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 .
Claim Status
Claims 152-172 are pending and are examined here.
Priority
Acknowledgement of domestic benefit of U.S. Provisional Application 62/363,193, filed on 07/15/2016, is noted. All claims enjoy the benefit of the filing date (07/15/2016) of Application ‘193.
Claim Rejections - 35 USC § 112
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.
Claim 160 is 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. Claim 152 recites “wherein the target precursor transcript is not SMN2 pre-mRNA.” Claim 160’s SEQ ID NOs: 3-5 appear to target SMN2 (see specification pg. 50, Table 6), so claim 160 appears to broaden the scope set forth in claim 152. 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.
In the interest of compact prosecution, claim 160 is interpreted to not recite SEQ ID NOs: 3-5, so claim will be examined for one of SEQ ID NOs: 6-8, which appear to target dystrophin pre-mRNA (see Table 13).
Claim Rejections - 35 USC § 102
Rejection of claims 152-159; 161-165; 167-172 under 102(a)(1) is maintained.
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 152-159; 161-165; 167-172 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. Patent to Stoffel et al. (US 8,541,385, referred as Stoffel).
Regarding instant claim 152, The Formula II is below, one species noted in the specification termed 2-O-NMA or (N-methyl acetamide) when R1 is hydrogen and R2 is a methyl (see pg. 22, line 14-15):
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Stoffel discloses chemically modified oligonucleotides (antagomirs) useful for modulating expression of microRNAs (miRs) (Col. 1, line 29-31). The antagomirs of Table 2a are single stranded and are 21 nt. in length, thus a species of recited range of 14-25 linked nt. (Col. 10, line 31-41) and are stabilized against nucleolytic degradation through nucleotide modification (Col. 2, lines 55-66). Claim 3 teaches a Markush group of 2’ modified nucleotide, including 2’-O-NMA (2’-O-N-methylacetamido, 2NMA) and 2’-O-methyl (2OMe), and 2’-O-MOE (2MOE); MPEP 2117 provides that a “Markush” claim recites a list of alternatively useable members and indicates members of the group share a single structural similarity and have a common use. Thus by definition all taught modification of a 2’ modification in a Markush claim are interchangeable, thus even though Stoffel discloses a species of a sequence with each nt. with a 2OMe modification (see Table 2a, Col. 10, line 31-41, all 4 antagomirs comprise with each nt. is a 2OMe modified nt.), any of the Markush species will, by definition, be used for the same purpose of providing stability and share the 2’-modification structure. And MPEP 2152.02(b) provides that in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. Here, the 2OMe species is enabled.
The antagomirs of Stoffel do not target a precursor transcript of survival of motor neuron 2 (SMN2) pre-mRNA.
Instant specification defines “splice site” is a region of a precursor transcript, and in the event that an oligonucleotide hybridizes to said region, the splicing of the precursor transcript is subsequently modulated. (pg. 7, line 30-31).
Stoffel discloses that miRNAs are processed from hairpin precursors of 70 nt. (pre-miRNA) which are derived from primary transcripts (pri-miRNA) (Col 1., line 45-50). Thus, antagomir-122 of Table 2a is complementary to its mature miRNA, a pre-miRNA, or pri-miRNA, since each of these sequences comprises the miR-122 sequence and thus, by definition, the antagomir is complementary to a splice site of a target precursor transcript.
Regarding instant claim 153, the limitation “modulates processing of the target precursor transcript” does not provide any additional structural limitation and antagomir taught by Stoffel meets the structural limitation of the claim. Under the principle of inherency in MPEP 2112.02, here, the prior art antagomir that meets all the structural limitation, in its normal and usual operation, would necessarily perform modulating processing of the target precursor transcript. Regardless, Stoffel discloses that the antagomir can modulate the function of the targeted precursor transcript (Col 1., line 45-50).
