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 .
Claims 1, 6-7, 15-18, and 22-30 are pending. Claims 17-18 and 25-28 are withdrawn from consideration as being drawn to a nonelected invention.
Status of the Application
Applicant’s responses and amendments filed 19 February 2026 and 13 April 2026 are acknowledged and entered.
As of 19 February 2026 Applicant has amended Claims 1, 6-7, 15, and 22-24. Applicant has cancelled Claims 4, 8-10, and 20-21. Applicant has added Claim 29. As of 13 April 2026 Applicant has amended Claim 15 and added Claim 30.
Response to Amendment
The declaration from Tom Hartl has been received and considered.
Applicant has amended Claims 1 and 15 and cancelled Claim 8 to overcome the 112a Written Description rejection; the 112a rejection is withdrawn.
Applicant has amended the claims to overcome the 112b rejections; the 112b rejections are withdrawn.
Applicant has amended the claims to overcome the 103 rejection; the 103 rejection is not withdrawn.
The NSDP rejections are maintained.
Claims 1, 6-7, 15-16, 22-24, and 29-30 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Information Disclosure Statement
The IDS(es) has been considered. See signed IDS(es).
Claim Objections
Claims 6 and 7 are objected to because of the following informalities: The claims should recite …wherein the TEG group is attached… (like Claims 22-23). Appropriate correction is required.
Claim Interpretation
Claims 1 and 15 recite … the nucleotide sequence of SEQ ID NO [#]. “Nucleotide sequence” is not defined in the Spec. so it’s interpreted according to its plain meaning: a sequence of nucleotides wherein nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate.
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 15, 22-24, and 29-30 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. These rejections are new and necessitated by the claim amendments.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.
In the present instance, Claim 15 recites the hydroxyalkoxylated AON consisting of the nucleotide sequence of SEQ ID NO 22345 [emphasis added]. Claims 22-24 and 29-30 recite the hydroxyalkoxylated AON. As discussed in §Claim Interpretation, “nucleotide sequence” is interpreted under its plain meaning (i.e., a sequence of nucleotides wherein nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate). Therefore it is unclear how the AON is hydroxyalkoxylated as recited in the claims.
Claims 15, 22-24, and 29-30 are rejected for those reasons. Claims 22-24 and 29-30 are rejected because they depend from Claim 15 and don’t remedy the issues.
In the interest of compact prosecution Claims 15, 24, and 29-30 are interpreted as requiring only the nt sequence of SEQ ID NO 22345.
Claims 22-23 recite the limitation "wherein the TEG group" in L1-2. There is insufficient antecedent basis for this limitation in the claim because all the claims ultimately depend from Claim 15 which doesn’t recite any TEG group.
Claims 22-23 are rejected for those reasons. In the interest of compact prosecution, the claims are interpreted as if they recite: The hydroxyalkoxylated AON of claim 15, wherein the AON is linked to a TEG group that is attached to the AON through a PO/PS linker.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 15 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by International Publication Number WO2018/007475 (published 11 January 2018, “WO475”; of record on IDS).
NOTE: all citations to WO475 cite to the p. # of the PDF document.
WO475 teaches antisense splice-switching oligonucleotides with improved characteristics that enhance clinical applicability for treating, ameliorating, and/or delaying neuromuscular disorders, such as DMD.
Regarding Claim 15 and limitations of Claim 1: WO475 teaches (p. 89, Table 3) SEQ ID NO 4568, which is shown in the following modified excerpt of the table:
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203
665
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That shows that the underlined nts are LNA nts, all the linkages are PS linkages, and the AON consists of 2’-O-methyl RNA monomers. WO475 teaches (p. 9 L15-25) BNA modification comprises LNA monomers and (p. 89 L24) AONs comprising BNA mods induce much higher exon skipping:
implementation of at least one BNA scaffold-modified nucleotide (resulting in an LNA monomer) in an AON improves exon 51 skipping levels when compared to an iso-sequential AON without a BNA scaffold modification… compared to the AON without a BNA scaffold modification (SEQ ID NO 452), the AONs with LNA nucleotides induced 10- to 40-fold higher exon 51 skipping levels.
Therefore, WO475 teaches that SEQ ID NO 4568 possesses the exact nt sequence of claimed SEQ ID NO 22345 and is the same as nt sequence as claimed SEQ ID NOs 22333 and 22345, down to the modification (i.e., Claim 15 and some limitations of Claim 1). Note that while the claims do not recite that the AON comprises 2’-OMe mods, the instant Spec. discloses (¶360) SEQ ID NOs 22333 and 22345 comprise 2’-OMe mods linked by PS linkages.
The following alignments show that WO475 SEQ ID NO 4568 has the exact same nt sequence as instant SEQ ID NOs 22333 and 22345 (it is noted that the nt sequences of SEQ ID NOs 22333 and 22345 are identical):
BET81395
ID BET81395 standard; RNA; 18 BP.
XX
AC BET81395;
XX
DT 22-FEB-2018 (first entry)
XX
DE Human dystrophin (DMD) gene exon 51 skipping antisense oligo, SEQ 4568.
XX
KW DMD gene; Dystrophin gene; antisense oligonucleotide; antisense therapy;
KW becker muscular dystrophy; duchenne dystrophy; gene regulation;
KW genetic disorder; genetic-disease-gen.; growth-disorder-gen.;
KW locked nucleic acid; muscular-gen.; neuroprotective; phosphorothioate;
KW prophylactic to disease; spinal muscular atrophy; splice-switching; ss;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT modified_base 1..2
FT /*tag= a
FT /mod_base= OTHER
FT /note= "OTHER = BNA scaffold modified base"
FT modified_base 6
FT /*tag= b
FT /mod_base= OTHER
FT /note= "OTHER = BNA scaffold modified base"
FT modified_base 18
FT /*tag= c
FT /mod_base= OTHER
FT /note= "OTHER = BNA scaffold modified base"
XX
CC PN WO2018007475-A1.
