DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communications filed 5-6-26.
Claims 1, 3-7, 9, 11, 20, 21, 33, and 34 are pending in the instant application.
Response to Arguments and Amendments
Withdrawn Objections/Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-7, 9, 11, 20, 21, 33, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims
The claims are broadly drawn to isolated cells, compositions and complexes produced by combining one to three mucopenetrating substances, a therapeutic nucleic acid, and a cationic linear or branched polymer in an amount sufficient to charge neutralize the therapeutic nucleic acid, which mucopenetrating substances are non-ionic emulsifiers and have mucolytic activity, which therapeutic nucleic acid and cationic polymer form a complex through ionic interactions, which cationic polymer optionally comprises a cationic lipid, which therapeutic nucleic acid is optionally an antisense oligonucleotide (ASO) optionally comprising mongersen (GED-0301), which cationic polymer optionally comprises polyallylamine (PALL), polylysine (PLL), or polyethyleneimine (PEI), which concentration of the cationic polymer in the composition is 10-30 mg/ml, which non-ionic emulsifier optionally comprises oleoyl polyoxyl-6 glyceride/oleoyl macrogol-6 glyceride, Pluronic F127, polysorbate 40, polysorbate 80, or Kolliphor P188, which cationic polymer and therapeutic nucleic acid are present at a ratio of at least 1:1, 5:1, or 10:1 cationic polymer:therapeutic nucleic acid.
Teachings in the specification
The specification utilizes ex vivo pig models to test various formulations.
FIG. 1 shows apical and basal jejunum tissue uptake of various formulations consisting of cationic polymers at different concentrations complexed to FAM-Mongersen.
FIG. 2 shows apical and basal jejunum tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with non-ionic emulsifiers at different concentrations.
FIG. 3 shows apical and basal jejunum tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with mucolytic agents at different concentrations.
FIGs. 4A-4B show relative change in tissue permeability and apical tissue accumulation of FAM-Mongersen using different molecular weight branched polyethyleneimine polymers.
FIG. 5 shows apical and basal jejunum tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with additional excipients: Non-ionic emulsifiers (Kolliphor P188, Labrafil, Tween 40, Tween 80), mycolytic (bromalein) or permeability enhancer/mucodisruptor (decanoic acid).
FIG. 6 shows apical and basal jejunum tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with non-ionic emulsifiers including Kolliphor P188, Poloxamer Labrafil, Tween 20, Tween 40, Tween 60, Tween 80.
FIG. 7 shows tissue uptake in esophagus, stomach, jejunum, colon and rectum of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with non-ionic emulsifiers (Labrasol and Tween 40).
FIG. 8 shows tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with non-ionic emulsifiers (Labrasol and Tween 40) in jejunum.
FIGs. 9A-9B show effect of charged surfactants on tissue uptake of formulations. FIG. 9A shows tissue uptake of various formulations consisting of cationic polymers complexed to FAM-Mongersen combined with non-ionic emulsifiers (Labrasol and Tween 40) in jejunum.
FIGs. 10A-10B show IHC analysis of the fluorescence signal of Fam labeled Mongersen in vivo in pigs in the jejunum, where the Mongersen is treated with various Mongersen-polyplex formulations. effect of charged surfactants on tissue uptake of formulations.
FIGs. 11A-11B shows uptake of FAM-Mongersen into apical (FIG. 11A) and basal (FIG. 11B) intestinal tissue.
FIGs. 12A-12B shows uptake of FAM-Mongersen into apical (FIG. 11A) and basal
(FIG. 11B) intestinal tissue for various formulations with and without mucolytics.
FIG. 13 shows transport through native porcine mucus obtained from the jejunum of various FAM-Mongersen formulations. Microdiffusion is calculated by measured FAM fluorescence intensity in receiver chamber compared to the initial donor fluorescence intensity after 1 hour of incubation.
FIG. 14 shows apical jejunum tissue uptake of various formulations consisting of cationic polymers complexed to Cy5-siRNA combined with non-ionic emulsifiers.
FIG. 15 shows apical jejunum tissue uptake of various formulations consisting of cationic polymers complexed to Cy3 conjugated plasmid DNA combined with non-ionic emulsifiers.
