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 .
Summary
Receipt of Applicant’s Amendments are Remarks filed on 07/16/2025 is acknowledged.
Claims 16-31, 33, 42-43 and 45 are pending.
Claims 17, 19, 25, 30, 33 are amended.
Claims 16-31, 33, 42-43 and 45 are pending and under examination in this application. in this application.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 nonobviousness.
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 16-31, 33, 42-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Cui et al. (WO 2014/186754) hereinafter the reference is referred as Cui in view of Vandepapeliere (US 2008/0279926).
Cui teaches dry vaccine composition and methods of freezing aluminum-containing vaccines such that when converted into a dried powder, the dry vaccine can be readily reconstituted to form a stable liquid vaccine without significant loss of activity (abstract). Additionally, Cui discloses aluminum-containing adjuvants have been widely used in human vaccines for decades and recently, there had been extensive efforts in identifying the relationship between the size of particulate vaccine carriers and their adjuvant activities, and it is clear now that the size of particulate vaccine carriers significantly affects their adjuvant activities (¶ 0004, lines 5-10). Furthermore, Cui discloses a dry vaccine comprising an antigenic protein and an aluminum adjuvant (¶ 0006), and in an aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and any of the compositions (e.g. vaccines) (¶ 0007).
Regarding claim 16, Cui teaches a method for preparing a vaccine thin film comprising: applying a liquid vaccine to a freezing surface; allowing the liquid vaccine to disperse and freeze on the freezing surface thereby forming a vaccine thin film (¶ 0008, claim 17, ¶ 0089), wherein said liquid vaccine comprises an aluminum adjuvant (claim 18), and wherein the vaccine comprises an excipient trehalose (¶ 0079-line 19, claims 37 and 40). The preparation method of Cui incorporates aluminum adjuvant differs from instant claims of monophosphoryl lipid A and/or saponin fraction QS-21 as the adjuvant. Thus the limitations of applying a liquid adjuvant composition to a freezing surface comprising a sugar (trehalose), allowing said liquid adjuvant composition to disperse and freeze on said freezing surface thereby forming an adjuvant thin film is met.
Regarding claim 17, Cui teaches antigenic protein, a protein may be an antigenic protein conjugated to a sugar (i.e. saccharide) (i.e. monosaccharide, disaccharide, polysaccharide) “antigenic protein saccharide conjugate”, and in embodiments, an antigenic protein may be an antigenic protein that is not conjugated to a sugar (saccharide) (¶ 0056), and adjuvants may increase an antigen specific immune response in a subject when administered to the subject with one or more specific antigens as part of a vaccine (¶ 0061 and 0068).
Regarding claim 19, Cui teaches methods of making dry vaccines that retain particle size and immunogenicity upon reconstitution would be useful and would address strict requirements of the vaccines to be kept refrigerated at 2-8 °C during transport and storage (¶ 0003) and it is clear now that the size of particulate vaccine carriers significantly affects their adjuvant activities (¶ 0004-page 2, lines 9-10). As stated above, Examiner interprets this claim to refer to particle size of the adjuvanted vaccine and thus Cui teaches aqueous vaccine composed of an agent and an aluminum adjuvant that form particles size of less than about 10 nm to about 200 nm, and the aqueous vaccine composition can be converted to a vaccine powder, for storage, for use as an inhalant, or use in other delivery modes (¶ 0084). Furthermore, Cui discloses in embodiments, the particle size of the Engerix-B vaccine after reconstitution from the TFFD powder was 3.29 ± 0.15 µm (¶ 0027).
particle size distribution within about 10-50% or about 30% of the range of the liquid adjuvant composition.
