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 .
Status of Claims
The amendments and arguments filed 2 October 2025 are acknowledged and have been fully considered. Claims 16-32, 34-35, and 37 are currently pending. Claims 16, 19, and 22 are amended; claims 1-15, 33, 36, and 38-49 are cancelled; claims 23-26, 32, and 34-35 are withdrawn; no claims are new.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Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. In particular, the rejection of claims under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendments to the claims. 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 § 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.
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.
Claims 16-17, 20-21, 28, and 37 are MAINTAINED rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. (Drug Delivery, 2004, Vol 11, 247-253; of record) in view of Beinborn et al. (European Journal of Pharmaceutics and Biopharmaceutics, 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 (more specifically sucrose or trehalose (Claim 21)) 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 (more specifically an antifungal agent (Applicant’s elected species)).
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.
Shah et al. teach a method of preparing a liposomal Amphotericin B dry powder inhaler (DPI) formulation for the treatment of invasive lung fungal infection (Abstract). Shah et al. further teach lyophilization of a liquid liposome composition and a cryoprotectant like maltose, dextrose, trehalose, lactose, and sucrose (Pg. 248 right column second paragraph).
As such, Shah et al. teach a method of freezing a liquid liposomal composition comprising: applying a liquid liposomal composition and a sugar; and allowing said liposomal composition to freeze, wherein the liposomal composition further comprises an antifungal agent, and wherein the liposomal composition is formulated for inhalation.
The method of Shah et al. differs from the instantly claimed method in the following ways:
Shah et al. do not teach forming a thin film liposomal composition; and
Shah 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 antifungal DPI compositions for the treatment of invasive fungal infections (Abstract). Beinborn et al. further teach that the formation of the DPI composition by thin film freezing (TFF) results in a low-density pharmaceutical powder that have been shown to be highly respirable (Pg. 601 left column fourth paragraph) capable of demonstrating high concentration of drug in the lungs 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 to have modified the method of Shah et al. to include 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, 21, 28, and 37 are rejected as prima facie obvious.
Claim 20 is drawn to the method of claim 16, wherein said sugar is present at about a lipid to sugar ratio of about 1:0.6 to 1:30 w/w.
Shah et al. further teach a sugar to lipid mass ratio of between 1:2 and 1:8 (Table 2 on pg. 249), overlapping with the instantly claimed range.
As such, claim 20 is rejected as prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. and Beinborn et al. as applied to claims 16-17, 20-21, 28, and 37 above, and further in view of Chen et al. (US 2018/0200186; of record).
The teachings of Shah 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.
Shah et al. further teach the liposomes comprising hydrogenated soya phosphatidylcholine, hydrogenated soya phosphatidylglycerol, and cholesterol (Pg. 248 left column).
Shah 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 Shah et al. by substituting dioleoyl phosphatidylcholine and distearoyl phosphatidylglycerol for hydrogenated soya phosphatidylcholine and hydrogenated soya phosphatidylglycerol, respectively. It would have been obvious to substitute known phosphatidylcholines and phosphatidylglycerols suitable for liposomal DPI compositions for another, with a reasonable expectation of success.
As such, claim 18 is rejected as prima facie obvious.
Claims 19, 27, and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. and Beinborn et al. as applied to claims 16-17, 20-21, 28, and 37 above, and further in view of Cui et al. (US 2019/0142936; of record).
The teachings of Shah et al. and Beinborn et al. have been set forth above.
Claim 19 is drawn to the method of claim 16, wherein said thin film has a particle size distribution upon reconstitution within about 10-50% the range of the liquid liposomal composition.
Shah et al. and Beinborn et al. are silent as to the size distribution upon reconstruction.
Cui et al. teach a similar TFF method (Par. [0039]) that produced dry powders suitable for use as DPI (Par. [0119]). Cui et al. further teach a powder produced by the TFF method having a particle size of 3.29±0.15µm after reconstitution compared to a particle size of 5.64±0.015µm before freezing (Par. [0027]), corresponding to a particle size distribution upon reconstitution within about 40% the range of the particle before freezing.
As Shah et al. and Beinborn et al. teach the same TFF method, one of ordinary skill in the art would reasonably expect the thin film produced by the method of Shah et al. and Beinborn et al. to have similar behavior upon reconstitution.
As such, claim 19 is rejected as prima facie obvious.
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 contact the droplets with a freezing surface having a temperature differential of at least about 30°C between the droplets and the surface.
