DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1, 15-22, 25-28, and 30-34 are examined; claims 40, 42, 43, 46, 65, 70, 72, 77, 82, 84, 85, 88, and 96 are withdrawn pursuant to Applicant’s election with traverse on 17 February 2026.
Applicant’s arguments, filed 16 July 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities: “comprise” in line 3 should be recited as --- comprises ---. Appropriate correction is required.
Response to Arguments
The objection above is maintained since claim 1 still contains the grammatical inconsistent terminology.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 15-22, 25-28, and 30-34 are rejected under 35 U.S.C. 103 as being unpatentable over Bettinger et al. (US 2009/0041833 A1) (hereinafter Bettinger).
Regarding claims 1, 17-19, Bettinger discloses gas-filled microcapsules comprising a bioactive agent ([0001]) having a polymeric and/or lipid shell/envelope ([0007]), wherein the bioactive agent is incorporated in a carrier preferably comprising a positively charged (i.e. cationic) lipid or polymer ([0014]). The cationic lipids include ethyl-DSPC ([0066]) and dioctadecylamidoglycyl spermine (DOGS), 2-3-dioleyloxy-N-(2(sperminecarboxyamido)ethyl)-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), or dipalmitoyl phosphatidyl-ethanolamidospermine (DPPES) ([0067]).
Together these would provide a microbubble composition as instantly claimed. The prior art is not anticipatory insofar as this combination must be selected from various lists/locations in the reference. It would have been obvious, however, to make the combination since all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See MPEP § 2143 (I)(A).
Regarding claim 1 reciting wherein a plurality of spermine molecules are coupled to an external surface of the surfactant shell, as noted by p. 2, lines 12-18 of the instant Specification, the plurality of spermine molecules may be coupled, covalently or non-covalently, and directly or indirectly, to the external surface of each microbubble. Accordingly, the DOGS or DOSPA of Bettinger, being spermine-based cationic lipids, or lipospermines, comprising a spermine molecule, glycyl/amido or carboxamido group as the linker, respectively, and a hydrophobic tail as anchor, under the broadest reasonable interpretation, reasonably appear to meet the limitation of a plurality of spermine molecules “coupled” to an external surface of the surfactant shell as instantly claimed.
Regarding claims 15 and 16, Bettinger further discloses wherein the gas may comprise fluorinated gases including perfluorocarbons such as perfluorobutane (i.e. decafluorobutane) ([0054]-[0056]).
Regarding claim 20, Bettinger further discloses wherein the cationic lipids may also be formulated in combination with PEG-modified phosphatidylethanolamines ([0069]).
Regarding claims 21-22, Bettinger further discloses wherein the carrier may further comprise a targeting ligand ([0015]). The targeting ligand can be linked to a molecule of the carrier through a reactive moiety including maleimides ([0088]). Thus, Bettinger reasonably appears to disclose a plurality of reactive groups, such as maleimides, linked to a molecule of the carrier, which is on the external surface of the shell.
Regarding claims 25-28, Bettinger further discloses wherein the bioactive agent includes proteins ([0028]) and genetic materials such as DNA ([0061]).
Regarding claims 30-31, Bettinger further discloses wherein suitable targeting ligands include antibodies ([0085]).
Regarding claims 32-34, Bettinger further discloses wherein an exemplary average diameter suitable for microcapsules include about 3 µm ([0126]). Accordingly, the claimed ranges (i.e. about 1-10 µm, about 1-5 µm, and about 3 µm, respectively) would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art (i.e. about 3 µm). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Response to Arguments
Applicant mainly asserts in the Remarks filed 16 July 2026 that Bettinger does not disclose or suggest wherein DOGS is coupled to the external surface of the microcapsule shell, and it does not disclose that DOGS provides a plurality of spermine molecules coupled to the external surface of the surfactant shell of each gas-filled microcapsule. Applicant further asserts that the instant claims use spermine molecules coupled to the microbubble surface to provide a spermine-decorated microbubble capable of associating with payload molecules, and Bettinger emphasizes that a bioactive agent is preferably substantially unbound and thus one of ordinary skill in the art would not have modified the microcapsule shell to present a plurality of spermine molecules coupled to the external shell surface with a reasonable expectation of success.
The Examiner does not find Applicant’s assertion to be persuasive. As noted by p. 2, lines 12-18 of the instant Specification, the plurality of spermine molecules may be coupled, covalently or non-covalently, and directly or indirectly, to the external surface of each microbubble. Therefore, the instant claims as amended do not limit a specific molecule to facilitate the coupling. As such, the DOGS or DOSPA of Bettinger, being spermine-based cationic lipids, or lipospermines, comprising a spermine molecule, glycyl/amido or carboxamido group as the linker, respectively, and a hydrophobic tail as anchor, under the broadest reasonable interpretation, reasonably appear to meet the limitation of a plurality of spermine molecules “coupled” to an external surface of the surfactant shell as instantly claimed.
In response to applicant's argument regarding the association of payload molecules with the microbubbles, it is noted that Applicant agrees Bettinger defines “substantially unbound” as more than 50%. As such, Bettinger does not limit the bioactive agent to unbound molecules. Thus, it reasonably appears the microcapsules of Bettinger are capable of associating with the bioactive agent. Moreover, as noted by p. 11, lines 1-2 of the instant Specification, the payload molecule may be electrostatically bound. Accordingly, absent explicit recitation to the contrary, it reasonably appears the microcapsules of Bettinger reasonably appear to meet the limitation of associating with a plurality of payload molecules as instantly claimed. As such, Applicant’s assertion is unpersuasive.
Response to Arguments of Non-Statutory Double Patenting
Applicant mainly asserts in the copending Application No. 18/554,944 has a later effective filing date and that provisional nonstatutory double patenting rejection should be withdrawn if the present application is otherwise in condition for allowance, consistent with the procedure set forth in MPEP § 804(I)(B)(1).
Although the Examiner does not find the allegation of patentability to be persuasive, nevertheless the nonstatutory double patenting rejection has been withdrawn upon consideration of the effective filing date of the copending Application.
Citation of State of the Art and Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Unger (US 2002/0159952 A1, 10/31/2002), directed to targeted therapeutic delivery systems comprising a gas or gaseous precursor filled microsphere comprising an oil, a surfactant, and a therapeutic compound.
Joyce (US 2004/0180094 A1, 09/16/2004), directed to compositions and method for therapeutic treatment comprising a gas-filled encapsulation vesicle, an activation agent, and an optional targeting ligand.
Khorsandi et al. (“Development of novel polyplex-conjugated microbubbles as vectors for gene delivery”, Spring 2020, IDS reference 02/17/2026), directed to polyplex-conjugated microbubbles utilizing spermine-conjugated dextran as a non-toxic polymer to complex DNA.
Zhou et al. (US 2019/0247515 A1, 08/15/2019, IDS reference of 04/12/2023), directed to DNA-targeted nanocarriers in the form of microbubbles.
Conclusion
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 LUCY TIEN whose telephone number is (571)272-8267. The examiner can normally be reached Monday - Thursday 8:30 AM - 6:30 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SAHANA KAUP can be reached at (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUCY M TIEN/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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