Regarding instant claim 154, the limitation “modulates processing of the target precursor transcript in the muscle or in the CNS” does not provide any additional structural limitation and antagomir taught by Stoffel meets the structural limitation of the claim. Under the principle of inherency in MPEP 2112.02, here, the prior art antagomir that meets all the structural limitation, in its normal and usual operation, would necessarily perform modulating processing of the target precursor transcript. Regardless, Stoffel discloses administration of desirable antagomir to a mammal suffering from a disease of the CNS (Col. 17, line 51). Stoffel also discloses local cortical administration in mice of antagomir to miR-16, which is expressed in the CNS (Col. 54-56, Col. 73, lines 11-24), to inhibit expression of miR-16, see Fig. 22 demonstrating decrease in miR-16 levels (also see Col. 73, lines 11-24), thus Stoffel compound’s modulates processing of the target precursor transcript occurring within the CNS.
Regarding instant claims 155, 156, 157, 158, 159, also termed 2-O-NMA or (N-methyl acetamide) when R1 is hydrogen and R2 is a methyl (see specification pg. 22, line 14-15)
Stoffel teaches a fully modified antagomir-122 in Table 7 with varying nt. length, SEQ ID NO: 33 is 19 nt., SEQ ID NO: 34 is 17nt. (Col. 69-70, relevant to instant cl. 155). Each nt. is modified with 2OMe and claim 3 of Stoffel teaches a Markush group of 2’ modified nucleotide, including 2’-O-NMA (2’-O-N-methylacetamido, also 2NMA) and 2’-O-methyl (2OMe), and 2’-O-MOE (2MOE); MPEP 2117 provides that a “Markush” claim recites a list of alternatively useable members and indicates members of the group share a single structural similarity and have a common use. Thus by definition all taught modification of a 2’ modification in a Markush claim are interchangeable, thus even though Stoffel discloses a species of a sequence with each nt. with a 2OMe modification, any of the Markush species will, by definition, be used for the same purpose of providing stability and share the 2’-modification structure (relevant to instant cl. 156-159).
Regarding instant claim 161-162, Stoffel in Table 7, discloses a specific SEQ ID NO: 34, a sequence of 17 linked nt. (Col. 69-70), a species within the recited range of the claims, thus reads on cl. 161 and 162.
Regarding instant claim 163, Stoffel discloses a phosphorothioate backbone and SEQ ID NO: 9 of Table 7 comprises an antagomir with each internucleotide linkage (INL) as a phosphorothioate (PS) (Col. 69-70).
Regarding instant claim 164, 165, Stoffel discloses in Table 7 SEQ ID NO: 5, an antagomir, that is 100% complementary to SEQ ID NO: 1, a miR-122 sequence (Col. 69-70, relevant to instant cl. 164). The antagomir does not target a precursor transcript of dystrophin pre-mRNA (relevant to instant cl. 165).
Regarding instant claim 167, 168, 169, Stoffel discloses antagomirs in Table 2a, which are single stranded and are 21 nt. in length and have a cholesterol conjugate at the 3’ end, thus a species of recited range of 14-25 linked nt. (Col. 10, line 31-41, relevant to instant cl. 167-168) and are stabilized against nucleolytic degradation through nucleotide modification (Col. 2, lines 55-66). Claim 3 teaches a Markush group of 2’ modified nucleotide, including 2’-O-NMA (2’-O-N-methylacetamido) and 2’-O-methyl (2OMe), and 2’-O-MOE (2MOE); MPEP 2117 provides that a “Markush” claim recites a list of alternatively useable members and indicates members of the group share a single structural similarity and have a common use. Thus by definition all taught modification of a 2’ modification in a Markush claim are interchangeable, thus even though Stoffel discloses a species of a sequence with each nt. with a 2OMe modification (see Table 2a, Col. 10, line 31-41, all 4 antagomirs comprise with each nt. is a 2OMe modified nt.), any of the Markush species will, by definition, be used for the same purpose of providing stability and share the 2’-modification structure. And MPEP 2152.02(b) provides that in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. Here, the 2OMe species is enabled.
Instant specification defines “splice site” is a region of a precursor transcript, and in the event that an oligonucleotide hybridizes to said region, the splicing of the precursor transcript is subsequently modulated. (pg. 7, line 30-31).