Regarding claim 20, Cui teaches certain sugars, for example trehalose, mannitol, dextran, and sucrose, have been shown to be effective at maintaining protein activity and stabilize aluminum salts in vaccine formulations during freezing process and trehalose forms fragile glass during freezing, resulting in an increase on the viscosity, which limits the mobility of protein molecules or aluminum salt particles and thus, prevents coagulation, and the formation of glass also resulted in a trehalose-containing phase with maximum concentration that prevents the non-ice concentration or pH induced aggregation of aluminum salts during freezing (¶ 0189-lines 6-16), thus to determine the optimal concentration of trehalose needed to prevent aggregation during thin film freeze drying (TFFD), Ovalbumin (OVA)-adsorbed aluminum hydroxide suspended in various concentrations of trehalose (i.e. 0%-5% w/v) was subjected to TFFD (¶ 0189-lines 21-23). Cui used trehalose alone as the sugar during the TFFD process and it is expected that other cryoprotectants (sucrose, glycine, amino acids, polyvinylpyrrolidone) may also help to prevent aggregation during TFFD process (¶ 0189-page 93, line 33 to page 94, lines 1-2). However, a person having ordinary skill in the art (PHOSITA) would have been able to convert the sugar units of w/v to w/w in a composition with known density of the solution. Furthermore, Cui discloses alternative sugar or sugar alcohol can be used and a PHOSITA would reasonably optimize the sugar concentration (% w/w) based on the selected sugar in order to prevent aggregation, stabilize and effectively maintain protein activity.
Regarding claim 22, Cui teaches dry vaccine is a vaccine comprising 5% or less of water (¶ 0068, lines 30-31 and ¶ 0077).
Regarding claims 23 and 24, Cui teaches the liquid vaccine includes an excipient and in embodiments, the excipient is a salt, sugar (saccharide), buffer, detergent, polymer, amino acid, or preservative (¶ 0091, claims 11, 12, 21, 37 and 37).
Regarding claim 25, Cui teaches the entire Markush listing of excipient as claimed (¶ 0091, claims 13, 39).
Regarding claim 26, Cui teaches the method of one of embodiments, wherein said liquid vaccine comprises about 0.1 or 10 % of said excipient/liquid vaccine (claims 79, 80). Therefore, the limitation of comprising from about 10% to about 40% of said excipient is taught.
Regarding claim 27, Cui teaches each droplets freeze upon contact with the freezing surface in less than about 50 to 2,000 milliseconds, and may freeze upon contact with the surface in about 50 or 150 t0 500 milliseconds (¶ 0129, claims 27, 91). Therefore, the limitation of said liquid adjuvant composition exposed to said freezing surface from about 50 milliseconds to about 5 seconds is taught.
Regarding claim 28, Cui teaches the step of spraying or dripping droplets is repeated to overlay one or more additional vaccine thin films on top of the vaccine thin film (¶ 0098).
Regarding claims 29 and 30, Cui teaches in embodiments, the method further includes contacting the droplets with a freezing surface having a temperature below the freezing temperature of the liquid vaccine (e.g. 1 or 100 degrees Celsius below the freezing temperature (¶ 0093), and the method further includes contacting the droplets with a freezing surface having a temperature differential of at least 30 °C between the droplets and the surface (¶ 0093-lines 5-7, claim 83), and in embodiments, the freezing rate of the droplets is between about 10 K/second and about 103 K/second (¶ 0096-lines, claim 88). Furthermore, Cui teaches in thin film freezing (TFF), liquid droplets fall from a given height and impact, spread, and freeze on a cooled solid substrate, and in embodiments, the size of the completely frozen droplet is about 2-12 mm in diameter and the droplets fall from a height of 10 cm (¶ 0202-lines 13-26). Therefore, the structural features and limitations are taught.
Regarding claim 31, Cui teaches a method of preparing a dry vaccine including a method of preparing a vaccine thin film and a method of removing a solvent from a vaccine thin film (¶ 0119), and in embodiments, the method may further include the step of removing the liquid (e.g. solvent, water) from the frozen material to form a dry vaccine (e.g. particles) (¶ 0124-lines 1-3), and the method of embodiment, wherein removing the water is done by a lyophilization process (page 51, line 5).
Regarding claim 33, Cui teaches in embodiments, the dry vaccine is administered by inhalation, through the nasal mucosa, bronchoalveolar mucosa (¶ 0118 and 0123), and in embodiments, the compositions can be formulated as liposomal formulations (¶ 0054, page 13, line 30) and aerosols (¶ 0054-page 14, line 8).
