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 1-4, 10, and 13 are pending.
Claims 5-9 and 11-12 are withdrawn.
Claims 1-4, 10, and 13 have been examined.
Priority
This application is a CON of 16011378 06/18/2018ABN
16011378 is a DIV of 14846536 09/04/2015 PAT 10029012
14846536 has PRO of 62046585 09/05/2014
Withdrawn Rejection
The rejection of claim 7 is withdrawn because claim 7 has been canceled.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
1. Claims 1-3 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. (US 2011/0274745 A1, previously cited 9/30/2022) in view of Shapland et al. (WO 96/22806, previously cited 7/2/2024), Jonghans et al. (Biochimica et Biophysica Acta 1544 (2001) 177-188, previously cited 10/19/2025) and Dinauer et al. (Journal of Controlled Release. 2004; 96: 497– 507, previously cited 9/30/2022).
Claim 1 is drawn to a method of treating a subject with overactive bladder comprising:
Administering into the bladder a composition comprising the antisense oligonucleotide GCCCGAGACGCCTCCCGA (SEQ ID NO: 10) against nerve growth factor;
A cationic polypeptide protamine with a mass ratio to the antisense oligonucleotide at 10:1; and
the protamine is administered in a concentration range between 20 to 120 μM.
Chancellor et al. teach administration of antisense oligonucleotides (AS-ODN) or siRNA that interact with or bind to messenger RNA (mRNA) coding for human nerve growth factor (NGF) to stop the synthesis of NGF to treat overactive bladder (Abstract). Chancellor et al. teach administration of 6 µM ODN with the sequence of 5'GCCCGAGACGCCTCCCGA3' (SEQ ID NO: 1 with 100% identity to this instant AS0ODN of SEQ ID NO: 10) [0094], reading on the limitation (i) a method of administering a pharmaceutical composition comprising the antisense oligonucleotide (SEQ ID No: 10) to treat a subject with overactive bladder. Chancellor et al. suggest the use of a delivery vehicle of a cationic polypeptide serving the same function as cationic liposomes (in replacement of liposome) for ODN delivery in bladder [0104]. Chancellor et al. teach the use of a catheter as a medical device to deliver AS-ODN [0095,0097]. Chancellor et al. suggest the preferred intravesical route of administration with the advantages of selective exposure of high concentrations of antisense ODN to the NGF producing cells in the urothelium and avoids systemic side effects and cost effective [0016].
Chancellor et al. did not teach a cationic polypeptide as a protamine to deliver AS-ODN of 5'GCCCGAGACGCCTCCCGA3'.
Similarly, Shapland et al. teach delivery of an agent to a bladder (Abstract). Shapland et al. teach the delivered agent is a therapeutic agent of antisense oligonucleotides (p5, line 21-24). Shapland et al. teach beneficial addition of protamine to enhance penetration of the primary therapeutic agent into the bladder wall (p6, line 9-14; p11, line13-15). Because Shapland et al. teach beneficially use of protamine for delivery of antisense oligonucleotides to enhance penetration of antisense oligonucleotides into the bladder wall, one of ordinary skill in the art would have found it obvious to use protamine as a penetration enhancer to enhance penetration of antisense oligonucleotides into the bladder wall as taught by Shapland et al. Jonghans et al. teach protamine is a cationic peptide with a molecular mass of approx. 4000 Da that is able to condense DNA and protamine was used to complex antisense oligonucleotides (ODNs) known in the art (Abstract), consistent with Shapland et al. Jonghans et al. teach a mass ratio of protamine to ODN is a result effective variable that can be determine by ODN binding assays. Jonghans et
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al. show all ODN bound to protamine or protamine sulfate at mass ratio of protamine/ODN equal to 10:1 as follows (p183, Fig 4); thus, one of ordinary skill in the art before the effective filing date of this invention would have found it obvious to prepare protamine to Chancellor’s AS-ODN at a mass ratio of 10:1, reading on the limitation (ii).
Chancellor et al. in view of Shapland et al. and Junghans et al. do not specify the concentration of protamine for ODN delivery.