Stoffel discloses that miRNAs are processed from hairpin precursors of 70 nt. (pre-miRNA) which are derived from primary transcripts (pri-miRNA) (Col 1., line 45-50). Thus, antagomir-122 of Table 2a is complementary to its mature miRNA, a pre-miRNA, or pri-miRNA, since each of these sequences comprises the miR-122 sequence and thus, by definition, the antagomir is complementary to a splice site of a target precursor transcript.
Regarding instant Claim 170, Stoffel discloses antagomir modification includes a targeting moiety such as carbohydrate sugars, such as N-acetylgalactosamine (Col. 22, line 66).
Regarding instant Claim 171, Stoffel discloses a pharmaceutical composition can include one or more oligonucleotide agents and a pharmaceutical acceptable carrier (Col. 42, line 11-15).
Regarding instant Claim 172, Stoffel discloses a Fig. 1A with no visible expression, i.e. modulated the expression of target precursor transcript, of miR-122 following intravenous treatment of mice with antagomir-122 (Col. 52, line 18-30). Here, the antagomir is capable of binding to all precursors as well as mature forms.
Response to Arguments
Applicant's arguments filed 12/09/2025 (hereinafter noted as the Remarks) have been fully considered but they are not persuasive.
Applicant raises various arguments (pg. 5-9):
The Remarks continue to cite the Arkley case, the Remarks note that “reference must clearly and unequivocally disclose the claimed compound or direct those skilled in the art to the compound without any need for picking, choosing and combining various disclosures” (pg. 6, underline emphasis added).
The argument is not persuasive. Here, for the anticipation rejection, only a single disclosure is applied, thus Arkley does not apply.
The Remarks argue that Stoffel does not teach every element of instant claim 1, i.e. does not teach the 12 consecutive nt. of the modified oligonucleotide each having a structure of Formula II; does not disclose that modified oligonucleotide is complementary to a splice site of a target precursor transcript (pg. 6). Further adds that Stoffel only discloses modified oligomer for “modulating expression of microRNAs and pre-microRNAs” (pg. 6, also pg. 9). The Remarks note additional meaning of splicing specifically targeting pre-mRNA, i.e. removal of introns to join together exons and distinguishes it from splicing of miRNAs (pg. 9).
The argument is not persuasive. Stoffel as indicated above does teach a Markush grouping in claim 3, including 2’-O-NMA, a species of instant Formula II, and discloses targeting a splice site as broadly interpreted in the light of the specification. Further, here, the limitation “the modified oligonucleotide is complementary to a splice site of a target precursor transcript” is a functional limitation and as much as the functional limitation requires a fully modified oligomer that is complementary to function as a splice switching oligomer, Stoffel discloses a fully modified oligomer that is complementary to the target splicing site as defined by the specification and therefore meets the functional limitation and fulfill the function as a splice-switching oligonucleotide, as understood by a skilled artisan, but is disclosed by Yang.
Further the Remarks argue that “[n]owhere” does Stoffel teach at least 12 consecutive nucleosides of modified oligonucleotide comprising modification of Formula II and thus the compounds of Stoffel are not identical (the Remarks, pg. 7). The Remarks note that 2’-O-NMA (methylacetamido) is mentioned 4 times as “one possible modification in a list of at least eleven potential modifications” and that Stoffel does not suggest specifically selecting 2’-O-NMA (pg. 6). The Remarks suggest that “one considering Stoffel would not have recognized or envisioned any compound in which at least 12 consecutive 2’-NMAs are present,” because it is mentioned only 4 times and no examples with the claimed modification are provided (pg. 7).
The argument is not persuasive. The Remarks conflate multiple statutory issues in arguing against an anticipatory rejection. The issue of “would not have recognized or envisioned” is a written description matter and lack of examples is an enablement matter. It is not clear if the Remarks suggest that the Patent of Stoffel has both the issues. A patent is presumed to be enabled. Here, the Remarks fail to provide evidence why the product would not work. A skilled artisan can envision (easily) an oligomer comprising a fully modified oligonucleotide, i.e. at least 12 consecutive nucleoside, with 2’-O-NMA modification. E.g. Stoffel discloses a modified SEQ ID NO: 8 (see below; Col. 10, line 38-40, Table 2a) and discloses in cl. 3, which is a Markush claim, 2’-modified nucleotides comprising a group of nine 2’-modifications, one includes 2NMA as a 2’-modified nucleotide.
