DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Claims 1-62 are canceled. Claims 71-79 have been withdrawn from consideration. Claims 63-81 are under consideration in this Office Action.
Maintained Grounds of Rejection
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.
3. Claims 63-70 and 80-81 are rejected under 35 U.S.C. 103 as being obvious over Conlan et al., (WO 2010124377 published Nov. 2010; priority to April 2009) in view of Ohtake et al (Journal Pharmaceutical Sciences, August 2011, 100/8:3076-3087; and Baheti et al (J. Excipients and Food Chem., 2010, 1(1):41-54).
4. The claims are drawn to a lyophilization medium for freeze-drying a Francisella tularensis (F. tularensis) strain wherein the F. tularensis strain is a mutant strain in which the clpB gene is inactivated wherein: the lyophilization medium comprises about 1% (w/v) of mannitol, about 1% (w/v) of a disaccharide, and about 0.25% (w/v) of gelatin in a phosphate buffer, wherein the disaccharide is selected from sucrose, trehalose, and wherein initial post-lyophilization medium of the F. tularensis strain is at least about 35% of the F. tularensis strain’s pre-lyophilization viability; and wherein the lyophilization medium is suitable for preserving viability of the F. tularensis strain during long-term storage in a lyophilized state.
Conlan et al., teach a mutant Francisella tularensis strain comprising an inactivated clpB gene and compositions comprising such mutant [abstract]; thereby teaching claim 63 and 80-81. The composition may be an anti-Francisella vaccine composition. The composition may also comprise a pharmaceutically acceptable diluent, carrier, or excipient [Field of Invention]. The composition may be in any suitable form; for example, the composition may be provided in powder form (for example, lyophilised). Dry powders may also include additives to improve stability and/or carriers to increase bulk/volume; for example, and without wishing to be limiting, the dry powder composition may comprise sucrose or trehalose. It would be within the competency of a person of skill in the art to prepare suitable compositions comprising the present compounds [Detailed Description of Invention]. Conlan et al., teach the lyophilizate of claim 81. Conlan et al., teach the inclusion of sucrose and trehalose, wherein the F. tularensis strain is a mutant strain in which the clpB gene as recited by claims 1 and 80-81. Conlan et al., provide a method of producing a mutant F. tularensis strain comprising the steps of: a) obtaining cells of a virulent F. tularensis strain; b ) inactivating the clpB gene; and c) selecting for viable cells with attenuated virulence and clpB inactivation [para 14]. When the composition is provided in suspension form, the carrier may comprise water, saline, a suitable buffer, or additives to improve solubility and/or stability; reconstitution to produce the suspension is effected in a buffer at a suitable pH to ensure the viability of the bacteria [para 43]. Bacteria were harvested after 48-72 h incubation at 37° C. into freezing medium comprising modified Mueller Hinton broth containing 10% w/v sucrose [para. 60]. Therefore, Conlan et al., teach a lyophilzate of freeze-dried F. tularensis strain, where the F. tularensis strain is a mutant strain in which the clpB gene and the lyophilized powder comprises sucrose and/or trehalose and a lyophilization medium for freeze-drying a Francisella tularensis (F. tularensis) strain wherein the F. tularensis strain is a mutant strain in which the clpB gene is inactivated wherein: the lyophilization medium comprises about 1% (w/v) of a disaccharide. However, Conlan et al., do not teach of the other ingredients for a lyophilization medium for freeze-drying the mutated F. tularensis strain.
Ohtake et al., teach that F. tularensis vaccine strain can be stabilized in the dried state using foam drying, a modified freeze dry method with sugar based formulations [abstract]. Ohtake et al teaches gelatin incorporated into a solution for freeze-drying Francisella tularensis (Table 6). Inclusion of 5% w/v gelatin to the base formulation comprising 30% w/v trehalose and 25 mM potassium phosphate, pH 8.0 improved the stability of F. tularensis, which was foam-dried and stored at 37°C (Fig. 4a). Inclusion of gelatin increased storage stability over formulations that lacked gelatin. The inocula consisted of: (1) a control sample of LVS, which was grown in MHB broth and frozen at −80°C; (2) samples of formulated and vialed LVS that were resuspended in a solution containing 1% gelatin in PBS; or (3) a control solution of 1% gelatin in PBS [Evaluation of LVS activity in Mice]. Ohtake et al., describe the Effect of Gelatin on Process Recovery and Storage Stability of Foam‐Dried F. tularensis, its inclusion may be beneficial. The relative effectiveness of the gelatin‐containing formulations became clearer upon comparing their storage stability at lower temperatures. There was a stabilizing effect was observed in the presence of gelatin (Table 7).
Ohtake et al., teach that F. tularensis harvested in late stationary growth phase had improved desiccation tolerance over cultures harvested at earlier growth stages. Ohtake et al., describes viability assays for F. tularensis. Two vials of foam dried F. tularensis were reconstituted using nanopure water to assess the titer at each time point. Each vial was assessed on two plates, and for each plate, several dilution ranges were examined [Viability Assay for F. tularensis LVS]. All foam dried F. tularensis LVS was stored at 37°C for up to 6 weeks and the viability of the bacteria was measured by the culturing assay as described above. Additionally, some formulations were stored at 4°C and 25°C for up to 12 weeks [Storage Stability of Foam Dried F. tularensis LVS].
