DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed October 10, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Status
Claim 2 is withdrawn.
Claims 1, 3 – 10, 14 – 17, and 19 – 22 are examined herein.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
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.
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 non-obviousness.
Claims 1, 3 – 10, 14 – 17 and 19 – 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes (US 2014/0220110 A1, of record) in view of Jauernig (US 2005/0244339 A1).
Hayes teaches the remote loading of drugs into liposomes for sustained release compositions (abstract, paragraph 0006). Hayes teaches that drug encapsulation in the interior of the liposome provides sustained release properties (paragraph 0006).
Hayes teaches the preferred composition of the liposomes is HSPC, cholesterol, and PEG-DSPE in the amount of 50 – 70 mol HSPC, 30 – 50 mol cholesterol, and 1 to 10 mol PEG-DSPE (paragraphs 0012, 0050). Hayes teaches the PEG component of PEG-DSPE is 750 – 5000 Daltons (paragraph 0046). Hayes’ liposomes are between 40 and 150 nm in size (paragraph 0093).
Hayes teaches the liposome encapsulates an internal aqueous medium which contains a complex of the trapping agent and therapeutic agent (paragraph 0030). Hayes teaches that the choice of trapping agent is an important factor of liposome loading, stability, and drug release rate (paragraph 0124) and provides examples of ammonium sulfate in the amount of 250 mM (paragraph 0126).
In Table 4, Hayes shows the encapsulation efficiency of carfilzomib drug remotely loaded via complexation with ammonium sulfate. Hayes teaches carfilzomib drug to HSPC as a gram to mole ratio with a low value of 91.8 grams carfilzomib per mole HSPC and a high value of 758.7 grams carfilzomib per mole HSPC (Table 4). Using a molecular weight of 719.91 g/mol for carfilzomib, this range can be converted to a range of 0.127 mol drug / mol HSPC to 1.05 mol drug / mol HSPC.
Hayes teaches a pharmaceutical formulation containing remotely-loaded liposomes can be used to treat respiratory conditions, including any chronic obstructive pulmonary disease (paragraph 0106).
Hayes does not teach the composition is an inhalable composition or tiotropium bromide.
Jauernig teaches the missing element of Hayes.
Jauernig teaches pulmonary administration of inhalable compositions containing poorly water-soluble active agents (abstract, paragraph 0048). Jauernig teaches that the treatment of pulmonary conditions by inhalation allows a targeted pharmaceutical approach because the active agent is delivered directly to the target site (paragraph 0002).
Jauernig teaches the inhalable composition may contain liposomes (paragraphs 0019, 0087, 0095 – 0098, claim 9). Jauernig teaches that aerosol particles with a smaller diameter have greater probability of reaching the peripheral parts of the lungs and that aerosol particles should have an aerodynamic diameter of less than 5 – 6 µm for administration to adults (paragraphs 0002, 0003).
Jauernig teaches tiotropium salts as suitable active agents for pulmonary delivery (paragraph 0123, 0167, claims 27, 29).
Claims 1, 3 – 10, 14 – 17 and 19 – 22 are rendered prima facie obvious over the combination of Hayes and Jauernig. The combination of Hayes’ and Jauernig’s teachings includes each of the claimed elements (liposomal composition, phospholipids, cholesterol, aqueous interior, trapping agent, active agent) and known methods (remote-loading, aerosolized delivery) to yield predictable results (a liposomal bronchodilator composition) which is prima facie obvious according to MPEP 2143(I)(a). A person of ordinary skill in the art would have been motivated to modify Hayes’ liposomal compositions to be suitable for pulmonary delivery because Jauernig teaches that treating pulmonary conditions by inhalation is advantageous because it allows for the active agent to be delivered directly to the target site (paragraph 0002).
The combination of Hayes’ teachings for liposomes (which are made of phospholipids and cholesterol) that encapsulate an internal aqueous medium which contains a complex of the trapping agent (such as ammonium sulfate) and therapeutic agent (paragraphs 0012, 0030, 0050, 0126) with Jauernig’s teaching for inhalable liposomal compositions containing tiotropium salts as an active agent (abstract, paragraphs 0019, 0048, 0087, 0095 – 0098, 0123, 0167, claims 9, 27, 29) reads on instant claim 1.
As discussed above, Hayes’ Table 4 shows the encapsulation efficiency of carfilzomib drug remotely loaded via complexation with ammonium sulfate, which can be converted to a molar ratio of drug to phospholipid ranging from 0.127 mol drug / mol HSPC to 1.05 mol drug / mol HSPC. This range overlaps the instantly claimed range of 0.1 to 1 mol/mol as recited in claim 1. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Hayes’ teachings of HSPC and cholesterol in the amount of 50 – 70 mol and 30 – 50 mol, respectively, can be converted to a ratio of HSPC: cholesterol ranging from 1:1 to 7:3 (50:50 to 70:30 paragraphs 0012, 0050) which overlaps on the claimed range of 1:1 to 3:2 as recited in instant claim 3. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(I).
As discussed above, Hayes teaches the inclusion of cholesterol in liposomal compositions (paragraphs 0012, 0050) which reads on claim 4 of the instant application.