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A skilled artisan can envision any one of the 2’-modification of claim 3 for SEQ ID NO: 8, i.e. all the lower case letters can be 2NMA and therefore has more than 12 consecutive modified nt. Further, being a Markush claim the species are presumed to function similarly, unless the Applicant can provide evidence otherwise.
Further, a disclosure does not require a minimum number of articulation before it becomes a disclosure, once is sufficient. Stoffel not only mentions it in its specification but also claims it. Although Stoffel mentions 2’-NMA four times (as Remarks indicate on pg. 6), the structure is described differently additional times (see Col. 26, line 33, as its described as a 2’-O-CH2CO-NHMe or even as its genus group of 2’-modification(s)). Regardless of the times 2’-O-NMA is described in the prior art, under MPEP, the structure only needs to be explicitly described by the prior art. Further, Stoffel demonstrates the activity of one of the Markush species of claim 3, antagomirs of various lengths (21 nt. to 17 nt.) that is fully modified with the 2OMe nt. modification.
The Remarks insist disclosure of 2OMe by Stoffel is irrelevant since the claims do not recite 2OMe modification (pg. 8). Further, based on claim 3 reciting nine possible 2’-modifications, the Remarks proceed to provide that claim 3 of Stoffel encompasses 915 to 925 different possible 15-25-mer oligomers (pg. 8). Thus, this astronomical number of theoretical possibilities is not a teaching of the identical invention and “picking and choosing is not a proper basis for anticipation” (pg. 8).
The argument is not persuasive. The disclosure is useful for all it discloses, and claim 3 of Stoffel patent discloses a Markush claim, and under MPEP 2117, a ‘Markush" claim recites a list of alternatively useable members.” So it is relevant that Stoffel notes 2OMe is a species, along with 2’-O-NMA, in claim 3. Further, it is relevant that Stoffel provides examples of one species, i.e. the 2OMe, from the genus of 2’-modified nucleotide of claim 3.
The instant claim encompasses a fully modified oligomer comprising all nucleotide having the same 2’-ribose modification and not a mixmer, i.e. different 2’-modifications in one oligomer. As noted above, e.g., Stoffel’s SEQ ID NO: 8 teaches a fully 2OMe modified and claim 3 teaches a Markush claim with nine different 2’-ribose nucleotide modifications that serve the same purpose. Here, a skilled artisan can substitute any of the 8 modifications, since 2OMe is also recited in claim 3, for similar function. Thus, there is no picking or choosing an astronomical number when a) the Markush claim provides that species are interchangeable and b) all 2’-modification are the same.
Thus, Stoffel clearly anticipates the invention of instant claims 152-159; 161-165; 167-172.
Claim Rejections - 35 USC § 103
Rejection of claim 152, 164 and 166 is maintained. While rejection of cl. 160 is withdrawn due to claim amendment, and upon further search, claim 160 is rejected as noted below.
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.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 USPQ2d 1385 (2007):
“Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.”
Claims 152, 164, 166 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (2013, PLoS One, 8, 1-8, referred as Yang) and Prakash et al. (2003, Organic Letters, 5, pg. 403-406, referred as Prakash).
Yang discloses a 2MOE-phosphorothioated-modified oligonucleotide of various lengths (20 and 25 nt.) that effectively induce exon skipping with improved dystrophin expression in vitro and in local intramuscular studies (pg. 7, see also Table 1 and Fig. 1, relevant to instant cl. 164, 166). Yang discloses a 20 nt. exon-splicing oligonucleotide (see Table 1 for the sequence associated with abbreviation “MOE20PS”).
Yang does not disclose 2’-O-NMA nt. modification.