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Chancellor’s 6 µM ODN with the sequence of 5'GCCCGAGACGCCTCCCGA3' (MW = 5492) against human nerve growth factor [0094] suggests the weight of ODN 0.03295 g summarized as follows. Similarly, Dinauer et al. teach cellular uptake of protamine, a cationic polypeptide, complexed with antisense oligonucleotides (AS-ODN) was significantly enhanced compared to naked oligonucleotides to inhibit gene expression (Abstract). Dinauer et al. teach complexation of AS-ODN with protamine could beneficially reduce the number of accessible binding-sites for nucleases and therefore provide protection against degradation (p503, col 1, para 1). Dinauer et al. further suggest the molecular weight of protamine about 6000 Da (p499, 2.2. Preparation of protamine based nanoparticles). The examiner further summarize the mass
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ratio range of Chancellor’s 6 µM ODN to protamine at 1:10, calculated as 54.9 µM and 82 µM of protamine depending on the selected protamine protein falling in the claimed range 50 µM ~ 120 µM of protamine, reading in the limitation (iii) and satisfying the limitation instant claims 1-2.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Chancellor’s antisense oligonucleotides (AS-ODN) with (ii) cationic polypeptide of protamine taught by Shapland et al. in view of Jonghans et al. because (a) Chancellor et al. suggest the use of a delivery vehicle of a cationic polypeptide serving the same function as cationic liposomes (in replacement of liposome) for ODN delivery in bladder [0104] (b) Shapland et al. teach beneficial addition of protamine to enhance penetration of the primary therapeutic agent of antisense oligonucleotides (p5, line 21-24) into the bladder wall (p6, line 9-14; p11, line13-15), and (c) Jonghans et al. is further cited to show a mass ratio of protamine to ODN is a result effective variable than can be determine by ODN binding assays. Jonghans et al. show all ODN bound to protamine or protamine sulfate at mass ratio of protamine/ODN equal to 10:1 (p183, Fig 4). The combination would have reasonable expectation of success because all references teach the use of a cationic polypeptide to deliver ODN and Shapland et al. teach protamine able to enhance penetration of the primary therapeutic agent into the bladder wall (p6, line 9-14; p11, line13-15). Dinauer et al. is further cited to show protamine beneficially reduce the number of accessible binding-sites of AS-ODN for nucleases (p503, col 1, para 1) and the molecular weight of protamine about 6000 Da (p499, 2.2. Preparation of protamine based nanoparticles) known in the art.
With respect to claim 3, Chancellor et al. teach administration of antisense oligonucleotides (AS-ODN) that interact with or bind to messenger RNA (mRNA) coding for human nerve growth factor (NGF) to stop the synthesis of NGF to treat overactive bladder (Abstract).
With respect to claim 13, the method developed in claim 13 comprises the same administration step by administering the same composition to the same subject to stop the synthesis of NGF to treat overactive bladder as suggested by Chancellor et al. (Abstract); thus, one of ordinary skill in the art would expect that the method and composition taught by the combined references as applied to claims 1-2 is capable of achieving the same result of reducing the frequency of urination and/or the feeling of urgency to urinate in a subject with overactive bladder as claimed.
Applicant’s Arguments
Applicant’s data of Figures 3A, 3C, and 4 show unexpected of protamine to antisense oligonucleotide at 10:1 mass ratio when protamine concentration < 50 µM (Remarks, p8, last para).
FIG. 4 of Jonghans merely relates to the formation of complexes between protamine and ODN. Even if mass ratio of protamine to ODN could be considered a result-effective variable for the formation of complexes (to which Applicant does not agree), the claimed method does not merely relate to formation of complexes (Remarks, p9, para 1).
Dinauer teaches that protamine concentration 5 μM or greater renders the invention unsuitable for its intended purpose (Remarks, p9, last two para to p10, para 1-2).
Response to Arguments
Applicant's arguments filed 1/27/2026 have been fully considered but they are not persuasive for the reasons as follows.
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Applicant’s argument (i) is not persuasive because (a) Chancellor’s 6 µM ODN to protamine at 1:10, calculated as 54.9 µM and 82 µM of protamine depending on the selected protamine protein falling in the claimed range 50 µM ~ 120 µM of protamine and (b) one or ordinary skill in the art would expect the weight ratio under prior art’s teachings to be operable. See MPEP 2121 (I) When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. In particular, applicant failed to provide sufficient data to show the mass ratio of the weight of protamine to the weight of 6 µM ODN at 10:1 under the prior art conditions (54.9 µM or 82 µM protamine) CANNOT downregulate nerve growth factor mRNA. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02.