Hayes teaches HSPC for the liposomal composition (paragraphs 0012, 0050) reading on instant claim 5.
Haye’s teaching of PEG-DSPE in the amount of 1 – 10 mol, per 100 moles of lipid in the composition is can also be written as 1 – 10 mol % (paragraph 0050), which overlaps on the claimed range of 0.0001 – 40 mol % recited by instant claim 6. Furthermore, HSPC and cholesterol, which make up the remaining 90 mol % (paragraph 0050) are neutral phospholipids and taught range of 1 – 10 mol % PEG-DSPE (paragraph 0050) overlaps on the claimed range of 0.001 – 5 mol % recited in instant claim 9.
Hayes’ teaching that the PEG component of PEG-DSPE is 750 – 5,000 Daltons (paragraph 0046) overlaps on the claimed range of 1,000 g/mol to 5,000 g/mol (1 g/mol is equal to 1 Dalton) recited in claim 7 of the instant application.
Haye’s teaching of PEG-DSPE (paragraph 0050) reads on instant claim 8.
Hayes teaches liposomes between 40 and 150 nm in size (paragraph 0093). The taught size range of 40 – 150 nm (paragraph 0093) overlaps on the claimed range of 50 – 1,000 nm recited in instant claim 10.
Jauernig’s teaching for inhalable liposomal compositions containing tiotropium salts as an active agent (abstract, paragraphs 0019, 0048, 0087, 0095 – 0098, 0123, 0167, claims 9, 27, 29) reads on instant claim 14.
As discussed above with regards to instant claim 1, the combination of Hayes and Jauernig teaches an inhalable liposomal composition. A person of ordinary skill in the art would be able to adapt Hayes’ teachings of HSPC, cholesterol, and PEG-DSPE in relative amounts (paragraph 0050) to achieve lipid concentration in the claimed range of 1 to 25 mM, as recited in instant claim 15. According to MPEP 2144.05(II)(a), differences in concentration do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.
Although Hayes’ liposomal composition does not contain bronchodilator drugs, it does contain sparingly water-soluble drug carfilzomib which is introduced to the liposome at a concentration of 10 mg/mL (paragraph 0121). A person of ordinary skill in the art would be motivated to substitute carfilzomib as taught by Hayes with a tiotropium salt as taught by Jauernig in order to treat a pulmonary condition. Furthermore, a person of ordinary skill in the art would have a reasonable expectation of success when substituting carfilzomib with tiotropium salt because both drugs are sparingly water-soluble. Therefore, the combination of Hayes’ teaching for a liposomal composition which contains 10 mg/mL active agent with Jauernig’s teaching for tiotropium salts as active agent overlaps on the claimed range of 1 to 15 mg/mL drug as recited in instant claim 16.
As discussed above, Hayes’ Table 4 shows the encapsulation efficiency of carfilzomib drug remotely loaded via complexation with ammonium sulfate, which can be converted to a molar ratio of drug to phospholipid ranging from 0.127 mol drug / mol HSPC to 1.05 mol drug / mol HSPC. This range overlaps the instantly claimed ranges of 0.1 to 0.7, 0.15 to 0.6, and 0.15 to 0.2 mol/mol as recited in claim 17.
Jauernig’s teaching that aerosol particles should have an aerodynamic diameter of less than 5 – 6 µm for inhalable administration to adults (paragraphs 0002, 0003) reads on instant claims 19 and 20. Jauernig’s teaching that the particles should have less than 5-6 µm diameter overlaps with the claimed rang of 0.5 to 5 µm recited in instant claim 20.
Haye’s teaching of PEG-DSPE in the amount of 1 – 10 mol, per 100 moles of lipid in the composition is can also be written as 1 – 10 mol % (paragraph 0050), which overlaps on the claimed range of 0.001 to 30 mol % and less than 6 mol % recited in instant claims 21 and 22.
Examiner’s Reply to Attorney Arguments Dated October 10, 2025
Applicant’s arguments with respect to combination of Yang and Hayes have been considered but are moot because the new ground of rejection does not rely on this combination of references.
Applicant alleges unexpected results with regards to storage stability (Remarks page 10).
The Examiner is not persuaded by this argument. As an initial matter, the Examiner notes that a proper side-by-side comparison to the closest prior art as required by MPEP 716.02(e) does not appear to have been made. Applicant argues generally with regards to storage stability, but does not appear to have identified a particular reference standard/control to which the comparison is directly made.
Furthermore, Applicant has not fully explained the significance of the data in arriving at the conclusion that results are unexpected as required by MPEP 716.01(c)(II) and 716.02(b)(II). While Applicant argues that the storages stability is increased, i.e. “no drug leakage out of the liposome” after storage at 4C for two months, Applicant does not provide any empirical data to support this assertion.
As such, it is not clear to the Examiner how Applicant’s argument is supported by the proffered evidence.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
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/TORIANA N. VIGIL/Examiner, Art Unit 1612
/FREDERICK F KRASS/Supervisory Patent Examiner, Art Unit 1612
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