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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 July 2026 has been entered.
Status of Claims
The amendments and arguments filed 20 July 2026 are acknowledged and have been fully considered. Claims 16-32, 34-35, and 37 are currently pending. Claims 16 and 20 are amended; claims 1-15, 33, 36, and 38-49 are cancelled; claims 23-26, 32, and 34-35 are withdrawn; no claims are new.
Claims 16-22, 27-31, and 37 are examined on the merits herein.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. In particular, the provisional nonstatutory double patenting rejection over Application No. 17/819,286 has been withdrawn in view of the abandonment of Application No. 17/819,286. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112(b)
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 16 and 20 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.
Claim 16 recites a lipid to sugar and/or sugar alcohol ratio of greater than 1:15, without defining what the ratio is with respect to (e.g., mol/mol, w/w, etc.), rendering the claim indefinite.
For examination purposes, claim 16 is interpreted as reciting a “ratio greater than 1:15 w/w”.
Claim 20 recites the method of claim 16, wherein said lipid to sugar and/or sugar alcohol ratio of about 1:250 to 1:1000 w/w, respectively. It is unclear whether the recites values of 1:250 and 1:1000 are intended to be maximum values for the lipid: sugar and lipid: sugar alcohol ratios, respectively; minimum values for the lipid: sugar and lipid: sugar alcohol ratios, respectively; or if the lipid: sugar and lipid: sugar alcohol ratio both fall in the range of 1:250 and 1:1000, rendering the claim indefinite.
For examination purposes, claim 20 is interpreted as “the method of claim 16, wherein said lipid to sugar and/or sugar alcohol ratio is from about 1:250 to about 1:1000 w/w.”
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.
Claims 16-17, 19, 21-22, 28, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Joshi et al. (AAPS PharmSciTech, 2001, Vol. 2, 25) in view of Beinborn et al. (Eur J Pharm Biopharm, 2012, Vol. 81, 600-608; of record).
Claim 16 is drawn to a method for preparing a thin film liposomal composition comprising: applying a liquid liposomal composition and a sugar or a sugar alcohol, wherein the sugar or sugar alcohol is present at a lipid to sugar and/or sugar alcohol ratio of greater than 1:15, to a freezing surface; and allowing said liquid liposomal composition to disperse and freeze on said freezing surface thereby forming thin film liposomal composition.
Claim 17 is drawn to the method of claim 16, wherein the thin film liposomal composition further comprises a drug or biologic agent.
Claim 28 is drawn to the method of claim 16, wherein exposure comprises dripping droplets of the liquid liposomal composition.
Claim 37 is drawn to the method of claim 16, wherein the thin film liposomal formulation composition is formulated for inhalation.
Joshi et al. teach a method of preparing a liposomal budesonide dry powder inhaler (DPI) formulation (Abstract). Joshi et al. further teach preparation of liposomes and lyophilization of the liposomal liquid with a sugar (Pg. 2), additionally teaching a weight ratio of lipid to sugar of 1:4 to 1:16 (Table 3), overlapping with the instantly claimed range.
As such, Joshi et al. teach a method of freezing a liquid liposomal composition comprising: applying a liquid liposomal composition and a sugar, wherein the sugar is present at a lipid to sugar ratio of greater than 1:15; and allowing said liposomal composition to freeze, wherein the liposomal composition further comprises a drug or biologic agent, and wherein the liposomal composition is formulated for inhalation.
The method of Joshi et al. differs from the instantly claimed method in the following ways:
Joshi et al. do not teach forming a thin film liposomal composition; and
Joshi et al. do not teach applying the liquid liposomal composition and sugar to a freezing surface.
Yet, as to 1 and 2: Beinborn et al. teach DPI formulations formed using thin film freezing (Abstract), further teaching that the use of thin film freezing (TFF) results in a low-density pharmaceutical powder that has been shown to be highly respirable (Pg. 601 left column fourth paragraph) capable of demonstrating high concentration of drug in the longs and clinically relevant plasma concentrations (Pg. 607 right column last paragraph). Beinborn et al. further teach freezing the liquid composition dropwise onto a rotating cryogenic steel surface to produce thin films (Pg. 601 right column third paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Joshi et al. to utilize the TFF method of Beinborn et al. It would have been obvious to use the known TFF technique to improve the known liposomal DPI composition in the same way by producing a low-density pharmaceutical powder that is highly respirable and capable of demonstrating high concentration of drug in the lungs and clinically relevant plasma concentrations, with a reasonable expectation of success.