FIG. 15 shows apical jejunum tissue uptake of various formulations consisting of cationic polymers complexed to Cy3 conjugated plasmid DNA combined with non-ionic emulsifiers.
FIG. 16 shows a Least Squares Means Plot of the relative change in apical tissue accumulation of FAM-Mongersen using different molecular weight branched polyethyleneimine polymers.
FIG. 17 shows the average apical tissue accumulation of FAM Mongersen using different molecular weight polyallylamine polymers combined with four (4) different non-ionic emulsifiers
FIG. 18 shows the average apical tissue accumulation of FAM-Mongersen using different molecular weight polylysine polymers combined with four (4) different non-ionic emulsifiers.
FIG. 19 shows the average apical tissue accumulation of FAM-Mongersen using different concentrations of polyallyllamine 15 kDa and non-ionic emulsifiers Kolliphor P188 and TWEEN 80.
The specification summarizes the optimal formulations in Tables 2 and 3:
…the average apical tissue accumulation of FAM-Mongersen was determined using the different molecular weight polyallylamine polymers (FIG. 17) or polylysine polymers (FIG. 18) combined with four (4) different non-ionic emulsifiers (Labrafil, Pluronic F127, polysorbate 40 (TWEEN 40) and polysorbate 80 (TWEEN 80).
The most effective molecular weight ranges for each polymer and emulsifier tested are provided in Table 2.
Table 3 provides a summary of the results, showing average Mongersen jejunum tissue accumulation fold change of PALL 15 kDa formulations with the non-ionic emulsifiers Kolliphor P188 and TWEEN 80, or TWEEN@80 alone, compared to non-formulated control.
[Emphases added] [Citations omitted]
The teachings in the specification and summarized in Tables 2 and 3, are not representative of the myriad of combinations and formulations instantly claimed.
expansive genus of molecules claimed. The specification fails to provide the requisite guidance for making and using the large genus of modulatory agents instantly claimed, and further whereby off target activity is reduced and/or on target activity is increased relative to an unmodified guide RNA.
Since the disclosure fails to describe the common attributes and characteristics concisely identifying members of the proposed genus of formulations and combined ingredients, and because the claimed genus is highly variant, the description provided is insufficient. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the vast genus of formulations and combinations of ingredients instantly claimed.
Thus, Applicant was not in possession of the broadly claimed genus.
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.
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, 3-7, 9, 11, 20, 21, 33, and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Suk et al (US 2017/0246320), Hipp et al (US 2018/0296663) and Bruun et al (WO 2009/080033), the combination in view of Frederick et al (US 2023/0081530), and Shariter et al (US 2020/0306191), the combination further in view of Fyfe, M. (2016/0096805).
The claims are drawn to compositions and complexes produced by combining one to three mucopenetrating substances, a therapeutic nucleic acid, and a cationic linear or branched polymer in an amount sufficient to charge neutralize the therapeutic nucleic acid, which mucopenetrating substances are non-ionic emulsifiers and have mucolytic activity, which therapeutic nucleic acid and cationic polymer form a complex through ionic interactions, which cationic polymer optionally comprises a cationic lipid, which therapeutic nucleic acid is optionally an antisense oligonucleotide (ASO) optionally comprising mongersen (GED-0301), which cationic polymer optionally comprises polyallylamine (PALL), polylysine (PLL), or polyethyleneimine (PEI), which concentration of the cationic polymer in the composition is 10-30 mg/ml, which non-ionic emulsifier optionally comprises oleoyl polyoxyl-6 glyceride/oleoyl macrogol-6 glyceride, Pluronic F127, polysorbate 40, polysorbate 80, or Kolliphor P188, which cationic polymer and therapeutic nucleic acid are present at a ratio of at least 1:1, 5:1, or 10:1 cationic polymer:therapeutic nucleic acid.
Suk et al (US 2017/0246320) teach gene carrier compositions comprising cationic polymers comprising PEI backbones and PEI side chains, with cationic polymers between 5000-100,000 Daltons, and further comprising mucolytic, mucus resistant and mucus diffusive polymers optionally neutrally charged. Suk teaches delivery of mucolytic PEI DNA cationic nanoparticles to treat cystic fibrosis (CF) patients (see esp. the Abstract, ¶¶ 0007, 0013, Figures 1-7, ¶¶ 0030-0036, 0069-0071, 0121, 0194-0252, claims 1-18).
