DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/03/2025 has been entered.
Previous Rejections
Applicant’s arguments, filed 12/03/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Rejections - 35 USC § 112 –
Indefiniteness and Broad Limitation followed by Narrow Limitation
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 97, 37-100, 103-104, 106 and 109 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claims 94, 103, 106 and 109 recite the broad recitations of the lipids, and the claims also recite abbreviations in parentheses, which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The Applicant is encouraged to remove the parentheses from the claims, at each instance of occurrence.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claims 94, 97-100, 103-104, 106 and 109 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Huang et al (US 2008/0175893 A1), in view of Unger et al (US 2003/0039613 A1) and further in view of Kopechek et al (University of Cincinnati, 2011).
Huang taught pharmaceutical compositions [0044] comprising xenon [0009] encapsulated [0031] echogenic liposomes [0013-0014], comprising phosphatidylcholine, generally, cholesterol and other lipids [0010, 0013-0014, 0031, 0043, 0046]. At ¶s [0069-0070], Huang taught liposomes composed of DPPC:DOPC:cholesterol at a 60:30:10 molar ratio. Huang suggested that lipid coatings stabilized the liposomes [0031, 0037].
Huang was silent DSPC, a PEGylated lipid, a phosphatidylglycerol, and amounts thereof; Huang was silent DPPG, each as recited in claim 94.
Unger taught gaseous or gas-filled [abstract; see xenon at ¶0287] echogenic [0214] liposomes, comprising lipids bearing 8 mol % polyethylene glycol (PEG), in order to improve the stability and size distribution of the gaseous liposomes [0144, 0320]; and, 1-10 mole % phosphatidylglycerol (PG), as a vesicle-forming lipid [claim 2 and ¶s 0131, 0143]. Additionally, Unger taught DSPC as a lipid to construct the vesicles, and chosen for stability [0130, 0148].
Kopechek taught echogenic liposomes, at the title. The liposomes were prepared with DPPG [pages 13 and 87, 1st paragraph at each page].
Since Huang suggested that lipid coatings stabilized echogenic gas-filled liposomes, it would have been prima facie obvious to one of ordinarily skill in the art to include, within the teachings of Huang, lipids bearing PEG, as taught by Unger. The ordinarily skilled artisan would have been motivated to improve the stability and size distribution of the gaseous liposomes, as taught by Unger et al at ¶ [0144]. The ordinarily skilled artisan would have been motivated to include PEG at 8 mole % because at the said amount, PEG improves the stability and size distribution of the gaseous liposomes, as taught by Unger.
Since Huang generally taught phosphatidylcholines as vesicle-forming lipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Huang, DSPC, as taught by Unger. The ordinarily skilled artisan would have been motivated to include a vesicle-forming lipid chosen for stability, as taught by Unger [0130, 0148]. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. In the instant case, it is prima facie obvious to select DSPC, for incorporation into a composition, based on its recognized suitability for the intended use as a liposome-forming lipid, as taught by Unger et al [0130, 0148].
Since Huang taught phospholipids, generally, as liposome-forming lipids, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Huang, DPPG, as taught by Kopechek. In the instant case, it is prima facie obvious to select DPPG, for incorporation into a composition, based on its recognized suitability for the intended use as a liposome-forming lipid, as taught by Kopechek et al, at pages 13 and 87 [1st paragraphs each].
The instant claim 94 recites the molar ratios of DSPC to DOPC to DPPG to PEG to cholesterol at 40-50: 20-30: 5-10: 5-10: 10-20.
Huang taught a first PC at 60 mol %, a second PC at 30 mol % and cholesterol at 10 mol %. Unger taught PG at 1-10 mol % and PEG at 8 mol %. At ¶ [0146], Unger taught 1:100 mole % non-cationic lipids (e.g., phosphatidylcholines). A prima facie case of obviousness exists because of overlap, as discussed above.
The instant claims 97-98 are rendered prima facie obvious because Huang taught mannitol [0036].
Regarding claim 99, Huang taught intravascular administration [0023, 0055, 0076, 0084], but was silent the diameter of the liposomes, as instantly recited. However, Unger taught that for intravascular application, the preferred size range is a mean outside diameter between about 30 nanometers and about 10 microns, with the preferable mean outside diameter being about 5 microns [0187].
Since Huang taught intravascular administration/delivery, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Huang, liposomes sized about 30 nanometers to about 10 microns, as taught by Unger. The ordinary skilled artisan would have been motivated to include a preferred diameter for intravascular application, as taught by Unger at [0187].
The instant claim 99 recites an average size of 0.4 to 10 microns.
Unger taught a mean outside diameter between about 30 nanometers and about 10 microns. A prima facie case of obviousness exists because of overlap, as discussed above.
The instant claim 100 is rendered prima facie obvious because Huang taught freezing/frozen [0031].
The instant claims 103-104, 106 and 109 are rendered prima facie obvious because Unger taught PEG-DPPE, with the PEG having a molecular weight of 2,000 [0144]. The motivation to combine Unger with Huang was previously discussed.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argued that the Action alleged a substitution of Huang’s DSPC with Unger’s DPPC. Applicant argued that Kopecheck teaches that DPPC [page 110] inhibits release of the therapeutic agent, that the skilled artisan would not want to improve stability (Unger’s teachings) at the expense of releasing the therapeutic agent, and that the combination of references would discourage the substitution.
The Examiner disagrees that a substitution rationale was used in the rejection of the claims. A motivation to include, rather than to substitute, was the relied upon to reject the claims.
The Examiner disagrees that Kopecheck taught that DPPC inhibits release of the therapeutic agent. Kopecheck referenced Evjen et al (2011), which did not mention whether the liposomes were echogenic. In this respect, the Applicant’s arguments against the cited combination of the prior art are moot. Additionally, as per Kopecheck, Evjen did not mention temperature measurements, so it was unclear what role thermal effects had on drug release. It was also unclear what role the high ultrasound intensity (1MHz or 20kHz) had upon drug release. See Kopecheck at pages 109-110. As such, the Applicant’s arguments against Kopecheck do not apply to Kopecheck’s teachings, nor to the teachings of Huang and Unger. The 35 USC § 103 rejection over Kopecheck is maintained.
Conclusion
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/CELESTE A RONEY/Primary Examiner, Art Unit 1612