DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1, 7, 27, 28, 30, 56-57, 59 are pending.
Claims 1, 7, 27, 28 are examined here, and claims 30, 56, 57, 59 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/21/2024.
Priority
The claim to benefit of the earliest provisional application 60/852,894, filed on 10/18/2006, and is continuation of several earlier filed non-provisional applications is recognized. All examined claims enjoy the filing date of ‘894.
Claim Rejections - 35 USC § 112
Rejection of claims 12 and 14 are withdrawn, the claims are canceled.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 7, 27, 28 are withdrawn due to the amendment of claim 1.
Claim Rejections - 35 USC § 103
Rejection of claims 1, 7, 27-28 is maintained as noted below.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 1, 7, 27, 28 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Swayze et al. (US20050059066, pub. 03/17/2005, thus one year prior to the date of the application, referred as Swayze, in IDS) and Godfray and Estibeiro (2003, Expert Opin. Ther. Targets, 7, 363-376, referred as Godfray).
Regarding instant cl. 1, Swayze discloses that the oligomer ranges from 14-30 nt. (par. 16) and indicates that at least one of each Nu1 and Nu3 is a high affinity modified nt., including a 4’-2’ bicyclic sugar modified nt. or 2’-O-(CH2)2-OCH3 (also called 2-methoxyethyl or 2MOE, par. 158), (see cl. 1, 2).
Swayze’s Table 2 (par. 344) discloses gapmers of varying lengths comprising various motifs: e.g., a 3-10-3 LNA motif, i.e. a 5’ and 3’ wing of 3 nt. composed of LNA with a 10 nt. “gap” composed of DNA, and a 2-14-2 MOE motif, i.e. a 5 and 3’ wing of 2 nt. composed of 2MOE with a 14 nt. “gap” composed of DNA. Thus Swayze discloses wings of 2, 3 and 5 nt. in length and gaps of 10, 12 and 14 nt. in length. Table 2 results suggest that modifying overall gapmer length by modifying the wing length and the gap length affects the efficiency of the gapmer, thus a skilled artisan would modify the lengths of wings and “gap” to identify potential improvement of gapmer.
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However Swayze does not disclose a gapmer of 14 nt. with a 2-10-2 mixed modification motif encompassing limitation a, b or c of claim 1.
Godfray discloses that although both 2MOE and LNA are extremely resistant to nuclease degradation, significant 2’-O-MOE (2MOE) modified oligonucleotides resulted in distribution away from most systemic tissues other than kidneys, along with excess renal excretion and indicate that in order to use MOE modification, further modification is required (pg. 364). While Godfray discloses that LNAs confers a massive increase in complementary hybridization strength, melting temperature values can be increased by as much as 10oC per substitution (pg. 365). But Godfray adds that due to their high affinity, too many LNAs may result in increased risk in nonspecific binding due to their high RNA-binding affinity (pg. 366).
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Here, Godfray discloses a drawback of using either a single 2MOE or LNA modification, arguably solely of 2MOE modification may result in excessive secretion, while solely LNA modification may result in nonspecific binding due to their high RNA binding affinity. Here, based on the results of Swayze demonstrating each wing modified with finite number of modification of either 2MOE or LNA and enabled for inhibition and based on Godfray’s suggestion of mixing the 2’ modifications to either increase gapmer circulation or reduce side-effect, a skilled artisan would mix LNA and 2MOE in the same gapmer, either within the same wing or in the same gapmer antisense oligonucleotide.
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. 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 the wing and gap lengths and composition of the wings of gapmers of Swayze in view of Godfray and arrive at the claimed invention with a reasonable expectation of success. Due to similar inhibition levels of an oligonucleotide comprising 2 nt. 5’ and 3’ wings of LNA or MOE, a skilled artisan would try to design different DNA gaps lengths (of 10, 12, and 14 nt.) and MOE and LNA wings lengths (2, 3, 5 nt.) and expect successful inhibition with either mixing LNA and MOE within each wing or alternating MOE at one wing and LNA at the other wing, thus claim 1 is obvious.
Regarding instant cl. 7, Swayze demonstrates inhibition with 4’-CH2-O-2’ methylene-oxy bicyclic nucleoside, i.e. a LNA.
Regarding instant cl. 27 and 28, Swayze discloses that oligonucleotides of Table 2 were fully phosphorothioated, i.e. each internucleotide linkage was a phosphorothioate modification.