XX
CC PD 11-JAN-2018.
XX
CC PF 05-JUL-2017; 2017WO-EP066845.
XX
PR 05-JUL-2016; 2016EP-00177973.
XX
CC PA (BIOM-) BIOMARIN TECHNOLOGIES BV.
XX
CC PI Van Deutekom JC, De Visser PC;
XX
DR WPI; 2018-02968E/08.
XX
CC PT Oligonucleotide for composition used for preventing, treating or delaying
CC PT e.g. Duchene muscular dystrophy comprises substituted monomers linked by
CC PT phosphorothioate and/or phosphodiester linkages, and monomer containing
CC PT bicyclic nucleic acid.
XX
CC PS Example 3; SEQ ID NO 4568; 107pp; English.
XX
CC The present invention relates to pre-mRNA splice switching or modulating
CC oligonucleotides with bicyclic scaffold moieties, useful in preventing,
CC treating or delaying genetic disorders. The antisense splice-switching
CC oligonucleotides comprise substituted monomers linked by phosphorothioate
CC and/or phosphodiester linkages, and monomers containing bicyclic nucleic
CC acids. The antisense splice-switching oligonucleotides have improved
CC characteristics and enhanced clinical applicability, useful in treating
CC Duchene muscular dystrophy, Becker muscular dystrophy and spinal muscular
CC dystrophy. The invention also provides a composition comprising the
CC antisense splice-switching oligonucleotide; and a method for preventing
CC and treating Duchene muscular dystrophy by administering the
CC oligonucleotide or the composition to a subject. Using the antisense
CC splice-switching oligonucleotides binding affinity to target strands is
CC increased, immunostimulatory effects are decreased, and biodistribution,
CC intra-tissue distribution and cellular uptake is improved. The present
CC sequence is a human dystrophin (DMD) gene exon 51 skipping antisense
CC oligo used in the therapeutic/prophylactic methods of the invention.
XX
SQ Sequence 18 BP; 4 A; 4 C; 5 G; 0 T; 5 U; 0 Other;
2 18 100.0 18 BET77417 -- 509 Human dystrophin (DMD) gene exon 51 skipping antisense oligo, SEQ 590.
ALIGNMENT:
Query Match 100.0%; Score 18; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18 SEQ ID NO 22333
||||||||||||||||||
Db 1 GGUAAGUUCUGUCCAAGC 18 WO475 SEQ ID NO 4568
BET81395
ID BET81395 standard; RNA; 18 BP.
XX
AC BET81395;
XX
DT 22-FEB-2018 (first entry)
XX
DE Human dystrophin (DMD) gene exon 51 skipping antisense oligo, SEQ 4568.
[same information as in preceding alignment; truncated to save space]
CC PN WO2018007475-A1.
XX
CC PD 11-JAN-2018.
XX
[same information as in preceding alignment; truncated to save space]
XX
SQ Sequence 18 BP; 4 A; 4 C; 5 G; 0 T; 5 U; 0 Other;
ALIGNMENT:
Query Match 100.0%; Score 18; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18 SEQ ID NO 22345
||||||||||||||||||
Db 1 GGUAAGUUCUGUCCAAGC 18 WO475 SEQ ID NO 4568
The image of Table 3 above shows that the mods of SEQ ID NO 4568 are the exact same mods as SEQ ID NO 22345. Here is a snapshot of a portion of WO475 Table 3 right next to a modified snapshot of the instant application’s Table 1 and relevant text. The snapshots show the sequences and mod patterns are identical:
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203
665
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282
589
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Therefore WO475 anticipates Claim 15.
Regarding Claim 24 (and some limitations of Claims 16 and 29-30): WO475 also teaches (p. 68 L20-25) the composition can be used as a medicament and can comprise a pharmaceutically acceptable carrier, which is a limitation of Claim 24.
THE FOLLOWING REJECTIONS ARE MAINTAINED BUT UPDATED IN RESPONSE TO THE CLAIM AMENDMENTS
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 6-7, 15-16, 22-24, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO2018/007475 (published 11 January 2018, “WO475”; of record on IDS) as applied to Claims 15 and 24 in the 102 rejection above, and further in view of US Patent No. 9238042 (issued 19 January 2016, “US042”; of record), Bonora (et al. 1997. Synthesis and Characterization of High-Molecular Mass Polyethylene Glycol-Conjugated Oligonucleotides. Bioconjugate Chem. 8[6]:793–797, “Bonora”, of record), and Gaziova (et al. 2014. Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect. Bioorg. Medicin. Chem. 22:2320-2326, “Gaziova”). This rejection is modified in response to the claim amendments.
NOTE: all citations to WO475 and US042 cite to the p. # of the PDF document.
The teachings of WO475 as applicable to Claim(s) 15 and 24 (and some limitations of Claims 1, 16, and 29-30) have been described in the 102 rejection above.
WO475 teaches the exact nt sequences of claimed SEQ ID NOs 22333 and 22345, including all the modifications. WO475 teaches pharmaceutical compositions comprising the AON and a pharmaceutically acceptable carrier.
WO475 teaches that (p. 13 L20-40) their invention provides an oligo that preferably… consists of 2’-O-methyl RNA monomers connected through a PS… backbone. The same passage teaches that all uracils of the AON have been substituted by … 5-methyluracil.
WO475 does not teach that the AON consists of an AON and one triethylene glycol group (Claims 1, 6-7, 16, 22-23, and 29-30) or that the TEG is at the 3’- or 5’-terminus (Claims 1, 6-7, and 16).