Prakash discloses various 2’-O-position ribose modification, including 2’-O-NMA and other amino based 2’-ribose modifications (relevant to instant cl. 152). When exposed to snake venom phosphodiesterase to assess metabolic stability, the 2’-O-NMAc lasted longer than 2MOE modified oligonucleotide (see Fig. 3, pg. 406). Further, Prakash postulates that 2’-O-NMAc should be more lipophilic than 2MOE thus improve protein binding and cellular permeation properties (pg. 403-404).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the 2MOE nt. modification of Yang in view of Prakash and arrive at the claimed invention with a reasonable expectation of success. Here, Prakash shows improved stability against enzymatic degradation of 2’-O-NMA than 2MOE, thus a skilled artisan would have expected an improved stability when the 2MOE modified exon-skipping oligonucleotide is substituted with a fully modified 2’-O-NMA nt. modification. Thus, claims 152, 164, 166 are obvious.
Claims 152, 160 are rejected under 35 U.S.C. 103 as being unpatentable over van Deutekom et al. (2007, N Engl J Med, 357, 2677-2686) and Prakash et al. (2003, Organic Letters, 5, pg. 403-406, referred as Prakash).
Claim 160 recites SEQ ID NO: 7 with a sequence of tcaaggaaga tggcatttct, a 20 nt. ASO.
van Deutekom discloses targeting DMD gene in human subjects with the following exon-skipping sequence: UCAAGGAAGAUGGCAUUUCU-3 (aka “PRO051”, the U is technically a T, since when a T is modified at its 2’-ribose position, it technically lacks a hydrogen (not a DNA), and all the nucleotides of PRO051 are 2’-OMe modified and, further, all internucleotide linkages are PS (pg. 2679). Thus, van Deutekom’s sequence is identical to instant SEQ ID NO: 7 and comprises at least 18 contiguous nucleobases of SEQ ID NO: 7 that are all modified with same 2’-modification. Further van Deutekom demonstrates administration of PRO051 “showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers” and found increased protein expression of dystrophin (abstract, p. 2677).
van Deutekom does not disclose 2’-O-NMA nt. modification.
Prakash discloses various 2’-O-ribose modification, including 2’-O-NMA (relevant to instant cl. 152). When exposed to snake venom phosphodiesterase to assess metabolic stability, the 2’-O-NMA lasted longer than 2MOE modified oligonucleotide (see Fig. 3, pg. 406). Further, Prakash postulates that 2’-O-NMAc should be more lipophilic than 2MOE thus improve protein binding and cellular permeation properties (pg. 403-404); thus it also reasons that due to 2’-O-methyl having fewer carbons than 2MOE that 2’-O-NMAc would also be more lipophilic than 2’-O-methyl.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the 2OMe modifications of PRO051 of van Deutekom in view of Prakash and arrive at the claimed invention with a reasonable expectation of success. Here, Prakash shows improved stability against enzymatic degradation of 2’-O-NMA than 2MOE and Prakash proposes that 2’-O-NMA is more lipophilic with improved cellular permeability, thus a skilled artisan would have expected an improved properties when the exon-skipping oligonucleotide with 2OMe modified nucleotides is substituted with 2’-O-NMA modified nt., since 2OMe is less lipophilic than 2MOE. Thus, claim 160 is obvious.
Response to Arguments
Applicant's arguments filed 12/09/2025 (“the Remarks”) regarding claims 152, 164, 166 have been fully considered but they are not persuasive.
The Remarks raises the following arguments:
Use of impermissible hindsight rationale (pg. 10).
The argument is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). All the prior art of record have been disclosed prior to the filing of the instant application.
Nothing in Yang would have led one of ordinary skill in the art to even consider a 2’-O-NMA nucleoside, since the 2MOE/PS AOs are effective; and the Examiner fails to provide a reason that a skilled artisan would modify AO of Yang (pg. 11).
The argument is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, it is not Yang alone, but rather in combination with Prakash. Prakash teaches the rationale for modifying an oligonucleotide with 2’-O-NMA modification.