Applicant’s argument (ii) is not persuasive because applicant argues a single reference of Jonghans whereas the rejection is based on Chancellor et al. (US 2011/0274745 A1, previously cited 9/30/2022) in view of Shapland et al. (WO 96/22806, previously cited 7/2/2024), Jonghans et al. (Biochimica et Biophysica Acta 1544 (2001) 177-188, previously cited 10/19/2025) and Dinauer et al. (Journal of Controlled Release. 2004; 96: 497– 507, previously cited 9/30/2022) as a whole. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 2145(IV).
Applicant’s argument (iii) is not persuasive because (a) Dinauer’s figure 5 shows Protamine/AS-ODN complex more active than naked AS-ODN at a dose dependent manner (p505, col 2, para 1) in contrast to applicant’s argument that protamine at 5 μM or greater renders the claimed method unsuitable for its intended purpose and (b) Dinauer et al. is cited to show the intended use of protamine comprising (1) protamine beneficially reducing the number of accessible binding-sites of AS-ODN for nucleases (p503, col 1, para 1) and (2) the molecular weight of protamine used is about 6000 Da (p499, 2.2. Preparation of protamine based nanoparticles) known in the art. The intended use of protamine is not changed by Dinauer’s figure 5 as argued by applicant.
2. Claims 1-4 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. as applied to claims 1-3, 7, 12 and further in view of Lee et al. (Nucleic Acids Res. 1987 Sep 25; 15(18):7639, previously cited 9/30/2022.).
Claim 4 is drawn to a protamine protein sequence.
Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. teach a method of administering a complex comprising protamine to: ODN at mass ratio 10:1 to treat overactive bladder via intravesical route of administration as applied to claims 1-3, and 13.
Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. do not specify a sequence of protamine protein.
Lee et al. teach a human protamine protein sequence with 100% identical to the instant
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SEQ ID NO: 1 as follows. It would be obvious to use human protamine protein to treat a disease of the same human species, reading on claim 4.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. with Lee’s human protamine because (a) Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. teach intravesical administration of a protamine-(AS-ODN) complex at a mass ratio of 10:1 to treat a human patient with overactive bladder and (b) Lee et al. teach a human protamine protein sequence. The combination would have reasonable expectation of success because Shapland et al., Jonghans et al., Dinauer et al. and Lee et al. teach a cationic protamine protein.
Response to Arguments
Applicant's arguments filed 1/27/2026 have been fully considered but they are not persuasive. See response to arguments above.
3. Claims 1-3, 10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. as applied to claims 1-3, 7, 12 and further in view of GeneBank M57399.1 (https://www.ncbi.nlm.nih.gov/nuccore/ M57399.1, previously cited 9/30/2022).
Claim 10 is drawn to a corresponding cDNA sequence of nerve growth factor.
Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. teach a method of administering a complex comprising protamine to: ODN at mass ratio 10:1 against human nerve growth factor to treat overactive bladder via intravesical route of administration as applied to claims 1-3, and 13.
Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. do not specify a nucleic acid sequence of human nerve growth factor.
GeneBank M57399.1 shows human nerve growth factor sequence with 100% homology to the instant SEQ ID NO: 9 as follows, reading on claim 10.
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One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. with GeneBank’s nerve growth factor sequence because (a) Chancellor et al. in view of Shapland et al., Jonghans et al. and Dinauer et al. teach intravesical administration of a protamine complexed AS-ODN against nerve growth factor in a patient and (b) GeneBank M57399.1 shows human nerve growth factor sequence with 100% homology to the instant SEQ ID NO: 9. The combination would have reasonable expectation of success because Chancellor et al. and GeneBank M57399.1 teach nerve growth factor.
Response to Arguments
Applicant's arguments filed 1/27/2026 have been fully considered but they are not persuasive. See response to arguments above.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 JIA-HAI LEE whose telephone number is (571)270-1691. The examiner can normally be reached Mon-Fri from 9:00 AM to 6:00 PM.
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/J.L/Examiner, Art Unit 1658
15-February-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658