However, US042, drawn to antisense oligos for modulating a different target, teaches appending TEG to an AON. US042 teaches (Col 3 L45-61) the AONs of their invention can be splice-switching AONs and can include LNA:
There are several antisense or RNA interference chemistries available and known to those skilled in the art. One important feature of certain antisense chemistries is the ability to hybridize to a target RNA without causing degradation of the target by RNase H, as with 2'-deoxy oligonucleotides (“antisense oligonucleotides” hereafter “AON”). Such compounds may also be referred to as splice-switching oligomers (SSOs) if they alter pre-mRNA splicing and translation suppressing oligomers (TSOs) if they block mRNA translation. Those skilled in the art will appreciate that TSOs and SSOs include, but are not limited to, 2' O-modified oligonucleotides and ribonucleosidephosphorothioates as well as peptide nucleic acids (PNA), morpholinos, locked nucleic acids (LNA), and other polymers lacking ribofuranosyl-based linkages. [emphasis added.]
Regarding the TEG of Claims 1, 6-7, 16, 22-23 and 29-30 and the 3’ or 5’ TEG of Claims 1, 6-7, 16: US042 teaches (Col 34-35 L58-5) a short-interfering RNA (siRNA) (i.e., an AON is a species of siRNA) can be modified to stabilize one or more 3’- or 5’-termini and such modifications can be non-nucleotidic compounds including triethylene glycol or hexaethylene glycol. Further regarding Claims 1, 6-7, and 16: Fig. 1b shows an ethylene glycol appended to the 5’-terminus of an AON. Therefore US042 teaches limitations of Claim 1 and some limitations of Claims 6-7, 22-23, and 29-30.
US042 also teaches (Col 27 L1-45) adding chemical moieties to improve an AON and teaches the moieties may be covalently attached. As discussed US042 teaches TEG is one such moiety as it increases resistance to nucleases. US042 teaches (same §) linkages that include PO and PS linkages.
Altogether, US042 teaches splice-switching AONs and placing TEG on either of the 3’- or 5’-termini of an AON.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the splice-switching AON for inducing splice switching in exon 51 to treat DMD, wherein the AON comprises SEQ ID NO 4568 of WO475 with the 3’- or 5’-terminal TEGs of US042 for the benefit of stabilizing the AON against exonucleases. One would have been motivated to do so with a reasonable expectation of success because US042 teaches placing a TEG at either terminus can stabilize the AON against nucleases. One would have been motivated to do so with a reasonable expectation of success because WO475 teaches (p. 3 L20-25) modifying AONs to resist nucleases and an artisan would have readily realized that the 3’- or 5’-terminal TEGs of US042 are yet another way to improve the AON. One would have been motivated to choose WO475’s SEQ ID NO 4568 out of all the sequences in that document because WO475 teaches (p. 43 L20-21) SEQ ID NO 4568 is one of only 10 most preferred sequences. Modifying the splice-switching AON comprising SEQ ID NO 4568 of WO875 with the 3’- or 5’-terminal TEGs of US042 would have produced all the limitations of Claims 1, 15-16, and 24.
WO475 and US042 do not explicitly teach that the TEG is attached to the AON through a PO or PS linkage (i.e., Claims 6-7, 22-23, and 29-30).
However, Bonora, drawn to synthesis and characterization of polyethylene glycol-conjugated oligonucleotides, teaches conjugating a polyethylene glycol moiety to the 3’ end of an antisense oligo. That is shown in this excerpt of Fig. 1:
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172
217
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That figure shows that MPEG is linked to the AON via a PO linkage (a limitation of Claim 6).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the AON wherein the AON comprises a 3’- or 5’-terminal TEG of WO475 and US042 with the PO linkage that attaches a terminal ethylene glycol moiety of Bonora for the benefit of improving stability of the molecule (i.e., the TEG of US042) and doing so using a linkage known to be suitable for attaching an ethylene glycol moiety to an AON (i.e., the PO of Bonora). One would have been motivated to do so with a reasonable expectation of success because US042 teaches stabilizing an AON by placing a 3’- or 5’-terminal TEG and because Bonora shows that their larger ethylene glycol moiety (PEG) was attached using a PO linkage indicating that adding an ethylene glycol moiety to an AON via a PO linkage was routine and customary. An artisan would have understood that they could use the same linkage that Bonora used to attach a larger PEG moiety to attach a smaller TEG moiety because PEG is merely a form of ethylene glycol that incorporates more subunits but that both TEG and PEG have the same atoms available to link to a PO linkage. Modifying the AON comprising a 3’- or 5’-terminal TEG of WO475 and US042 by attaching it via a PO linkage of Bonora would have produced the limitations of Claims 6, 22, and 30.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to attach the TEG of US042 to the AON of WO475, US042, and Bonora via the PS linkage of WO475 for the benefit of producing a stable molecule. One would have been motivated to do so with a reasonable expectation of success because WO475 allows for—even prefers—PS linkages, as described in WO475 (p. 44 L20-30) which discloses preferred embodiments comprising the SEQ ID NOs 4565 and 4568 linked by only PS backbone linkages, and because artisans know that (WO475 p. 13 L20-35) PS linkages are more stable than natural linkages. Attaching the TEG group to the AON of WO475, US042, and Bonora using the PS linkage of WO475 would have produced the limitations of Claims 7, 23, and 29.
WO475, US042, and Bonora teach a hydroxyalkoxylated AON consisting of the nt sequence of SEQ ID NO 22333 or SEQ ID NO 22345 wherein a TEG group is attached to the AON.
WO475, US042, and Bonora do not teach yet another reason to apply TEG.
However, Gaziova, drawn to PEG–siRNA conjugates with enhanced gene silencing effects teaches (§Abstract) therapeutic application of RNAi can suffer from poor bioavailability caused by rapid degradation and elimination but that a PEG comprising only 12 ethylene glycol units enhances the pharmacokinetic properties of such RNAi biomacromolecules.