The Remarks then proceeds to challenge the use of Prakash reference by detailing the reference and notes that four 2’-O different amino groups were tested (pg. 11) and that Prakash does not specifically highlight improved properties of 2’-O-NMA (pg. 11), nor does Prakash compare RNA or DNA hybridization (pg. 11). The Remarks note that Prakash highlights the following: “The enzymatic stability of the 2’-O-modified oligonucleotides studied decreased in the following order 2’-O-DMAEAc > 2’-O-NMAc > 2’-O-DMAc > 2’-O-NAc > 2’-O-MOE >> 2’-deoxy” and that “[a]ll four of the tested 2’-O-[2(amino)-2-oxoethyl] modifications outperformed the 2’-O-MOE modification with 2’-O-DMAEAc, not 2’-O-NMA, showing the most stability” and then also notes that 2’-O-DMAEAc and 2’-O-NMAc -oligonucleotides were the most synthetically feasible and have been selected for further biological evaluation” (pg. 11).
The argument is not persuasive. The Remarks itself provides rationale that was cited in the action or can be gleaned by a skilled artisan. The Action noted improved nuclease resistance when exposed to snake venom phosphodiesterase and more lipophilic than known 2MOE modification as rationales for substituting an oligonucleotide with 2NMA of Prakash for the 2MOE of Yang, and are sufficient rationales under a reasonable basis for an obviousness rejection. DNA hybridization is not required, since the target is a complementary RNA. Prakash discloses Tm data for the oligonucleotides hybridized to complementary RNA showing improved Tm data, i.e. improved binding to target complementary RNA (see Table 2). It is not essential that Prakash did not perform a comparison between their novel 2’ modifications and 2MOE for hybridization to a complementary strand, Prakash demonstrates that the novel modifications i) imparted significant stability, ii) showed excellent binding affinity and iii) nuclease stability (pg. 406); and (iv) will be pursuing further studies with 2’-O-NMAc and 2’-O-DMAEAc oligonucleotides since they are synthetically feasible (as also noted by the Remarks). Thus a skilled artisan would reasonably expect similar or improved activity, since the 2’-amino modifications of Stoffel did not interfere with the hybridization.
Regarding the argument that 2’-O-DMAEAc would be preferred by a skilled artisan, the MPEP 2123 notes that patents are relevant as prior art for all they contain, and a preferred embodiment does not constitute a teaching away from a nonpreferred embodiment. Regardless, reviewing the Prakash for all it discloses, a skilled artisan may prefer 2NMA over 2’-O-DMAEAc based on both Tm data and nuclease data, as Tm data for 2’-NMA shows a stronger hybridization (1.7 delta Tm/unit) than for 2’-O-DMAEAc (1.4 delta Tm/unit) (see Table 2), while both have improved nuclease resistant compared to 2MOE. Further, addition of reasonable number of the same 2’-modification would be obvious. A skilled artisan based on Stoffel’s data, would reasonably expect success adding four or more, i.e. 12 to 20, 2’-NMA modification.
Finally, the Remarks argue for unexpected results. The data (Ex. 1-5) discussed in the Remarks are concerning targeting SMN2 (pg. 14). The Remarks add that results based on 2-NMA “could not have been expected based on Prakash” (pg. 14).
The argument is not persuasive. SMN2 data is not relevant, as both independent claims recite “target precursor transcript is not SMN2.” Regardless the instant specification shows a slight improvement with the 2NMA (443305 compound) modification compared to 2MOE (396443 compound), but in view of the data noted by Prakash, the improved results are expected. The Remarks do not provide sufficient evidence as to why the results could not have been expected based on Prakash. Prakash demonstrates an improved nuclease resistance and suggests an improved cellular permeation for 2NMA, thus a skilled artisan would expect improved results.
Further the claims are broader in scope than the results provided; MPEP 716.02(d) requires unexpected results to be commensurate with claimed invention. The Formula II is a genus of multiple recited species and discloses only the results of the following species of Formula II, wherein R1=H and R2 is methyl.
Double Patenting
Rejection of all examined claims under obvious double patenting in view of US Patent 6,147,200 is maintained, while the rejection in view of US Pat. 1129973 or US Apps. 18/940375 or 17/187018 has been withdrawn due to claim amendment or the application has been abandoned.
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.
