, a reporter molecule, a vitamin, a drug, a toxin, a polymer, a
peptide, an antibody or a functional fragment, a carbohydrate, a nucleic
acid cleaving complex, a metal chelator, an intercalator, a crosslinking
agent, a cholesterol, a lipid moiety, a phospholipid, biotin, phenazine, a
folate, phenanthridine, anthraquinone, acridine, a fluorescein, rhodamine, a
coumarin, a dye, an active drug substance, or a group that enhances a
pharmacodynamic property selected from construct uptake, construct
resistance to degradation, and/or sequence-specific hybridization with the
transcript, wherein the RNAi core is linked to said one or more terminal moieties either directly or through one or more linkers, wherein said bimodal partner is an antisense, a ribozyme, an RNAi molecule which antagonizes the function of a gene other than the target gene. See pages 47-52.
A pharmaceutical composition comprising the RNAi construct of claim 1 and one or more chemotherapeutic agents which function by a non-RNAi mechanism or anti-inflammatory drugs (page 51).
The RNAi can be used to target the EGPS1 gene (page 9). The RNAi can be used to reduce gene expression in both the nucleus and cytoplasm (pages 12-21).
Each strand of the RNAi can be 25-27 nucleotides in length. The strands of the RNAi can be chemically modified with 2’O-Me or a phosphorothioate internucleotide linkage. The RNAi could target a sequence associated with cellular factors (page 49). The RNAi core on either the 5’ or 3’ terminus is linked to a terminal moiety via a linker. The linker can be repeating units are ethylene glycol or amino acid unit or linkers comprise one or more functionalities selected from: an amino group, a hydroxyl group, a carboxylic
acid, a thiol group, a phosphoramidate, a phosphate, a phosphite, or an unsaturation.
The RNAi construct can be used to treat overexpression of a target gene that leads to a disease condition associated with cancer, retinopathy, autoimmune disease, inflammatory disease, viral disease, miRNA disorder or cardiovascular disease (pages 7-8). Page 29 discloses that the conjugate delivery peptides can help localization of the RNAi cores and construct to specific regions of a cell, including the cytoplasm ad nucleus.
‘028 does not specifically teach a synthetic bifunctional molecule comprising a first domain comprising an antisense oligonucleotide (AON) that is complementary to a target RNA; and conjugated to a domain comprising a small molecule; wherein the small molecule specifically binds to a target endogenous protein; wherein the bifunctional molecule does not comprise a ligand having an affinity for a receptor on a target cell.
However, Tyler discloses, " modified BET1 bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro or in vivo (abstract)." This can be used a framework that allows clickable drug surrogates to be used as versatile molecule probes. Tyler synthesized derivatives of the BET inhibitors JQ1 and iBET-762-namely, JQ1-propargyl amide (JQ-PA) [and] JQ1-trans-cyclooctene (JQ1-TCO)"). This can be used to study drug distribution and cells of interest. BET inhibitors can be used to treat cancer (page 1399).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘028 taken with Tyler to use a small molecule (JQ1 or iBET762) that targets an intracellular endogenous protein as the second domain in the molecule, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to try JQ1 (a selective inhibitor of BRD4) or IBET762 as the small molecule in the second domain to observe an additive effect for treating cancer with a reasonable expectation of success. See MPEP 2143(I)E. JQ1 and iBET762 have a molecular weight of 900 daltons or less. See MPEP 2141(I)(C): “Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art.” Depending on the desired target sequence, one of ordinary skill in the art would arrive at the antisense stand having 30% to 60% GC content. The RNAi can be used to reduce gene expression in both the nucleus and cytoplasm by targeting a mRNA in the cell (pages 7-9 and 21 of ‘028). Since RNAi and antisense oligonucleotides can reduce expression of a target sequence in a cell (page 45 of ‘028), it would have been a simple substitution to replace the RNAi with an antisense oligonucleotide and conjugate the antisense oligonucleotide to a small molecule.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over ‘028 and Tyler as applied to claims 26-30, 36, 37, 39-41 and 44-47 above, and further in view of Nakamura et al. (US 20120165401, of record).
‘028 teaches that the linker includes a chain structure of repeating units of ethylene glycols (page 49).
‘028 and Tyler do not specifically teach using a linker set forth in instant claim 31 to connect the first domain to the second domain, wherein the linker is a polyethylene glycol linker.
However, Nakamura disclose using nucleotide and non-nucleotide linkers, including polyethylene glycol linkers to conjugate an oligonucleotide to another compound (paragraph 62).
The specification of the instant disclosure does not appear to teach that the linker is critical to the claimed invention. Thus, it would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘028 and Tyler taken with Nakamura as a simple substitution with a reasonable expectation of success to use a polyethylene (hexaethylene) glycol as set forth in instant claim 31 to connect to the first domain to the second domain, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to try a polyethylene glycol as the linker to increase stability of the first and second domains since the linker is well known in the prior art to connect two compounds as taught by Nakamura. See also MPEP 2143(I)A, B, and G.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 31 and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over ‘028 (supra) and Tyler as applied to claims 26-30, 36, 37, 39-41 and 44-47 above, and further in view of Behlke et al. (WO 2012033848, of record).