Gaziova teaches (§3. Discussion ¶1) PEGylation increases circulation time and masks immunostimulatory effects of modified oligonucleotides. Gaziova teaches (§3. Discussion ¶2) PEG can reduce RNAi potency but that reduction in potency is proportional to length of the PEG chains.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to attach the TEG of US042 to the AON of WO475, US042, and Bonora specifically for the specific benefits taught by Gaziova: increasing circulation time and masking immunostimulatory effects. One would have been motivated to do so with a reasonable expectation of success because WO475 teaches (p. 8 L8-11) modifying their AON to decrease immunostimulatory effects and increase biostability and because Gaziova teaches PEG, including short PEG, produces the outcomes of increased biostability and masking of immunostimulatory effects. Gaziova’s teaching that reduction in potency is proportional to length of the PEG chains would have motivated an artisan to use the shorter triethylene species of PEG disclosed by US042. Therefore, the outcome of a TEGylated AON reducing immunostimulatory effects vs the same AON without TEG would have been obvious in view of WO475, US042, Bonora, and Gaziova. Therefore all limitations of Claim(s) 1, 6-7, 15-16, 22-24, and 29-30 would have been obvious in view of WO475, US042, Bonora, and Gaziova.
Claim(s) 1, 6-7, 15-16, 22-24, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over WO475, US042, Bonora and Gaziova as applied to Claims 1, 6-7, 15-16, 22-24, and 29-30 above, and further in view of Kilanowska (and Studzinska. 2018. In vivo and in vitro studies of antisense oligonucleotides – a review. RSC Adv. 10:34501, “Kilanowska”, of record). This rejection is updated.
The teachings of WO475, US042, and Bonora as applicable to Claim(s) 1, 6-7, 15-16, 22-24, and 29-30 have been described above.
WO475, US042, Bonora and Gaziova teach a hydroxyalkoxylated AON consisting of one AON a one or two TEGs wherein the antisense oligonucleotide comprises SEQ ID NO 22333 or SEQ ID NO 22345, and many other potential modifications.
WO475, US042, Bonora and Gaziova do not teach yet another reason to apply TEG.
However, Kilanowska, drawn to a review about AON, teaches that (§3. FDA/EMA approved antisense Therapies- 3.10 Golodirsen [Vyondys 53™], Table 1) the FDA has approved the drug Golodirsen which is a 25-mer ASO for treating DMD. Kilanowska teaches that Golodirsen has a triethylene chain at its 5’end. That would have indicated to an artisan that the triethylene chain of Kilanowska is commonly used in exon-skipping AONs.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the AON of WO475, US042, Bonora and Gaziova with the 5’ TEG of Kilanowska for the benefit of improving stability of an AON using a moiety that is comprised by an FDA approved drug that treats the same condition as the AON sequences of WO475. One would have been motivated to do so with a reasonable expectation of success because Kilanowska teaches that Golodirsen is an AON drug for treating DMD that comprises a triethylene chain at its 5’ end, and the AON of WO875, US042, Bonora and Gaziova is also an AON for exon skipping. Modifying the hydroxyalkoxylated AON of WO475, US042, Bonora and Gaziova with the 5’ TEG of Kilanowska would have produced the limitations of Claims 1, 6-7, 15-16, 22-24, and 29-30.
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 1, 6-7, 15-16, 22-24, and 29-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US Pat No. 12331293 (previously copending Application No. 17309140 [reference application, “App140”]) in view of International Publication Number WO2018/007475 (published 11 January 2018, “WO475”; of record on IDS). All references are of record. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to (Claims 1, 6-7, and 16) a hydroxyalkoxylated AON consisting of an ASO and a TEG group, wherein the AON consists of the nt sequence of SEQ ID NO 22333 and the 3’- or 5’-terminal monomer of the AON is linked to the TEG group, or to (Claims 15 and 24) an AON consisting of the nt sequence of SEQ ID NO 22345, or to (Claims 22-23 and 29-30) an AON consisting of the nt sequence of SEQ ID NO 22345 wherein the AON is linked to a TEG group; to any of those AON wherein the TEG group can be attached to the AON through a PO or PS linker, and to pharmaceutical compositions comprising the AON consisting of the nt sequence of SEQ ID NO 22345, the TEGylated AON of SEQ ID NO 22333-PO or -PS, or the TEGylated AON of SEQ ID NO 22345-PO or -PS.
The issued App140 claims are directed to a compound comprising first and second AONs linked by a linking moiety wherein the first AON consists of the base sequence of SEQ ID NO 14; wherein the linking moiety can be a PEG, TEG, or HEG; wherein the AON comprises various modifications including BNA or LNA scaffold mods.
An artisan would not know what is instant SEQ ID NO 22333 or App140 SEQ ID NO 14 so they would go to each SEQ listing and find that those are identical sequences, as shown by the following alignment:
US-17-309-140A-14
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18
||||||||||||||||||
Db 1 GGUAAGUUCUGUCCAAGC 18
Therefore, both claim sets are directed to AONs comprising the same sequence and a TEG moiety. Even though the App140 claims recite a first and second AON, an artisan would have known they could use each piece individually. Furthermore the SEQ listings show that at least App140 SEQ ID NO 15980 (Claimed in App140 Claim 12) has the exact same modifications as instant SEQ ID NO 22345. Therefore it would not be possible to use the compounds of the App140 without the compounds of the instant claims.
Furthermore, although the App140 claims don’t explicitly recite using TEGylated SEQ ID NO 14 by itself, an artisan would have known that they could do so because WO475 teaches (p. 89, Table 3; p. 9 L15-25; p. 89 L24; p. 68 L20-25) using that nucleic acid sequence to induce skipping of exon 51. Therefore the instant claims would have been obvious in view of the App140 claims and WO475. In addition, instant Claim 15 now recites only the AON nucleotide sequence of SEQ ID NO 22345 and that is recited (although it’s called by a different SEQ ID NO) in the patented claims.