Based on all of the foregoing, claims 16-17, 28, and 37 are rejected as prima facie obvious.
Claim 19 is drawn to the method of claim 16, wherein said thin film has a particle size distribution upon reconstitution with about 10-50% of the range of the liquid liposomal composition.
Joshi et al. further teach sonicating the liquid liposomal composition to obtain the desired particle size prior to lyophilization (Abstract), further teaching the average particle size prior to freezing of 1.90 µm to 2.38µm (Postsonication in Table 4 on pg. 5) and after reconstitution of 1.89µm to 2.43µm (Postrehydration in Table 4 on pg. 5).
As such, claim 19 is rejected as prima facie obvious.
Claim 21 is drawn to the method of claim 16, wherein the sugar or sugar alcohol is mannitol, sucrose, and/or trehalose.
Joshi et al. further teach sucrose and trehalose as suitable cryoprotectants (Pg. 7 left column first paragraph).
As such, claim 21 is rejected as prima facie obvious.
Claim 22 is drawn to the method of claim 16, wherein said thin film comprises less than about 5% water (wt/wt).
Joshi et al. further teach the water content of the DPI formulation between 0.69% and 0.93% (Water content in Table 4 on pg. 5).
As such, claim 22 is rejected as prima facie obvious.
Claim 17 is ADDITIONALLY rejected under 35 U.S.C. 103 as being unpatentable over Joshi et al. and Beinborn et al. as applied to claims 16-17, 19, 21-22, 28, and 37 above, and further in view of Shah et al. (Drug Delivery, 2004, Vol. 11, 247-253; of record).
The teachings of Joshi et al. and Beinborn et al. have been set forth above.
Claim 17 is drawn to the method of claim 16, wherein the thin film liposomal composition further comprises a drug (more specifically an antifungal agent (Applicant’s elected species)).
Joshi et al. and Beinborn et al. do not teach Applicant’s elected species of an antifungal agent.
Shah et al. also teach liposomal DPI compositions made by freezing liposomal compositions, wherein the compositions comprise the Amphotericin B for the treatment of invasive lung fungal infection (Abstract).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the thin film liposomal composition of Joshi et al. and Beinborn et al. to include Amphotericin B as taught by Shah et al. It would have been obvious to combine the known liposomal DPI composition with the known use of Amphotericin B in liposomal DPI compositions to yield the predictable result of a liposomal DPI suitable for treating invasive lung fungal infection, with a reasonable expectation of success.
As such, claim 17 is rejected as prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Joshi et al. and Beinborn et al. as applied to claims 16-17, 19, 21-22, 28, and 37 above, and further in view of Chen et al. (US 2018/0200186; of record).
The teachings of Joshi et al. and Beinborn et al. have been set forth above.
Claim 18 is drawn to the method of claim 16, wherein the liquid liposomal composition comprises dioleoyl phosphatidylcholine and cholesterol.
Applicant’s elected species of liquid liposomal composition comprises phosphatidylcholine, cholesterol, and distearoyl phosphatidylglycerol.
Joshi et al. further teach the liposomes comprising egg phosphatidylcholine and cholesterol (Abstract).
Joshi et al. and Beinborn et al. do not teach the liposomes comprising dioleoyl phosphatidylcholine or distearoyl phosphatidylglycerol.
However, Chen et al. teach similar liposomal compositions for delivery via DPI (Abstract). Chen et al. further teach dioleoyl phosphatidylcholine and distearoyl phosphatidylglycerol as suitable phospholipids for use in the liposomal DPI composition (Par. [0074]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the liposomes of Joshi et al. to include dioleoyl phosphatidylcholine and distearoyl phosphatidylglycerol. It would have been obvious to substitute known phospholipids suitable for liposomal DPI compositions for another, with a reasonable expectation of success.
As such, claim 18 is rejected as prima facie obvious.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Joshi et al. and Beinborn et al. as applied to claims 16-17, 19, 21-22, 28, and 37 above, and further in view of Susa et al. (Cryobiology, 2021, Vol. 98, 46-56).