‘028 and Tyler do not specifically teaching using locked nucleic acids (LNA) in the antisense oligonucleotide.
However, Behlke teaches LNA is one of the chemical modification that can be made to antisense oligonucleotide (pages 4, 12-13, 27-34, Tables 5-8). Pages 15-16 discloses that the oligonucleotide can be linked to a ligand.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘028 and Tyler taken with Behlke to use a LNA at an internal position of the antisense strand in the RNAi molecule, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated as a simple substitution to use LNA at an internal position or terminus of the oligomer to increase stability of the oligomer in a cell. See MPEP2143(I)A. Behlke teaches that a compound may be conjugated to an antisense oligonucleotide with an additional S18 (hexaethyleneglycol) spacer (page 16).
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over ‘028 and Tyler as applied to claims 26-30, 36, 37, 39-41 and 44-47 above, and further in view of Kapoor et al. (Cell Death and Disease 10:924, pages 1-12, December 2019, of record).
‘028 and Tyler do not specifically teach the small molecule is ibrutinib in the second domain.
Kapoor teaches that Ibrutinib (BTK inhibitor) was well known in the prior art to treat several types of cancer in a human patients (page 1). However, sometimes in patients complete responses are infrequent and acquired resistance to BTK inhibition can emerge. Inhibition of PI3K and AKT increased ibrutinib-induced apoptosis in ibrutinib-resistant (IB-R) cell lines. AKT siRNA was administered to cells treated with ibrutinib (pages 5-6). AKT inhibition upregulating FOXO3a levels and sensitizes IB-R cells.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘028 and Tyler taken with Kapoor to use AKT siRNA or antisense oligonucleotide targeting AKT as the first domain and ibrutinib as the small molecule that targets an intracellular endogenous protein as the second domain in the molecule, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to try molecule to observe an additive effect for treating IB-R cancer cells with a reasonable expectation of success. See MPEP 2143(I)E.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 26-31, 36, 37, 39-42 and 44-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-6, 8, 10-12, 16, 17, 19, 22-23, 25, 27, 29, 31-32, and 36 of copending Application No. 18694854, effective filing date (EFD) 9/22/21 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a synthetic bifunctional molecule comprising: a first domain comprising a 2' O-methoxyethyl modified antisense oligonucleotide (ASO), wherein the first domain specifically binds to a target ribonucleic acid (RNA) sequence; and a second domain comprising a small molecule or an aptamer, wherein the second domain specifically binds to a target endogenous protein; and wherein the first domain is conjugated to the second domain, wherein the target endogenous protein comprises an intracellular endogenous protein or BRD4 or wherein the second domain comprises JQ1, iBET762 or ibrutinib. The linker in claim 27 of '854 reads on the linker in instant claim 31. Claim 29 of '854 recites the ASO comprises a sequence comprising 30% to 60% GC content or a length from 8 to 30 nucleotides as set forth in instant claims 36-37. Claim 36 of '854 discloses the limitation in instant claims 44-45.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 26, 27, 29-31, 33-37, 39, and 44-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-50 of copending Application No. 17920769, EFD 4/21/20(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a synthetic bifunctional molecule for degrading a target RNA in a cell, the synthetic bifunctional molecule comprising: a first domain comprising a first small molecule or an ASO, wherein the first domain specifically binds to an RNA sequence of the target RNA; a second domain comprising a second small molecule or an aptamer, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain, wherein the target polypeptide degrades the target RNA in the cell. The linker in claim 34 of '769 reads on the linker in instant claim 31. Claims 6-8 of '769 recite the ASO comprises a locked nucleic acid (LNA) as set forth in instant claims 33-35. Claims 9 and 10 of '769 recite the ASO comprises a sequence comprising 30% to 60% GC content or a length from 8 to 30 nucleotides as set forth in instant claims 36-37. Claims 21 and 22 of '769 disclose the limitation in instant claims 44-45.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 26, 27, 29-31, 33-37, 39, and 44-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-48 of copending Application No. 17920752(EFD 4/21/20, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a synthetic bifunctional molecule for degrading a target RNA in a cell, the synthetic bifunctional molecule comprising: a first domain comprising a first small molecule or an antisense oligonucleotide, wherein the first domain specifically binds to an RNA sequence of the target RNA; a second domain comprising a second small molecule or an aptamer, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain, wherein the target polypeptide degrades the target RNA in the cell. The linkers in claim 29 of '752 reads on the linker in instant claim 31.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 2/6/26 have been fully considered but they are not persuasive because the provisional NSDP rejections are not the only rejections of record.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Rusling et al. (DNA conjugates and sensors RSC Biomolecular Sciences No. 26, Chapter 3, pages 75-102, 2012) teach there was a reasonable expectation of making oligonucleotide-small molecule conjugates.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
See attached PTO-326 for disposition of claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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