Response to Arguments
Applicant’s arguments, see pg. 7, filed 04/11/2025, with respect to the rejection(s) of claim(s) 27-28 under 103 over the Lima reference and Swayze have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Swayze and Godfray.
Double Patenting
Rejection of claims 1, 7, 27-28 are maintained under nonstatutory double patenting as noted below.
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.
Patent 9550988
Claims 1, 7, 27-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 9 of U.S. Patent 9550988 (issued 01/24/2017). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of ‘988 teaches a gapmer oligonucleotide of 10 to 24 linked nt. with a gap region of 6-10 deoxynucleotides, comprising a 5’ wing region consisting of 1 to 7 linked nt., with each nt. of 5’ wing comprising a modified sugar with at least one being a 2MOE modified nt., and comprising a 3’ wing region consisting of 1 to 7 linked nt., wherein at least one nucleoside of the 3′ wing region is a 4′ to 2′ bicyclic nucleoside, and wherein the plurality of INL of the gapmer are phosphorothioate INL. Since the claimed species of wing (2nt.) and gap (10 nt.) lengths lies inside ranges disclosed by ‘988, here there is a prima facie case of obviousness (MPEP 2144.05, relevant to instant cl. 1). Further, ‘988’s modification of a nt. in a wing is a genus of instant species of specific modification pattern of each wing, thus there is a prima facie case of obviousness (relevant to instant cl. 1). Claim 5 of ‘988 teaches wherein at least one nt. of the 5’ wing region is a 4’ to 2’ bicyclic nt. (relevant to instant cl. 1, elements a, b); of ‘988 teaches plurality of INL are phosphorothioate, it corresponds to instant cl. 27, 28.
Cl. 1 of ‘988 teaches 2′-O(CH2)2OCH3 (2MOE), corresponding to instant cl. 1.
Cl. 2, 3 of ‘988 teaches methyleneoxy (4′-CH2-O-2′) or ethyleneoxy (4′-CH2CH2-O-2′) bicyclic nucleoside, corresponding to instant cl. 7.
Claim 4 of ‘988 teaches each wing region consists of 1 to 3 linked nucleosides, thus under MPEP 2131.03 here ‘988 teaches a range the overlaps or touches the claimed range (of 2 nt. wing) and thus anticipates claimed range (relevant to instant cl. 1, 7, 27-28). Similarly, instant cl. 5 Claim 5 of ‘988 teaches wherein at least one nt. of the 5’ wing region is a 4’ to 2’ bicyclic nt. (relevant to instant cl. 1, elements a, b). Here within the disclosed prior art of each wing being 1-3 nt. and 5’ wing, under claim 1 and 5, having at least one 2MOE and one bicyclic nucleoside, the genus of prior art corresponds to instant cl. 1, 7, 27-28.
Patent 10493092
Claims 1, 7, 27-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 8, 9, 10, 21 of U.S. Patent No. 10493092, issued 12/3/2019. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of ‘092 teaches that a gapmer consisting of 12 to 24 nt. with 5’ wing consisting of 1 to 7 nt. in length and the 5’ wing comprises a modified sugar with at least one nt. is a 2MOE or 2O-CH3 (2OMe), and with 3’ wing consisting of 1 to 7 nt. in length and the 3’ wing comprises a modified sugar with at least one is a methyleneoxy (4′-CH2—O-2′) or ethylene bicyclic nt. and comprises a plurality of phosphorothioate INLs (relevant to instant cl. 1, 27-28); cl. 6 of ‘092 teaches at least one nt. of 3’ wing is a methyleneoxy bicyclic nt. (relevant to instant cl. 7); cl. 7 teaches each wing region is 1 to 3 linked nt., cl. 2 teaches at least one nt. in 5’ wing is 2MOE and cl. 10 teaches one nt. in 5’ wing is 4’-2’ bicyclic nt., similarly cl. 4 teaches 3’ wing is an ethyleneoxy bicyclic nt. and cl. 6 teaches at least one nt. is methyleneoxy bicyclic nt., while cl. 15 teaches the gap region is 8 to 10 linked nt., here the prior art is either close or overlaps with instant species disclosed that it either anticipates instant claims or the instant claims are prima facie obvious.
Patent 9695418
Claims 1, 7, 27-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9695418, issued 07/04/2017 and in view of Swayze et al. (US20050059066, pub. 03/17/2005, thus one year prior to the date of the application, referred as Swayze, in IDS) and Godfray and Estibeiro (2003, Expert Opin. Ther. Targets, 7, 363-376, referred as Godfray).