Claims 1, 6-7, 15-16, 22-24, and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18179064 (reference application, “App064”) in view of US Patent No. 9238042 (issued 19 January 2016, “US042”, of record), Bonora (et al. 1997. Synthesis and Characterization of High-Molecular Mass Polyethylene Glycol-Conjugated Oligonucleotides. Bioconjugate Chem. 8[6]:793–797, “Bonora”, of record), and Gaziova (et al. 2014. Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect. Bioorg. Medicin. Chem. 22:2320-2326, “Gaziova”). This rejection is updated.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to (Claims 1, 6-7, and 16) a hydroxyalkoxylated AON consisting of an ASO and a TEG group, wherein the AON consists of the nt sequence of SEQ ID NO 22333 and the 3’- or 5’-terminal monomer of the AON is linked to the TEG group, or to (Claims 15 and 24) an AON consisting of the nt sequence of SEQ ID NO 22345, or to (Claims 22-23 and 29-30) an AON consisting of the nt sequence of SEQ ID NO 22345 wherein the AON is linked to a TEG group; to any of those AON wherein the TEG group can be attached to the AON through a PO or PS linker, and to pharmaceutical compositions comprising the AON consisting of the nt sequence of SEQ ID NO 22345, the TEGylated AON of SEQ ID NO 22333-PO or -PS, or the TEGylated AON of SEQ ID NO 22345-PO or -PS.
The copending App064 claims are directed to an AON comprising the sequence of SEQ ID NOs including SEQ ID NO 4568 wherein the AON has a fully PS backbone, at last one 5-methyl C, and at least one BNA mod; wherein the AON can have other mods; and to methods of using the AON to treat DMD.
An artisan would not know what is claimed SEQ ID NO 22333 or App064 SEQ ID NO 4568 so they would consult the SEQ listing and find that the sequence are identical, as shown by the following alignment:
US-18-179-064-4568
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18
||:|||::|:|:||||||
Db 1 GGTAAGTTCTGTCCAAGC 18
Furthermore they wouldn’t know what is instant SEQ ID NO 22345 so they would consult the SEQ listing and find that it is identical to the sequence and mod pattern shown in App064 Claim 12. Therefore, both claim sets are directed to AONs comprising the same sequence.
The App064 claims don’t teach a TEG.
US042 teaches (Col 3 L45-61) splice-switching AONs that can include LNA and that (Col 34-35 L58-5) a short-interfering RNA (siRNA) (i.e., an AON is a species of siRNA) can be modified to stabilize one or more 3’- or 5’-terminus and such modifications can be non-nucleotidic compounds including triethylene glycol or hexaethylene glycol. Bonora, drawn to synthesis and characterization of polyethylene glycol-conjugated oligonucleotides, teaches a PEG linked to an AON via a PO linkage. That is shown in this excerpt of Fig. 1:
PNG
media_image3.png
172
217
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Greyscale
In addition, Gaziova teaches (§Abstract; §3. Discussion ¶1-2) pharmacokinetic, immunological, and persistence benefits of using PEG chains and, specifically, shorter PEG chains.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the AON of the App064 claims with the terminal TEG of US042 and Gaziova and attach it with the PO linkage of Bonora for the benefits of improving stability of the molecule, masking immunostimulatory effects, and increasing circulation time. One would have been motivated to do so with a reasonable expectation of success because US042 teaches adding a terminal TEG to improve nuclease resistance (which indicates that conjugating TEG to the AON improves its stability) and Gaziova teaches doing so to mask immunostimulatory effects, and increase circulation time. One would have attached the TEG via a PS linkage because US042 teaches (Col 25, 27) attaching moieties and PS linkages.
Therefore it would not be possible to use the compounds of the instant claims without the compounds of the App064 claims, US042, Bonora, and Gaziova. In addition, instant Claim 15 now recites only the AON nucleotide sequence of SEQ ID NO 22345 and that is recited (although it’s called by a different SEQ ID NO) in the copending claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6-7, 15-16, 22-24, and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-19 and 21-31 of copending Application No. 18192480 (“App480”) in view of International Publication Number WO2018/007475 (published 11 January 2018, “WO475”, of record on IDS). All references are of record. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to (Claims 1, 6-7, and 16) a hydroxyalkoxylated AON consisting of an ASO and a TEG group, wherein the AON consists of the nt sequence of SEQ ID NO 22333 and the 3’- or 5’-terminal monomer of the AON is linked to the TEG group, or to (Claims 15 and 24) an AON consisting of the nt sequence of SEQ ID NO 22345, or to (Claims 22-23 and 29-30) an AON consisting of the nt sequence of SEQ ID NO 22345 wherein the AON is linked to a TEG group; to any of those AON wherein the TEG group can be attached to the AON through a PO or PS linker, and to pharmaceutical compositions comprising the AON consisting of the nt sequence of SEQ ID NO 22345, the TEGylated AON of SEQ ID NO 22333-PO or -PS, or the TEGylated AON of SEQ ID NO 22345-PO or -PS.
The copending App480 claims are directed to an AON comprising or consisting of the sequence of SEQ ID NOs including SEQ ID NO 79; wherein the AON has at least one modification and can have various modifications including LNAs; and wherein the AON comprises a hydroxyalkoxy group that can be an ethylene glycol monomer/oligomer/polymer, including TEG or HEG; and to methods of inducing skipping of exon 51 in a subject with DMD.
An artisan would not know what is instant SEQ ID NO 22333 or App480 SEQ ID NO 79 so they would go to each SEQ listing and find that those are identical sequences, as shown by the following alignment:
US-18-192-480-79
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18
||:|||::|:|:||||||
Db 1 GGUAAGUUCUGUCCAAGC 18
Therefore, both claim sets are directed to AONs comprising the same sequence and a PEG, TEG, or HEG moiety.