Regarding claim 45, Cui teaches active ingredient is contained in a therapeutically or prophylactically effective amount, i.e., an amount effective to achieve its intended purpose, and the actual amount effective for a particular application will depend, inter alia, on the condition being treated, and determination of a therapeutically or prophylactically effective amount of a composition is well within the capabilities of those skilled in the art (¶ 0088).
Cui fails to specifically teach dioleoyl phosphatidylcholine and cholesterol, varicella zoster virus glycoprotein E or comprises one, two, three or four distinct influenza hemagglutinin antigens.
Vandepapeliere teaches an immunogenic composition in a dose volume suitable for human use comprising an antigen or antigenic preparation, in combination with an adjuvant which adjuvant comprises an immunologically active saponin fraction derived from the bark of Quillaja Saponaria Molina presented in the form of a liposome and a lipopolysaccharide wherein said saponin fraction and said lipopolysaccharide are both present (abstract).
Regarding claims 16 and 18, Vandepapeliere teaches monophosphoryl lipid A (MPL) (¶ 0013) and discloses a strong synergy when a lipopolysaccharide (3D-MPL) was combined with Quillaja saponin (QS21) with good adjuvant properties as immunostimulants in an adjuvant composition (¶ 0037), and preparation of MPL/QS21 liposomal adjuvant comprises adjuvant named AS01, comprises 3D-MPL and QS21 in a quenched form of cholesterol, and the AS01B adjuvant comprises liposomes, which in turn comprises dioleoyl phosphatidylcholine (DOPC), cholesterol and 3D-MPL (¶ 0394). Furthermore, Vandepapeliere discloses that in the process of production of liposomes containing MPL, the dioleyl phosphatidylcholine (DOPC), cholesterol and MPL are dissolved in ethanol, wherein a lipid film is formed by solvent under vacuum (¶ 0395) . Therefore, the limitation of comprising monophosphoryl lipid A and/or QS-21, and a sugar, dioleoyl phosphatidylcholine and cholesterol are taught.
Regarding claim 21, Vandepapeliere teaches varicella zoster virus antigen or antigens or antigenic preparation thereof, and an adjuvant comprising an immunologically active saponin fraction derived from the bark of Quillaja Saponaria Molina presented in the form of a liposome and a lipopolysaccharide (¶ 0047) and influenza hemagglutinin antigens (¶ 0062, ¶ 0323-0348).
Regarding claims 42 and 43, Vandepapeliere teaches in specific embodiment, QS21 is provided in it less reactogenic composition where it is quenched with an exogenous cholesterol, and in another embodiment the saponin/cholesterol is in the form of a liposome structure containing a neutral lipid phosphatidylcholine, for example egg-yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC), and the liposome may contain charged lipid which increases the stability of the liposome QS21 structure for liposomes composed of saturated lipids (¶ 0103).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing an adjuvant thin film comprising applying a liquid adjuvant composition to a freezing surface, allowing the composition to disperse and freeze on said freezing surface thereby forming an adjuvant thin film as taught by Cui and incorporate the adjuvant composition comprising monophosphoryl lipid A and/or saponin fraction QS-21 as taught by Vandepapeliere.
One would have been motivated to do so because the combined teaching of Cui in view of Vandepapeliere discloses methods for preparing an adjuvant thin film with the method of Thin Film Freeze Drying (TFFD). One of ordinary skill in the art would have been motivated to use the TFFD of Cui in view of Vandepapeliere to formulate a dry liposome adjuvant vaccine for inhalation because both the references are drawn to methods of optimizing the sugar or sugar alcohol content and the particle size in the adjuvanted vaccine to be effective in an inhalation formulation.