Claim 1 recites the following:
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Claim 1 of ‘418 has various species of gapmers from 10-20 nt. long with 5’ and 3’ wings with central deoxynucleoside gap, and claim 1 provides several species with varying lengths of deoxynucleotide gaps (7-8 nt. in length) and 2’ modified wings (3-7 nt. in length). Claims 11-12 of ‘418 teaches one modified INL, a PS INL (relevant to cl. 27-28).
Cl. 1 of ‘418 for e.g. has the species BBB-(D)7-BBA, with a gap region length of 7 nt. and wing length of 3 nt., thus oligonucleotide of 13 nt., while another species of BBB-(D)7-BBBAA, an oligo of 15 nt. Cl. 8 of ‘418 teaches at least one A is 2MOE, while claim 4 teaches at least one B is a LNA nt. (relevant to instant cl. 1 and 7). These two species teach a range of 13 and 15 nt. While it has several species with mixed B and A motif at 5’ end and complete “B” modified nt. at 3’ wing, with wings greater than 2 nt. (e.g. ABBABB-(D)8-BBB).
‘418 does not teach a gapmer of 14 nt. in length, nor teach a wing of 2 nt. in length nor teach same modification motif as instant claims.
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Swayze teaches various functional gapmers of various lengths with varying inhibitory efficiency, with deoxynucleotide “gaps” of various lengths and 5’ and 3’ wings of various lengths, see Table 2 (par. 344-345, see below).
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Godfray discloses that although both 2MOE and LNA are extremely resistant to nuclease degradation, significant 2’-O-MOE (2MOE) modified oligonucleotides resulted in distribution away from most systemic tissues other than kidneys, along with excess renal excretion and indicate that in order to use MOE modification, further modification is required (pg. 364). While Godfray discloses that LNAs confers a massive increase in complementary hybridization strength, melting temperature values can be increased by as much as 10oC per substitution (pg. 365). But Godfray adds that due to their high affinity, too many LNAs may result in increased risk in nonspecific binding due to their high RNA-binding affinity (pg. 366).
Godfray discloses a drawback of using either a single 2MOE or LNA modification since it may result in excessive clearance from the body or may result in nonspecific binding due to their high RNA binding affinity, respectively.
Here, based on the results of Swayze demonstrating varying gap and wing lengths and each wing modified with finite number of modification of either 2MOE or LNA resulting in target inhibition and based on Godfray’s suggestion of mixing the 2’ modifications to either increase gapmer circulation or reduce side-effect, a skilled artisan would mix LNA and 2MOE in the same gapmer, either within the same wing or in the same gapmer antisense oligonucleotide.
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. 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 the wings of gapmers of ‘418 in view of Swayze and Godfray and arrive at the claimed invention with a reasonable expectation of success. Here ‘418 teaches various embodiments comprising 5’ and 3’ wings of LNA or MOE, a skilled artisan would try to design different DNA gap lengths (of 10, 12, 14 nt.) and MOE and LNA wings lengths (of 2, 3, 5 nt.) and expect successful inhibition with either mixing LNA and MOE at each wing or alternating MOE at one wing and LNA at another wing, thus claim 1, 7, 27-28 are obvious.
Response to Arguments
Rejection of examined claims under obviousness-type double patenting over 9,914,922, 10,202,599, 10,260,069 is withdrawn due to claim amendments.
The Remarks of 04/11/2025 requests that the rejection of obviousness-type double patenting be held in abeyance.
MPEP 804, part (I)(B)(1) provides the following:
Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03. Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner.
Heading over to MPEP 714.03:
Where an amendment substantially responds to the rejections, objections, or requirements in a non-final Office action (and is a bona fide attempt to advance the application to final action) but contains a minor deficiency (e.g., fails to treat every rejection, objection, or requirement), the examiner may simply act on the amendment and issue a new (non-final or final) Office action. The new Office action may simply reiterate the rejection, objection, or requirement not addressed by the amendment (or otherwise indicate that such rejection, objection, or requirement is no longer applicable). This course of action would not be appropriate in instances in which an amendment contains a serious deficiency (e.g., the amendment is unsigned or does not appear to have been filed in reply to the non-final Office action).
As provided by MPEP 804 above, the rejection cannot be held in abeyance. Although, the response is a bona fide response, this instant final Office Action is issued. The rejection has not been overcome by amendment, substantive argument or the filing of a proper terminal disclaimer. Thus, the rejection is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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