The teachings of Joshi et al. and Beinborn et al. have been set forth above.
Claim 20 is drawn to the method of claim 16, wherein said lipid to sugar and/or sugar alcohol ratio is from about 1:250 to about 1:1000 w/w.
Joshi et al. and Beinborn et al. do not teach the sugar to lipid ratio in the range of 1:250 to 1:1000 w/w.
Joshi et al. teach the percent drug remaining entrapped as being dependent on the ratio of lipid to sugar (Table 3 on pg. 5), indicating that the lipid to sugar ratio is a result dependent variable.
Susa et al. also teach freezing of liposomes with cryoprotectants (Title, Abstract). Susa et al. further teach a sucrose to lipid molar ratio of 220:1 or 230:1 (Pg. 47 right column second last paragraph), corresponding to a sucrose to lipid weight ratio of 101:1 or 102:1 as calculated by examiner, indicating that significantly higher sugar to lipid ratios are suitable for protecting the liposomes during freezing.
As discussed by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454)): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the sugar to lipid ratio is clearly a result-effective variable, determining the drug encapsulation of the liposomes. Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal sugar to lipid ratio in order to best achieve the desired results.
As such, claim 20 is rejected as prima facie obvious.
Claims 27 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Joshi et al. and Beinborn et al. as applied to claims 16-17, 19, 21-22, 28, and 37 above, and further in view of Cui et al. (US 2019/0142936; of record).
The teachings of Joshi et al. and Beinborn et al. have been set forth above.
Claim 27 is drawn to the method of claim 16, wherein said liquid liposomal composition is exposed to said freezing surface from about 50 milliseconds to about 5 seconds.
Claim 29 is drawn to the method of claim 28, wherein the freezing surface temperature is about -180°C to about 0°C, the diameters of the droplets are about 2-5 millimeters, and the droplets are dropped from a distance about 2 cm to 10 cm from the freezing surface.
Claim 30 is drawn to the method of claim 28, further comprising contacting the droplets with a freezing surface having a temperature differential of at least about 30°C between the droplets and the surface.
Joshi et al. and Beinborn et al. are silent as to the freezing time, droplet diameters, distance the droplets are dropped, and temperature differential between the droplets and the surface.
However, Cui et al. teach a similar TFF method (Par. [0039]) that produced powders suitable for use as DPI (Par. [0119]). Cui et al. further teach a freezing time of between about 50 and 2,000 milliseconds (Par. [0097]); droplet diameters of between 0.1 and 5mm (Par. [0098]); a temperature differential between the surface and droplets of at least 30°C (Par. [0094]); a freezing surface having a temperature of below 250 K (Par. [0121]) corresponding to a temperature of -23.15°C as calculated by examiner; and droplets dropped from about 10 cm (Par. [0462]), overlapping with the instantly claimed ranges.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Joshi et al. and Beinborn et al. to utilize the temperature, time, height, and diameter parameters taught by Cui et al. It would have been obvious to combine the known TFF method with known parameters suitable for forming a dry powder via TFF to yield the predictable result of a method for forming a dry powder via TFF, with a reasonable expectation of success.
As such, claims 27 and 29-30 are rejected as prima facie obvious.
Claim 31 is drawn to the method of claim 30, wherein the freezing rate of said droplets is between about 10 K/second and about 103 K/second.
Cui et al. further teach the freezing rate of droplets being between 10 K/second and 105 K/second (Par. [0097]), overlapping with the instantly claimed range.
As the method of Joshi et al., Beinborn et al., and Cui et al. is substantially identical to the method of Cui et al., one of ordinary skill in the art would reasonably expect the method of Joshi et al., Beinborn et al., and Cui et al. to obtain the same freezing rates taught by Cui et al.
As such, claim 31 is rejected as prima facie obvious.
Response to Arguments
Applicant's arguments filed 20 July 2026 have been fully considered but they are moot in view of the new grounds of rejection set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Paul Hoerner whose telephone number is (571)270-0259. The examiner can normally be reached Monday - Friday 9:00am - 5:00pm eastern.
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/PAUL HOERNER/Examiner, Art Unit 1611
/CRAIG D RICCI/Primary Examiner, Art Unit 1611