The App480 claims do not recite the specific mod pattern of instant SEQ ID NO 22345 but WO475, also directed to AONs for skipping exon 51, teaches (p. 89, Table 3) SEQ ID NO 4568 which has the exact same modification pattern. WO475 teaches (p. 43 L20-21) SEQ ID NO 4568 is one of only 10 most preferred sequences. In addition those modifications are encompassed by the App480 claims. Therefore an artisan would have been motivated to modify the AON of the App480 claims with the mod pattern of WO475 SEQ ID NO 4568 for the benefit of using a specific AON sequence that comes highly recommended.
Therefore it would not be possible to use the compounds of the App480 without the compounds of the instant claims, and it would not be possible to use the compounds of the instant claims without the compounds that would have been obvious in view of the App480 claims and WO475. In addition, instant Claim 15 now recites only the AON nucleotide sequence of SEQ ID NO 22345 and that is recited (although it’s called by a different SEQ ID NO) in the copending claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6-7, 15-16, 22-24, and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 18311789 (reference application, “App789”). All references are of record. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to (Claims 1, 6-7, and 16) a hydroxyalkoxylated AON consisting of an ASO and a TEG group, wherein the AON consists of the nt sequence of SEQ ID NO 22333 and the 3’- or 5’-terminal monomer of the AON is linked to the TEG group, or to (Claims 15 and 24) an AON consisting of the nt sequence of SEQ ID NO 22345, or to (Claims 22-23 and 29-30) an AON consisting of the nt sequence of SEQ ID NO 22345 wherein the AON is linked to a TEG group; to any of those AON wherein the TEG group can be attached to the AON through a PO or PS linker, and to pharmaceutical compositions comprising the AON consisting of the nt sequence of SEQ ID NO 22345, the TEGylated AON of SEQ ID NO 22333-PO or -PS, or the TEGylated AON of SEQ ID NO 22345-PO or -PS.
The copending App789 claims are directed to a method of treating a subject with DMD by administering to the subject AON1 at certain doses and/or intervals.
An artisan would not know what is instant SEQ ID NO 22333 or App789 AON1 so they would go to the SEQ listing and the App789 Spec. and find that (¶32) they comprise identical sequences, as shown by the following alignment:
US-18-311-789-1
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18
||:|||::|:|:||||||
Db 1 GGUAAGUUCUGUCCAAGC 18
Furthermore, App789 defines (¶32) that AON1 comprises a TEG at its 5’end and the same modifications as instant SEQ ID NO 22345. Therefore, both claim sets are directed to AONs comprising the same sequence and a TEG moiety. In addition, instant Claim 15 now recites only the AON nucleotide sequence of SEQ ID NO 22345 and that is recited (although it’s called by a different SEQ ID NO) in the copending claims.
Therefore it would not be possible to use the compounds of the instant claims without the compounds of the App789 claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6-7, 15-16, 22-24, and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-42 of copending Application No. 19205950 (reference application, “App950”) in view of International Publication Number WO2018/007475 (published 11 January 2018, “WO475”; of record on IDS). This rejection is maintained and updated in view of the claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to (Claims 1, 6-7, and 16) a hydroxyalkoxylated AON consisting of an ASO and a TEG group, wherein the AON consists of the nt sequence of SEQ ID NO 22333 and the 3’- or 5’-terminal monomer of the AON is linked to the TEG group, or to (Claims 15 and 24) an AON consisting of the nt sequence of SEQ ID NO 22345, or to (Claims 22-23 and 29-30) an AON consisting of the nt sequence of SEQ ID NO 22345 wherein the AON is linked to a TEG group; to any of those AON wherein the TEG group can be attached to the AON through a PO or PS linker, and to pharmaceutical compositions comprising the AON consisting of the nt sequence of SEQ ID NO 22345, the TEGylated AON of SEQ ID NO 22333-PO or -PS, or the TEGylated AON of SEQ ID NO 22345-PO or -PS.
The copending App950 claims are directed to compounds for exon skipping and a method of treating a subject with DMD by administering to the compounds. The compounds comprise certain sequences and can comprise a TEG and a BNA. App950 claim 17 recites the compound comprises the base sequence of SEQ ID NO 14. App950 claims recite different modification patterns that encompass the same modification pattern as claimed SEQ ID NO 22333.
An artisan would not know what is instant SEQ ID NO 22333 or App950 SEQ ID NO 14 so they would go to the SEQ listing and the App950 Spec. and find that they comprise identical sequences, as shown by the following alignment:
US-19-205-950-14
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGUAAGUUCUGUCCAAGC 18
||:|||::|:|:||||||
Db 1 GGTAAGTTCTGTCCAAGC 18
Therefore, both claim sets are directed to AONs comprising the same sequence and a TEG moiety. Even though the copending claims recite a first and second AON, an artisan would have known they could use each piece individually.
Furthermore, although the App950 claims don’t explicitly recite using TEGylated SEQ ID NO 14 by itself, an artisan would have known that they could do so because WO475 teaches (p. 89, Table 3; p. 9 L15-25; p. 89 L24; p. 68 L20-25) using that nucleic acid sequence to induce skipping of exon 51. Therefore the instant claims would have been obvious in view of the App950 claims and WO475. In addition, instant Claim 15 now recites only the AON nucleotide sequence of SEQ ID NO 22345 and that is recited (although it’s called by a different SEQ ID NO) in the copending claims.
Therefore it would not be possible to use the compounds of the App950 without the compounds of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 19 February 2026 and 13 April 2026 have been fully considered but they are not persuasive. Each argument is addressed under the appropriate heading below. Arguments that are no longer relevant are not addressed.
Objections
The claim objections are applied because the claims recite minor typographical errors.
112(b)
The 112(b) rejections are applied because the claims are indefinite as discussed in the rejections.
102
The 102 rejection is necessitated by the claim amendments filed 13 April 2026. As explained in §Claim interpretation and the rejection, Claim 15 now requires only that the AON consists of the nucleotide sequence of SEQ ID NO 22345 which is interpreted to encompass a sequence of nucleotides wherein nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. The claim does not require any TEG.