U.S. Patent No. 6147200
Claims 152-164, 166, 172 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 15, 28, 29, 30, 46 of U.S. Patent No. 6147200 (referred as Ionis, issued 11/14/2000; it is understood that Isis Pharmaceuticals Inc. received the patent, but Isis changed their name to Ionis) in view of Yang et al. (2013, PLoS One, 8, 1-8, referred as Yang) and Prakash et al. (2003, Organic Letters, 5, pg. 403-406, referred as Prakash).
Excerpt of Ionis claims 15, 28, 29, 30, 45 are below:
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The teaching of claims 15, 28-30 is directed to an oligomeric compound comprising a modified oligonucleotide consisting of 14-25 linked nt., where there is an overlap of range, i.e. claims 15 and 30, MPEP 2131.03(II) teaches that the prior anticipates the ranges, and where there is while MPEP 2144.05 provides that where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exit, i.e. cl. 15, 28-30. Further, claim 45 teaches that both E1 and E2 are CH3, both a species of genus of Formula II. Thus, Ionis teaches a 14-25 linked nt. with one embodiment is a modified oligonucleotide with 2’-O-NMA modified nt. (relevant to instant cl. 152, 161, 162).
Ionis does not teach at least 12 consecutive nucleosides of the modified oligonucleotide each comprising the 2’-acetomide structure nor where the nucleobase sequence is complementary to a splice site of a target precursor transcript.
MPEP 2144(VI)(B) provides that duplication of parts has no patentable significance unless a new an unexpected result is produced. Here, since Ionis teaches a linked 14-25 modified oligonucleotide along with synthesis of monomer of 2’-O-NMA, they can be duplicated as many times as necessary to create a functional oligonucleotide (relevant to instant cl. 152, 155)
Further, Prakash discloses various 2’-O-position ribose modification, including 2’-O-NMAc (same as 2’-O-NMA noted above, see Fig. 1 of Prakash below).
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When exposed to snake venom phosphodiesterase to assess metabolic stability, the 2’-O-NMAc lasted longer than 2MOE modified oligonucleotide (see Fig. 3, pg. 406). Further, Prakash postulates that 2’-O-NMAc should be more lipophilic than 2MOE thus may have better protein binding and cellular permeation properties (pg. 1). Thus Prakash discloses the inherent beneficial properties of 2’-O-NMA.
Neither Ionis nor Prakash teach a modified oligonucleotide complementary to a splice site of a target precursor transcript (cl. 152, 153) nor teach oligomeric compound modulating processing of the target precursor transcript in the muscle or CNS (cl. 154) nor teach oligomeric compound wherein each nucleoside of the modified oligonucleotide is selected form a nucleoside of Formula II and a nucleoside comprising a 2’-MOE sugar moiety (cl. 157), nor teach the target precursor transcript is dystrophin pre-mRNA (cl. 166), nor a method of modulating processing of target precursor transcript, comprising contacting a cell with an oligomeric compound (cl. 172).
Yang discloses a fully modified 2MOE-phosphorothioated-modified oligonucleotide of various lengths (20 and 25 nt.) that effectively induce exon skipping with improved dystrophin expression in vitro and in local intramuscular studies (pg. 7, see also Table 1 and Fig. 1, relevant to instant cl. 152, 153, 154, 156, 157, 163, 164, 166, 172). Yang provides that incorporating phosphorothioate bonds (PS) instead of phosphodiester (PO) in 2MOE chemistry increases stability and sequence-specificity (pg. 3). Yang postulates that 2MOE-PS modified oligonucleotide improved cellular uptake (pg. 7). Further exon-splicing oligonucleotides are capable of effecting splice correction of aberrant disease-related pre-mRNA transcript by exclusion of dysfunctional exons and restoring a functional dystrophin, although a shorter product, which has potential to treat Duchenne Muscular Dystrophy (DMD) (pg. 1). Yang discloses a 20 nt. exon-splicing oligonucleotide, thus the 20 nt. sequence designated MOE20PS has at least 12 nucleobases (4-As, 4-Ts, 4-Gs) of instant SEQ ID NO: 3 (see Table 1, pg. 2, for the sequence associated with abbreviation “MOE20PS”, relevant to instant cl. 160).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the 2’-O-NMA of Ionis in view of teachings of Prakash and Yang and arrive at the claimed invention with a reasonable expectation of success. Here, Ionis shows making the 2’-O-NMA oligonucleotide and Prakash shows improved stability against enzymatic degradation of 2’-O-NMA than 2MOE, thus a skilled artisan would have expected an improved stability activity when the 2MOE nt. modified exon-skipping oligonucleotide of Yang is substituted with a fully modified 2’-O-NMA nt. modification. Thus, claim 152-164, 166, 172 are obvious.