Bruun et al (WO 2009/080033) teach compositions for oral delivery comprising metformin for treating diabetes. Bruun teaches compositions comprising mucoadhesive agents, absorption enhancers and mucolytic agents, which enhancers optionally comprise polysorbate 40 or 80, or oleoyl polyoxyl-6 glyceride/oleoyl macrogol-6 glyceride (see esp. the Abstract, pages 2-3, 6, 12, 15-118, 20, 30).
Hipp et al (US 2018/0296663) teach pharmaceutical compositions for in vivo delivery comprising complexes of at least one cationic, oligocationic and/or polycationic component and at least one nucleic acid molecule, which compositions further comprise 40, polysorbate 80 and enhancers for transdermal delivery (see esp. pages 62, 63, 65-67).
The primary references do not teach compositions comprising GED-0301.
Frederick et al (US 2023/0081530) teach compositions comprising ionizable lipids and nucleic acids, non-cationic helper lipids, phospholipids, PEG lipids (¶¶ 0461-0777, 1149-1220), and further comprising emulsifying agents and self-assembled DNA ¶¶ 1545-1549 1630-1631) Frederick teaches nucleic acid delivery compositions comprising cations, and formulations with multiple nucleic acids, optionally comprising siRNA, shRNA, miRNA and/or mRNA (¶¶ 1545-1549). Frederick teaches cationic polymer compositions comprising cationic polymer:nucleic acid ratios of at least 1:1-10:1, and cationic polymer concentrations of approximately between 10-30 mg/ml and compositions comprising polysorbates as emulsifiers (see Tables 36-39, ¶¶ 132-138, 142, 0216, 1438-1447, 1523-1524, 1549).
Shariter et al (US 2020/0306191) teach compositions comprising nucleic acid lipid nanoparticles encapsulating mRNA, and further comprising one or more surfactants optionally comprising polysorbates (¶ 0314), and cationic phospholipids neutralizing negatively charged lipids and phospholipids (¶ 0327), antisense and other therapeutic molecules ¶¶ 0361-0364). Shariter also teaches compositions comprising emulsifying agents, cation surfactants, nucleic acid polymers, mucolytic agents for nucleic acid delivery (¶¶ 0568-0569), and which compositions further comprise the polymers PLGA, PLLA, PLL and PLA (¶¶ 0509-0511 0514, 0515 – 0519, 0548, 0606, 0616, 0618).
Fyfe, M. (2016/0096805) teach therapeutic compositions comprising the antisense molecule, mongersen (GED0301), for treating gastrointestinal disorders (see esp. ¶ 0127).
It would have been obvious to provide therapeutic compositions comprising neutrally charged combinations of nucleic acids, cationic polymers comprising PEI backbones and PEI side chains, which cationic polymers are between 5000-100,000 Daltons, and further comprising mucolytic, mucus resistant and mucus diffusive polymers optionally neutrally charged because the prior art taught compositions with these components, as shown in the teachings of Suk, Hipp and Bruun. What’s more, Frederick teaches nucleic acid delivery compositions comprising cations and formulations with multiple nucleic acids, optionally comprising siRNA, shRNA, miRNA and/or mRNA, and emulsifiers comprising polysorbates. And Shariter teaches compositions comprising emulsifying agents, cation surfactants, nucleic acid polymers, mucolytic agents for nucleic acid delivery. One would have been motivated to combine the components claimed because the prior art taught the effective delivery of therapeutic agents using the instant compositions claimed. One would have reasonably expected that antisense, including mongersen (GED0301), would be successfully delivered to a subject for treating digestive disorders in combination with the cationic, lipid, and emulsifier agents, relying on the combined teachings of Suk, Hipp, Bruun, Frederick, Shariter and Fyfe.
For these and the aforementioned reasons, the instant invention would have been obvious to one of ordinary skill before the effective filing date of the claimed invention.
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.
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
6-4-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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