103
Applicant argues against the 103 rejection on pp. 7-17 of the response filed 19 February 2026 and pp. 5-7 of the response filed 13 April 2026. Applicant’s declaration discusses (¶7-15) their results produce unexpected benefits.
Applicant argues that (§B) the cited references don’t provide a reason to arrive at the claimed AONs with a reasonable expectation of success and (§C) the claimed compounds produce unexpected results.
Regarding §B, Applicant argues that (p. 9, last ¶) US042 is directed to different compounds that are used for modulating IL-17 and/or IL-23 signaling.
That is not persuasive because all the compounds are nt compounds and the benefits imparted by TEG have nothing to do with any particular nt sequence but, rather, that TEG is attached to the nt sequence. Furthermore, as discussed in this and previous versions of the rejection, US042 teaches (Col 3 L45-61) the AONs of their invention can be splice-switching AONs and can include LNA. That means US042 teachings encompass linking TEG to either end of a splice-switching AON.
Applicant argues (p. 10 ¶1) TEG is in a generic list of terminal modifications and that doesn’t provide specific motivation to select TEG for a single stranded AON. Applicant argues that one of ordinary skill wouldn’t have taken a single TEG and attached it to the known AONs and arrive at the unexpected results discussed in §C.
That isn’t persuasive because an artisan would have used any of the components taught in US042 because US042 teaches specific modifications that stabilize the RNAi agent. Contrary to Applicant’s arguments that the teachings disclose “a laundry list” of potential modifications, there are really only 10-15 items on the list. In addition, Gaziova teaches PEG increases RNAi circulation time and masks immunostimulatory effects. Gaziova teaches although PEG can reduce RNAi potency, any reduction in potency is proportional to the length of the PEG chains. Those teachings would have motivated an artisan to select shorter PEG chains, including the TEG of US042.
Applicant argues (§B iii) that Bonora’s PEG is very large and a person of ordinary skill would have understood that large PEG—not a small PEG like TEG—would be necessary to stabilize an AON.
That isn’t found persuasive because Applicant has provided no evidence that only large PEG can stabilize an AON (and US042’s teaching indicates otherwise).
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
MPEP §716.01(c)
Furthermore, teachings in US042 indicate that TEG can stabilize an RNAi molecule—US042 specifically discloses using TEG for such purpose. In addition, Applicant’s argument isn’t persuasive in view of Gaziova’s teachings that disclose benefits of a 12-unit PEG and that shorter PEG chains reduce RNAi potency less than longer PEG chains.
Applicant argues (§B iii) that Kilanowska doesn’t render obvious a TEGylated AON because the compound in Kilanowska is a phosphorodiamidate morpholino (PMO). Applicant argues that Kilanowska teaches away from the claimed compounds because it teaches PMOs are more stable than a PS AON.
Those arguments aren’t persuasive because US042 and Gaziova both teach that TEG and short PEG have known functions and those functions result from their own structure—not the kind of molecule to which they’re attached. Applicant hasn’t provided any evidence or even stated any reasons why the terminal TEG moiety cares what kinds of linkages link the backbone of the AON to which it is appended. US042 discusses adding a terminal TEG to improve AON stability, and Applicant hasn’t explained why the backbone of either molecule is relevant to TEG’s effects.
Applicant then argues (§C, pp. 12-17; pp. 6-7) the claimed compounds produce unexpected results and provides data and cites three papers (van Deutekom and Oppeneer) to substantiate that assertion. Applicant argues that the improved properties are not taught or suggested, nor could they have been predicted based on the references cited in the Office Action.
That isn’t persuasive because Gaziova teaches that PEGylation achieves an increase in circulation time by reduction of renal filtration, masks immunostimulatory effects of modified oligonucleotides, and that longer PEG reduces RNAi potency in proportion to length of PEG chains. Those teachings indicate that linking a known AON to a short PEG (such as the known TEG of US042) was known to prolong circulation time in blood and to mask immunostimulatory effects. An artisan would understand that longer circulation time means there is a greater likelihood for any PEGylated AON—including a TEGylated AON—to be taken up by any tissues, including desirable target tissues such as the heart. An artisan would understand that the fact that PEG was known to mask immunostimulatory effects means a TEGylated AON would induce less complement activation than a nonTEGylated AON.
Applicant’s arguments (pp. 12-13) that Figs 1 and 2 increase dystrophin levels vs vehicle aren’t persuasive of unexpected results because an artisan would have expected that any known exon-skipping ASO would induce exon skipping at greater levels than a vehicle comprising no active ingredient. Furthermore, Fig. 1 shows Cmpd 1 (no TEG) and Cmpd 2 (TEG) induce similar levels of exon skipping. Similarly, and regarding Applicant’s arguments about ALP/ALT/AST (Fig. 3), both Cmpds 1 and 2 induce similar levels of ALP/ALT/AST.
Applicant’s arguments (pp. 13-14 and pp. 16-17) that Cmpd 2 results in lower complement levels than Cmpd 1 are not persuasive of unexpected results because the art (Gaziova) teaches that PEGylation was known to mask an RNAi’s immunostimulatory effects. While Applicant’s arguments and statements in their Declaration (¶8-12) that lower levels of C3a are particularly beneficial have been considered, they are not found persuasive in view of Gaziova’s teaching that PEGylation was known to mask an RNAi’s immunostimulatory effects. Note that whether the RNAi is an AON or a double stranded siRNA doesn’t bear on the obviousness of PEGylating an RNAi: the PEGylation itself masks an RNAi’s immunostimulatory effects.