Ohtake et al., concludes that the trehalose-based formulation may be broadly applicable for stabilization of other bacterial strains. The prior art of Ohtake et al does not teach the use of mannitol and sucrose; however, Conlan et al., taught lyophilized composition comprising sucrose or trehalose.
Furthermore, Baheti et al., teach lyophilization formulations for freeze-drying comprising bulking agents and buffering agents for example. Baheti et al., teach classification of commonly used excipients used in lyophilization of molecules, the excipients include mannitol, sucrose and trehalose, sodium phosphate buffer, as well as gelatin. The art teaches that a need based approach is utilized to select the appropriate excipients for lyophilization (Figure 5, p. 46). The combined teachings of the prior art teach a lyophilization medium for freeze-drying, the medium being used to lyophilize/freeze-dry vaccines. Baheti et al., teach classification of commonly used excipients used in lyophilization of molecules, the excipients include mannitol, sucrose and trehalose, sodium phosphate buffer, as well as gelatin. “The nature of lyophilized cake also depends on the ratio of drug and bulking agent, showing an increased crystallization with an increase in amount of bulking agent.” (p. 49) “Control of pH is critical to avoid degradation of drug during processing, storage and reconstitution, thereby necessitating addition of buffering agent in the lyophilized formulation. The choice of buffer depends on the pH stability profile of active ingredient, as drug needs to be reconstituted and stored for some time before it could be administered to the patient.
For this purpose, the pH of maximum stability of drug should be known and maintained. Selection of a suitable buffer and its concentration is important for sensitive molecules. For example, in aspartame lyophilizates, the presence of 0.1M phosphate buffer caused the half-life of the material to decrease from 921 days in unbuffered material to 98 days; increasing the buffer concentration further causes a reduction to 77 days.” (p. 49) “Lyophilization is a commonly used technique for formulation development of small molecules which are unstable in aqueous medium and/or are thermolabile in nature. Lyophilization of drug alone, however, presents certain formulation development challenges, which may be overcome by incorporation of excipients (e.g. bulking agents, buffering agents, tonicifying agent, wetting agent and cosolvents, preservatives and collapse temperature modifiers) in the formulation. A need-based approach should be employed for proper selection of excipients in the formulation for lyophilization, so as to keep the formulation simple for easier processing, while simultaneously maintaining an optimal functionality.” (p. 53).
It is noted that claim 63 recites wherein initial post-lyophilization medium of the F. tularensis strain is at least about 35% of the F. tularensis strain’s pre-lyophilization viability; and wherein the lyophilization medium is suitable for preserving viability of the F. tularensis strain during long-term storage in a lyophilized state. However the Patent Office does not have the facilities for examining and comparing applicants’ pre-lyophilized viability and preserved viability, of the prior art reference, the burden is upon the applicants to show an unobvious distinction between the material structural and functional characteristics of the claimed peptide of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594. The Office points out that the lyophilization medium has the same components; therefore the medium of the prior art has the same inherent characteristics. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Additionally, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. See MPEP 2112(I) and (II).
Therefore, it would have been obvious to a person skilled in the art at the time the invention was made to prepare the lyophilization medium as recited in claim 63 by combining the teachings of Conlan et al., Ohtake et al., and Baheti et al., and common general knowledge, various excipients are needed for lyophilization’s to protect the antigen or a vaccine component. The prior art teaches the claimed invention except for specific component concentrations, however it would have been obvious to one having ordinary skill in the art at the time the invention was made to determine the specifically concentrations, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). The claimed invention is prima facie obvious in view of the combined teachings of the prior art, absent any convincing evidence to the contrary.
It is noted, that while the references refer to viability preservation; neither specifically recite at about 4OC or -20 oC for at 1 or 3 years. Regarding the specific temperatures and time periods recited in instant claims 64-70, MPEP 2144.05 states, "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)."
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to provide a medium comprising mannitol, sucrose, and gelatin in phosphate buffer, wherein there is no change in the respective function of the disaccharides, gelatin, or mannitol, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
5. Applicant's arguments filed July 24, 2025 have been fully considered but they are not persuasive. Applicant argued that the Conlan et al., reference was not citable as prior art because of the 102(b)(2)(C) exception. However Conlan et al., WO 2010124377 was published Nov. 2010. The provisional application 62645409 for which the instant application claims priority to was filed March 20, 2018. The Conlan et al., reference was published more than seven years before the earliest date for this application. Therefore all the references were all patented, described in a printed publication, or in public use, or otherwise available to the public more than one year before the effective filing date of the claimed invention obviously also applies. All the references were published well before the grace period. The 102(b)(2)(C) exception does not disqualify the Conlan et al., reference because it was also published more than one year before the effective filling date.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
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Applicants are reminded that the scope of the claims is a product or the medium per se. What is highlighted above is the medium’s intended use. The medium is not limited to just freeze drying a F. tularensis strain.
Thus, it would have been obvious to a person skilled in the art at the time the invention was made to prepare the medium as recited in claim 63 by combining the teachings of Conlan et al., Ohtake et al., and Baheti et al., and common general knowledge, various excipients are needed for lyophilization’s to protect the antigen or a vaccine component. Therefore the claimed invention is prima facie obvious in view of the combined teachings of the prior art, absent any convincing evidence to the contrary and the rejection is maintained.
Conclusion
6. No claims are allowed.
7. 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.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Gary Nickol, can be reached on 571-272-0835. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645