Claims 152, 164, 165, 167, 168, 169, 170, 171 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 28, 29, 30, of U.S. Patent No. 6147200 (referred as Ionis) in view of Yang et al. (2013, PLoS One, 8, 1-8, referred as Yang) and Prakash et al. (2003, Organic Letters, 5, pg. 403-406, referred as Prakash) as applied to claims 152-164, 166, 172 and further in view of U.S. Patent to Stoffel et al. (US 8,541,385, referred as Stoffel, issued 09/24/2013).
Disclosure of rejection of 152-164, 166, 172 is noted above.
Neither Ionis, Yang and Prakash teach a conjugated oligomeric compound comprising a conjugate, where the conjugate is a cholesterol or GalNAc nor a non-SMN2 and non-dystrophin precursor target transcript (cl. 165) nor a pharmaceutical composition of oligonucleotide and pharmaceutical carrier (cl. 171).
Stoffel discloses in Fig. 1A (see below) that antagomir-122, which is bound at 3’ end with a cholesterol moiety conjugate, demonstrates a “striking reduction of endogenous miR-122,” (see Table 2a, Col. 10, line 31; and Col. 52, line 24-30, relevant to instant cl. 165, 167-169), while the unconjugated yet chemically-stabilized single-stranded RNAs with complete (fS) phosphorothioate backbone and 2OMe sugar modification (anti-122fS) led to incomplete effect following intravenous injection of the oligonucleotides in mice to detect the target endogenous miR-122 in the liver (Col. 52, line 30-36).
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Stoffel discloses antagomir modification includes a targeting moiety such as carbohydrate sugars, such as N-acetylgalactosamine (Col. 22, line 66, relevant to instant cl. 170). Stoffel discloses a pharmaceutical composition can include one or more oligonucleotide agents and a pharmaceutical acceptable carrier (Col. 42, line 11-15, relevant to instant cl. 171).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified Ionis oligonucleotide comprising 2’-O-NAc in view of Yang and Stoffel and arrive at the claimed invention with a reasonable expectation of success. Here, based on Stoffel’s striking results with a cholesterol conjugate bound to an oligonucleotide to inhibit target gene in vivo, a skilled artisan would reasonably expect a successful outcome of conjugating a cholesterol moiety to an Ionis oligomeric compound for inhibiting a target gene in vivo. Similarly, a skilled artisan would reasonably expect a successful outcome by conjugating a GalNAc moiety to target relevant cells. Thus, claims 152, 164, 165, 167, 168, 169, 170, 171 are obvious.
Response to Arguments
Applicant's arguments filed 12/09/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue the following:
Regarding Patent 6,147,200 (‘200), the Remarks note many deficiencies of ‘200 and note that the Yang, Prakash and Stoffel fail to cure the deficiencies “[f]or at least the reasons discussed above” (pg. 17).
The argument is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The reference(s) addressed for the 103 rejection has been noted above. The references noted make the claims obvious.
Regarding Patent 11,299,737, the Remarks argue that the independent claims are amended to recite “wherein the target precursor transcript is not SMN2 pre-mRNA” (pg. 18).
The argument is persuasive. The rejection of claims in view of ‘737 is withdrawn.
Regarding Application, 18/940,375, the Remarks argue that the independent claims are amended to recite “wherein the target precursor transcript is not SMN2 pre-mRNA” (pg. 19).
The argument is persuasive. The provisional rejection in view of ‘375 is withdrawn.
Regarding Application 17/187,018, the Remarks argue that the application is withdrawn.
The argument is persuasive. The provisional rejection is withdrawn since the application is abandoned as of 06/04/2025.
Allowable Subject Matter
No claim allowed.
Conclusion
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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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600