One of ordinary skill in the art would have found it obvious to apply the different methods of adjuvant vaccine preparation to improve the stability without significant loss of the vaccine’s immunogenic activity during use, storage and transport as taught by the beneficial TFFD method of Cui in view of Vandepapeliere. A PHOSITA would have been motivated to use Vandepapeliere’ s lipopolysaccharide (3D-MPL) combined with Quillaja saponin (QS21) because of the strong synergy, with good adjuvant properties as immunostimulants in an adjuvant composition and look to Cui’s method of preparation to optimize the adjuvant thin film, retain particle size and immunogenicity upon reconstitution and improve the strict requirements of storage, use and during transport relating to temperature range within 2-8 °C.
It is obvious to combine prior art elements according to the known methods to yield predictable results. Please see MPEP 2141 (III)(A)-(G).
Response to Amendments/Arguments
The objection to claims 30 and 33 and the rejection of claims 17, 19 and 25 under 35 U.S.C. 112(b) are withdrawn in view of the amendments.
Applicant's arguments filed 7/16/2025 have been fully considered but they are not persuasive. Applicants argue that office action (filed 04/16/2025) failed to point Vandepapeliere compositions were prepared as liquid solutions while Cui relates to dry powder compositions made through freezing process, and further pointing that compositions containing saponins are sensitive to temperature and are readily damaged by freezing temperatures (specification, page 1, lines 24 to page 2, line 4), (Matthias et al., 2007). and that there is no motivation to combine references to result in a useful composition if the composition is frozen.
Examiner respectfully disagrees because the combined references teaches the scope and limitations of subject matter. While compositions containing saponins are sensitive to temperature and are readily damage by freezing temperatures as stated in specification paragraph above. Examiner would like to point out that AS01B is NOT a saponin itself but is an adjuvant system that contains a saponin component, specifically QS-21. AS01B is a liposome-based formulation combining two immunostimulants that work synergistically, namely 3-O-desacyl-4’-monophsophoryl lipid A (MPL) and QS-21 (Specification, page 1, lines 16-18). So, while AS01B includes a saponin (QS-21) as a key component, it is a complex adjuvant system, not a standalone saponin. Matthias et al., 2007, further disclose that technologies with slower freezing rate (e.g., conventional shelf freeze-drying) may result in phase separation and thus damage of proteins (e.g., denaturation and/or aggregation) and/or aggregations of the liposomal AS01B or AS01B-adjuvanted vaccines (specification, page 12, lines 24-29), and a cryoprotectant (trehalose) may be added to the vaccine composition to protect the organisms or agents present in the composition (either live or dead) from damage during the freezing process (specification, page 24, lines 29-32), and the thin-film freeze-drying (TFFD) method were utilized in forming AS01B.
Vandepapeliere teaches saponin, AS01B, and lyophilization and Cui teaches the method of TFFD, cryoprotectant (trehalose) and lyophilization. Therefore, it would have been obvious to PHOSITA to use the composition containing saponin of Vandepapeliere and incorporate the method of TFFD as taught by Cui in order to arrive to the claimed invention, because the TFFD method is a known method utilized in formulating sensitive biologics, proteins, adjuvants and antigens and thus it would have been obvious for a PHOSITA to try this TFFD method with compositions containing saponins. Additionally, the notion that these vaccines containing saponin component should be in storage at 2°C -8 °C is taught (Vandepapeliere, page 1 and page 2 Figure 1), and sensitive to temperature which could result in damage is also suggested.
Furthermore, all the components in the methods are taught, for example, applying a liquid adjuvant composition to a freezing surface comprising 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 is taught by Cui.
Vandepapeliere teaches monophosphoryl lipid A (MPL) (¶ 0013) and discloses a strong synergy when a lipopolysaccharide (3D-MPL) was combined with Quillaja saponin (QS21) with good adjuvant properties as immunostimulants in an adjuvant composition (¶ 0037). Therefore, the limitation of comprising monophosphoryl lipid A and/or QS-21, and a sugar, dioleoyl phosphatidylcholine and cholesterol are taught. Therefore, a person having ordinary skill in the art (PHOSITA) would have been motivated to combine the teachings of Cui in view of Vandepapeliere because both references disclose methods for preparing an adjuvant thin film with the method of Thin Film Freeze Drying (TFFD) and a prima facie case is properly established.
Conclusion
No claims are allowed.
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 ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615