Shah 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. 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 Shah 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 Shah 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 Shah 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.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. and Beinborn et al. as applied to claims 16-17, 20-21, 28, and 37 above, and further in view of Franze et al. (Pharmaceutics, 2018, Vol. 10, 139; of record).
The teachings of Shah et al. and Beinborn et al. have been set forth above.
Claim 22 is drawn to the method of claim 16, wherein the thin film comprises less than about 5% by weight water.
Shah et al. and Beinborn et al. are silent as to the water content of the thin film.
However, Beinborn et al. teach further lyophilizing the thin film to result in a dry composition (Pg. 601 right column third paragraph).
Franze et al. teach freezing and freeze-drying methods for liposomes (Title, Abstract). Franze et al. teach “The possible limitations in the development of liposomal dosage forms are usually related to phenomena of oxidation and/or hydrolysis of lipids, drug leakage, the formation of aggregates or vesicle fusion, with consequent alteration of the in vivo biodistribution and, therefore, efficacy and safety” (Introduction second paragraph). Franze et al. further teach that drying liposomes can overcome these instability issues as they are all water dependent (Introduction second paragraph), indicating that the stability of liposomes is directly related to the water content.
And 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 concentration of water in the thin film is clearly a result-effective variable, determining the stability of the liposomes in the film. Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal concentration of water in the thin film in order to best achieve the desired results.
As such, claim 22 is rejected as prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 16-18, 22, 27-31, and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-18, 22, 27-30, and 33 of copending Application No. 17/819,286 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 16 of Application No. ‘286 recites a method for preparing an adjuvant thin film comprising: applying a liquid adjuvant composition to a freezing surface, wherein said liquid adjuvant composition comprises monophosphoryl lipid A and/or saponin fraction QS-21 (i.e., a liquid liposomal composition), and a sugar or a sugar alcohol; and allowing said liquid adjuvant composition to disperse and freeze on said freezing surface, thereby forming an adjuvant thin film, overlapping with instant claim 16.
Claim 17 of Application No. ‘286 recites the method of claim 16, wherein the liquid adjuvant composition further comprises an antigen, overlapping with instant claim 17.
Claim 18 of Application No. ‘286 recites the method of claim 16, wherein the liquid adjuvant composition comprises dioleoyl phosphatidylcholine and cholesterol, overlapping with instant claim 18.
Claim 22 of Application No. ‘286 recites the method of claim 16, wherein the adjuvant thin film comprises less than about 5% water, overlapping with instant claim 22.
Claim 28 of Application No. ‘286 recites the method of claim 16, wherein exposure comprises spraying or dripping droplets of the liquid adjuvant composition, overlapping with instant claim 28.
Claim 29 of Application No. ‘286 recites 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, overlapping with instant claim 29.
Claim 30 of Application No. ‘286 recites the method of claim 27, 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 and or wherein the freezing rate of said droplets is between about 10 K/second and about 103 K/second, overlapping with instant claims 30-31.
Claim 33 of Application No. ‘286 recites the method of claim 16, wherein the thin adjuvant film is formulated as an aerosol for inhalation in the lungs or the nasal cavity, overlapping with instant claim 37
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 2 October 2025 have been fully considered but they are not persuasive.
Applicant argues on pg. 6-7 of the remarks that the combination of Shah et al. and Beinborn et al. would not have resulted in predictable results, stating “the Applicant notes that the combination of these references would suggest the destruction of the liposomes within the formulation.”
This argument is not persuasive. As Shah et al. teaches a liposomal formulation that is suitable for freezing by lyophilization, one of ordinary skill in the art would reasonably expect the thin film freezing method of Beinborn et al. to successfully improve the liposomal formulation of Shah et al. 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. Further, as stated in the instant specification, the formation of large ice crystals and thick ice channels that result in disruption of the liposomal membrane as argued on pg. 6 of the Remarks are linked to slow freezing process, and fast freezing processes such as the TFF of Beinborn et al. overcome this issues.
And, as discussed in MPEP 716.01(c), “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” As Applicant has not provided objective evidence of the alleged destruction of the liposomes within the formulation, the statement is considered mere argument, and is not sufficient to overcome the prima facie case of obviousness.
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.
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/PAUL HOERNER/Examiner, Art Unit 1611
/CRAIG D RICCI/Primary Examiner, Art Unit 1611