Furthermore, PEG’s effects on reducing immunogenic reactions were known in the art. In addition to Gaziova, Stokman (et al. 2010. Application of siRNA in targeting protein expression in kidney disease. Adv. Drug Deliv. Rev. 62: 1378–1389, “Stokman”) teaches the effect was known:
(§4.2. Chemical modification of siRNA ¶6) immunogenic reactions may also be reduced by PEG complexing. PEG is nontoxic and soluble. PEG conjugated ODNs have longer half-life, higher stability against exonucleases and PEG increased cellular uptake. PEG coupling to an ASO induced more than 10-fold increase in exonuclease stability and prolongation of plasma half-life [79], but did not affect the ability of ODN hybridization [80]. Furthermore, the cellular uptake of ODNs can also benefit from PEGylation [81]. PEGylation … facilitate[es] cellular uptake of the conjugated drug. Additionally, PEGylation could potentially diminish the immunostimulatory effects of the ODNs.
Veronese (and Pasut. 2005. PEGylation, successful approach to drug delivery. Drug Discov. Today 10[21]:1451-1457, “Veronese”) teaches (§Abstract, Fig. 1) PEG-drug conjugates have several advantages and teaches mechanisms by which those advantages are imparted: the physical presence of the PEG prevents access by enzymes and antibodies. An artisan would have been familiar with such knowledge about PEG and would have PEGylated any drug, including an ASO for the known benefits of preventing its interaction with proteins in the body.
Applicant then argues (pp. 13-15, p. 7; Declaration ¶13-14) that van Deutekom and both Oppeneer papers show the TEGylated AON accumulates in the heart at greater levels than the same AON without TEGylation. Applicant argues that those results are unexpected.
Those arguments aren’t found persuasive because the art (US042 and Gaziova) teaches PEGylation—including a species of short PEG, TEG—inhibits nucleases and increases circulation time. Stokman discusses PEGylation prolongs plasma half-life and improves cellular uptake of oligonucleotides. An artisan would have expected that increased accumulation in the heart or any other tissue would be an inevitable outcome of PEG’s known functions. Longer half-life, better uptake, increased circulation time, and nuclease inhibition would all allow a molecule to persist longer in the body which increases the likelihood that it will reach (and be taken up by) any organ.
As stated previously, some benefits would have been expected when adding a TEG to any AON simply based on the teachings of US042 that terminal TEG(s) protects against nucleases and of Gaziova that PEG increases circulation time and masks immunostimulatory effects. Protection from nucleases allows the TEG-AON to persist in the blood stream and the longer it persists, the more likely it will accumulate in the heart. When arguing any results are “unexpected”, Applicant should consider that a known modification (in this case terminal TEG) will impart a known benefit (in this case resistance to nucleases, increased circulation time, making of immunostimulatory effects), so some improved performance by applying TEG to SEQ ID NO 22333 is expected. An “unexpected” result is a result that improves on that known benefit beyond what would have been expected already knowing that the modification produces benefits.
Altogether, none of the results presented or discussed demonstrate anything beyond what would have been expected by modifying the known elements of the prior art. All 103 rejections are maintained.
NSDP
Applicant’s arguments regarding App140 are not persuasive because both claim sets require a sequence identical to claimed SEQ ID NO 22345 (in the App140 claims it is called SEQ ID NO 14, as the alignment in the rejection made clear). Both claim sets require a TEG moiety. Furthermore, WO475 teaches App140’s SEQ ID NO 14 which demonstrates it was known to be effective even without a second AON. Therefore it would not be possible to use the claimed compounds without the compound of the App140 claims and it would not be possible to use the compound of the App140 claims without the claimed compound. Even though the App140 claims recite a first and second AON, an artisan would have known they could use each piece individually. Applicant argues that using the first or second AON separately would defeat the purpose of combining the AONs to provide a synergistic effect but that is not found persuasive because App140’s SEQ ID NO 14 was known to be useful by itself. In addition, instant Claim 15 now recites only the AON nt sequence and that is recited (by SEQ ID NO) in the patented claims.
Regarding Applicant’s arguments about App064 are not persuasive for the same reason their arguments against the 103 rejection are not persuasive: US042 teaches a TEG moiety, Bonora teaches adding an ethylene glycol moiety via an inter-nt linkage, and Gaziova teaches pharmacokinetic, immunological, and persistence benefits of using PEG chains and, specifically, shorter PEG chains. Those teachings would have motivated an artisan to add a short PEG, namely the TEG of US042 to the AON of the App064 claims. They would have thereby produced the claimed invention. In addition, instant Claim 15 now recites only the AON nt sequence and that is recited (by SEQ ID NO) in the copending claims.
Regarding Applicant’s arguments about App480, those are not found persuasive because App480 claim 1 recites SEQ ID NO 79 whose nt sequence is identical to the instantly claimed sequence, which the rejection shows. Regarding Applicant’s arguments about App789, the rejection explains how both claim sets are directed to AONs comprising the same sequence and a TEG moiety. An artisan would therefore realize it is not possible to use the copending App789 compounds without the claimed compounds. If and when allowable subject matter is indicated the rejections over later-filed App480 and App789 will be withdrawn but it cannot be withdrawn until allowable subject matter is indicated. In addition, instant Claim 15 now recites only the AON nt sequence and that is recited (by SEQ ID NO) in the copending claims.
Regarding Applicant’s arguments about App950, those are not found persuasive for the same reason the arguments against the rejection over App140 were not found persuasive: although the App140 claims don’t explicitly recite using TEGylated SEQ ID NO 14 by itself, an artisan would have known that they could do so because WO475 teaches (p. 89, Table 3; p. 9 L15-25; p. 89 L24; p. 68 L20-25) using that nucleic acid sequence to induce skipping of exon 51. In addition, instant Claim 15 now recites only the AON nt sequence and that is recited (by SEQ ID NO) in the copending claims.
Therefore all NSDP rejections are maintained.
Conclusions
Claims 1,6-7,15-16,22-24 and 29-30 are rejected.
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.
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights