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 .
Claim Status
Claims 15 and 17-27 are pending (claim set as filed on 12/30/2023). Claims 15 and 17-27 are currently under examination and were examined on their merits.
Terminal Disclaimers
The Terminal Disclaimers filed on 12/30/2025 regarding U.S. Patent No. 11,202,799 and application 17/524,388 (U.S. Patent No. 12,390,489) have been received and considered.
Declaration
Applicant’s Declaration filed on 12/30/2025 has been received and considered.
Withdrawn Objections/Rejections
The previous double patenting rejections have been withdrawn in light of Applicant’s terminal disclaimers filed on 12/30/2025.
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 15 and 17-24 are rejected under 35 U.S.C. 103 as being unpatentable over Nivoliez (WO 2014/009349 A1, published on 01/16/2014).
Nivoliez’s general disclosure relates “to the use of thiosulphate in order to potentiate the anti-pathogen effect of Lactobacillus bacteria” (see entire document, including abstract).
Regarding claim 15, pertaining to a method for treatment of candidiasis in a patient, Nivoliez teaches a method for treatment of candidiasis in a patient (“the invention also relates to a pharmaceutical composition … for its use in the treatment of urogenital infections such as vaginosis, candidiasis”; page 7, lines 15-18), the method comprising vaginally administering to said patient a pharmaceutical composition comprising i) as therapeutic active agent 3.5x107 to 3.5x109 CFU of lactobacilli; and ii) approximately 80.5 mg of thiosulfate (“These pharmaceutical compositions are formulated for vaginal administration”, “compositions including lactobacilli in combination with thiosulfate, the thiosulfate potentiating the anti-pathogenic effect of said lactobacilli.”, “thiosulfate is used in a quantity of about 230 mg/ gram of powder, for a powder including between 108 and 1010 CFU of lactobacilli per gram,”, “350 mg of powder per capsule”, “administration of one or two 350 mg capsules per day”; page 1, lines 5-6; page 6, lines 3-5; page 7, line 12 and lines 26-27; page 13, lines 26-27). The Examiner notes that a thiosulfate concentration of 230 mg/g and a lactobacillus concentration of 108-1010/g corresponds to an amount of 80.5 mg thiosulfate and 3.5x107-3.5x109 CFU of lactobacillus in a 350 mg capsule (“administration of one or two 350 mg capsules per day”; page 7, lines 26-27).
Claim 15 recites ‘wherein the pharmaceutical composition is used as a substitute for a chemical antifungal’ wherein ‘substitute for a chemical antifungal’ is considered intended use. Since the intended use ‘substitute for a chemical antifungal’ does not impart a structural limitation on the product itself, the intended use is not given patentable weight (see MPEP 2111.02).
Regarding claims 17 and 18, pertaining to thiosulfate, Nivoliez teaches wherein the pharmaceutical composition comprises about 80.5 mg of thiosulfate (“thiosulfate is used in a quantity of about 230 mg/gram of powder, for a powder including between 108 and 1010 CFU of lactobacilli per gram”, “350 mg of powder per capsule”, “administration of one or two 350 mg capsules per day”; page 6, lines 3-5; page 7, lines 26-27; page 13, lines 26-27; as discussed above, 230 mg thiosulfate/g corresponds to 80.5 mg thiosulfate per 350 mg capsule).
Regarding claim 22, pertaining to the lactobacilli, Nivoliez teaches wherein the lactobacillus is Lactobacillus rhamnosus, Lactobacillus crispatus, and Lactobacillus casei (page 4, line 27; page 6, lines 13-14).
Regarding claim 23, pertaining to candidiasis, Nivoliez teaches wherein candidiasis is vulvovaginal candidiasis (page 5, lines 19-23).
Regarding claim 24, pertaining to the administering of the pharmaceutical composition, Nivoliez teaches wherein the pharmaceutical composition is formulated to be administered in one dose, once per day (page 7, lines 26-27).
Additionally, Nivoliez teaches “the use of thiosulfate to potentiate the anti-pathogenic effect of lactobacillus bacteria” (page 3, lines 31-32), wherein “[t]his “anti-pathogenic” effect is characterized in particular by an inhibition of the growth of vaginal pathogens such as Gardnerella vaginal is, Prevotella bivia, and especially Candida albicans.” (page 3, lines 23-25). Nivoliez discloses complete removal of a starting concentration of about 106 CFU/mL of C. albicans in the presence of a Lactobacillus strain and thiosulfate within 24 hours (“Co-culture of the strain Lcr35 (L. rhamnosus) formulated with 113 g/liter of thiosulfate, and Candida albicans”, “Counts showed a total inhibition at T24h of the pathogenic strain with a formulation of Lcr35® containing 113 g/I of thiosulfate; see Example 7A on page 17, lines 4-12; see Fig. 6). Nivoliez further discloses wherein “[t]he optimal modes of administration, dosing schedules and dosage forms of the compounds and compositions according to the invention can be determined according to the criteria generally taken into account in the establishment of a pharmaceutical treatment suited to a patient, such as, for example, the patient’s age or weight, the gravity of the patient’s general state, the tolerance for the treatment and the side effects observed.” (page 7, lines 21-26).
Nivoliez does not teach
wherein the pharmaceutical composition comprises at least 5x1010 CFU of lactobacilli (instant claim 15), at least 1x1011 CFU of lactobacilli (instant claim 20), or from 1x1011 CFU to 1x1012 CFU of lactobacilli (instant claim 21).
wherein the pharmaceutical composition comprises from 60 mg to 80 mg of thiosulfate (instant claim 19).
wherein the method comprises inhibiting within 12 to 20 hours a pathogen selected from the group consisting of: Candida albicans, Candida glabrata, and Candida tropicalis, with an inhibition of at least approximately 2log10 (instant claim 15).
While Nivoliez does not teach wherein the pharmaceutical composition comprises at least 5x1010 CFU of lactobacilli (instant claim 15), at least 1x1011 CFU of lactobacilli (instant claim 20), or from 1x1011 CFU to 1x1012 CFU of lactobacilli (instant claim 21), or wherein the pharmaceutical composition comprises from 60 mg to 80 mg of thiosulfate (instant claim 19), the instantly recited amounts and ranges would be within the realm of routine experimentation since Nivoliez teaches a pharmaceutical composition comprising 3.5x107 to 3.5x109 CFU of lactobacilli and about 80.5 mg of thiosulfate (see above). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined the optimal amounts of CFU of lactobacilli and thiosulfate for a given Lactobacillus strain in the pharmaceutical composition, in order to identify how much is needed for efficient treatment of candidiasis, and to further improve the treatment method. One would have expected success since Nivoliez’s teachings are directed to multiple Lactobacillus strains (see above), and therefore, manipulation of the CFU of lactobacilli and of the thiosulfate concentration based on the teachings of the reference would be within the purview of an artisan. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[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 (CCPA1955). See MPEP § 2144.05 part II A.
Regarding claim 15, the claim recites ‘wherein the method comprises inhibiting within 12 to 20 hours a pathogen selected from the group consisting of: Candida albicans, Candida glabrata, and Candida tropicalis, with an inhibition of at least approximately 2log10.’. The recited inhibition naturally results from performing the recited method steps in the claim, and therefore, the inhibiting effect is considered inherent to the method. As such, modified Nivoliez’s teachings would implicitly result in the same or similar pathogen inhibition. Since Nivoliez teaches complete removal of a starting concentration of about 106 CFU/mL of C. albicans in the presence of a Lactobacillus strain and thiosulfate within 24 hours (“Co-culture of the strain Lcr35 (L. rhamnosus) formulated with 113 g/liter of thiosulfate, and Candida albicans”, “Counts showed a total inhibition at T24h of the pathogenic strain with a formulation of Lcr35® containing 113 g/I of thiosulfate; see Example 7A on page 17, lines 4-12; see Fig. 6), it is highly expected that the method rendered obvious over Nivoliez would result in the same or similar, i.e. obvious, pathogen inhibition as described in instant claim 15.
Claims 15 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Nivoliez (WO 2014/009349 A1, published on 01/16/2014), in view of De Simone (US 7,052,688 B2, published on 05/30/2006).
Modified Nivoliez’s teachings have been set forth above.
Regarding claim 25, pertaining to the pharmaceutical composition, Nivoliez teaches wherein the pharmaceutical composition is in the form of a tablet or capsule (“the dosage forms used will be capsules, tablets”; page 7, line 13).
Modified Nivoliez does not teach wherein the pharmaceutical composition is in the form of an immediate-release tablet or capsule (instant claim 25).
De Simone’s general disclosure relates to “to a combination of lactic acid bacteria and its use for making a food supplement, a hygiene product or a pharmaceutical preparation for the prevention and/or treatment of infections and inflammatory conditions caused by bacteria, viruses or fungi, especially in the mouth, vagina, urethra, nose, eyes and ears.” (see entire document, including column 1, lines 10-15).
Regarding claim 25, pertaining to the pharmaceutical composition, De Simone teaches wherein the pharmaceutical composition comprising lactobacilli, wherein the pharmaceutical composition is in the form of an immediate-release tablet (“Preparation of Fast-Release Vaginal Tablets”, “Lyophilized and screened lactic acid bacteria (30 x 109 of L. brevis, 30 x 109 of L. salivarius and 90 x 109 of L. plantarum per gram)”; see example 5 in column 6, lines 23-30; see Table in column 6).
While Nivoliez does not teach wherein the pharmaceutical composition is in the form of an immediate-release tablet or capsule (instant claim 25), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined Nivoliez’s method with De Simone’s teachings on fast-release tablets, in order to create a method for treatment of candidiasis wherein the pharmaceutical composition is in the form of an immediate-release tablet. One would have been motivated to do so in order to develop a method that provides immediate treatment of candidiasis by releasing the active components of the composition quickly. A skilled artisan would have reasonably expected success in combining Nivoliez’s and De Simone’s teachings, since both references are directed to treatment of vaginal infections using lactobacilli (see above).
Claims 15 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Nivoliez (WO 2014/009349 A1, published on 01/16/2014) in view of Gamble et al. (WO 2016/003870 A1, published on 01/07/2016)
Modified Nivoliez’s teachings have been set forth above.
Regarding claim 26, pertaining to the pharmaceutical composition, Nivoliez teaches wherein the pharmaceutical composition is in the form of a tablet (“the dosage forms used will be capsules, tablets”; page 7, line 13).
Modified Nivoliez does not teach
wherein the pharmaceutical composition is in the form of a multilayer tablet comprising: at least one immediate-release layer comprising, in relation to the total weight of all the immediate-release layers, at least 5x1010 CFU of lactobacilli and from 60 mg to 300 mg of thiosulfate; and at least one sustained-release layer, comprising, in relation to the total weight of all the sustained-release layers, from 1x107 CFU to 1x1010 CFU of lactobacilli (instant claim 26).
wherein in the multilayer tablet, the sustained-release layer comprises from 10% to 40% by weight of hydroxypropylmethylcellulose in relation to the total weight of said layer (instant claim 27).
Gamble’s general disclosure relates to “dietary supplement and pharmaceutical formulations comprising layered acid protective oral dosage formulations comprising probiotics and provided as single unified or cohesive dosage form units” (see entire document, including abstract).
Regarding claim 26, pertaining to the pharmaceutical composition, Gamble teaches wherein a pharmaceutical composition comprising lactobacilli is in the form of a multilayer tablet (“multi-layered and bi-layered acid protective oral dosage formulations comprising probiotics”, “the dosage form is a multi-layered tablet”, “Probiotics of the present invention include, for example and without limitation, members of the genus Lactobacillus”; page 1, lines 8-9; page 5, lines 10-11, page 8, line 8), comprising: an immediate-release layer comprising probiotics and a sustained release layer comprising probiotics (“A layered dosage form comprising a first layer and a second layer, wherein each layer comprises one or more distinct probiotics”, “wherein the first layer is characterized by a first release rate and the second layer is characterized by a second release rate”, “wherein the first release rate provides an immediate release and the second release rate provides an extended release”; see claims 1-3).
Regarding claim 27, pertaining to the sustained release-layer, Gamble teaches wherein the sustained-release layer comprises from hydroxypropylmethylcellulose (“Additional components of the probiotic formulations include hydrophilic agents”, “Hydrophilic agents may be selected from a group comprising … hydroxypropyl methylcellulose (HPMC) (also known as Hypromellose)”, “The addition of the hydrophilic agent will retard the release of the probiotic from the dosage form.”, “level of controlled release from a separate side of the bi-layer dosage form granted through the use of a matrix comprised of a hydrophilic agent and the lyophilized probiotic”; page 6, lines 7-24; page 19, lines 21-22 and 24-26). Gamble further teaches an hydroxypropyl methylcellulose (HPMC) concentration of about 26 % in one side of a bilayer tablet (“One side of a bi-layer dosage form as a tablet, approximately 382 mg, containing a hydrophilic agent, an electrolytic agent, and a probiotic pre-blend may be prepared as shown in Table 5.”, see Example 5 on page 20, lines 4-6, and Dosage Formulas in Table 5; it is noted that 100 mg HPMC in a 382 mg preparation corresponds to 26.2%).
While modified Nivoliez does not teach wherein the pharmaceutical composition is in the form of a multilayer tablet comprising: at least one immediate-release layer comprising, in relation to the total weight of all the immediate-release layers, at least 5x1010 CFU of lactobacilli and from 60 mg to 300 mg of thiosulfate; and at least one sustained-release layer, comprising, in relation to the total weight of all the sustained-release layers, from 1x107 CFU to 1x1010 CFU of lactobacilli (instant claim 26), and wherein in the multilayer tablet, the sustained-release layer comprises from 10% to 40% by weight of hydroxypropylmethylcellulose in relation to the total weight of said layer (instant claim 27), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined Nivoliez’s modified method with Gamble’s teachings on multilayer tablets comprising probiotics and hydroxypropylmethylcellulose, to have created a method for treating candidiasis wherein the pharmaceutical composition is in the form of a multilayer tablet comprising: at least one immediate-release layer comprising lactobacilli and thiosulfate; and at least one sustained-release layer, comprising, lactobacilli and thiosulfate, and wherein in the multilayer tablet, the sustained-release layer comprises about 26% by weight of hydroxypropylmethylcellulose in relation to the total weight of said layer. One would have been motivated to do so, in order to create a superior treatment method of candidiasis that combines immediate and prolonged treatment for successful reduction and elimination of pathogenic Candida. A skilled artisan would have reasonably expected success in combining Nivoliez’s and Gamble’s teachings since both references are directed to pharmaceutical compositions comprising lactobacilli (see above).
While modified Nivoliez does not teach the immediate-release layer comprising, in relation to the total weight of all the immediate-release layers, at least 5x1010 CFU of lactobacilli and from 60 mg to 300 mg of thiosulfate; and the sustained-release layer, comprising, in relation to the total weight of all the sustained-release layers, from 1x107 CFU to 1x1010 CFU of lactobacilli (instant claim 26), the instantly recited ranges would be within the realm of routine experimentation since Nivoliez teaches a pharmaceutical composition comprising 3.5x107 to 3.5x109 CFU of lactobacilli and about 80.5 mg of thiosulfate (see above). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined the optimal amounts of CFU of lactobacilli and thiosulfate in the immediate-release and sustained-release layer of a multilayer tablet, in order to identify how much is needed for successful immediate and prolonged treatment of candidiasis. Further, one would have expected success since Nivoliez’s teachings are directed to multiple Lactobacillus strains (see above), and therefore, manipulation of the CFU of lactobacilli and of the thiosulfate concentration based on the teachings of the reference would be within the purview of an artisan. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[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 (CCPA1955). See MPEP § 2144.05 part II A.
Response to Arguments
Applicant has traversed the previous rejections of claims 15 and 17-27 under 35 U.S.C. §103 (remarks, pages 4-8). Applicant arguments filed on 12/30/2025 have been fully considered but they are not persuasive.
In Applicant’s response, Applicant states that “[t]here is no teaching or guidance in the cited documents that would have incited or suggested to the person skilled in the art to achieve the presently claimed subject matter, which is to use a pharmaceutical composition comprising at least 5x1010 CFU of lactobacilli with at least 60 mg of thiosulfate as a first-line treatment of candidiasis as a substitute for a chemical antifungal, for inhibiting within 12 to 20 hours a pathogen selected from the group consisting of: Candida albicans, Candida glabrata and Candida tropicalis, with an inhibition of at least approximately 2log10” (remarks, page 7, paragraph 4).
The Examiner responds 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). In this case, regarding claim 15, Nivoliez teaches a method for treatment of candidiasis in a patient comprising vaginally administering to said patient a pharmaceutical composition comprising lactobacilli and thiosulfate. Nivoliez teaches a thiosulfate amount of 80.5 mg (page 6, lines 3-5; page 7, lines 26-27) which is within the claimed range of thiosulfate amounts (“at least 60 mg”, instant claim 15). The instantly claimed range of at least 5x1010 CFU of lactobacilli would be within the realm of routine experimentation, in order to determine the optimal amount of bacteria for maximum pathogen inhibition. As discussed above, manipulation of the lactobacillus amount would be within the purview of an artisan, since Nivoliez teaches an amount of 3.5x107 to 3.5x109 CFU of lactobacilli (page 6, lines 3-5; page 7, lines 26-27), and further discloses the use of different Lactobacillus strains (page 4, lines 23-27; page 6, lines 13-14), which would require adjusting the amount of CFU for a given strain in a pharmaceutical composition. It is further noted that since Nivoliez teaches thiosulfate potentiating the anti-pathogenic effect of a Lactobacillus concentration of 107 to 1010 CFU/g (page 3, lines 17-22), and that no anti-pathogenic effect is observed in the presence of thiosulfate alone (page 16, lines 30-31 - page 17, lines 1-2), Nivoliez teaches that the Lactobacillus amount is a result effective variable.
The Examiner explains that, as discussed above, the technical effect of "inhibiting within 12 to 20 hours a pathogen selected from the group consisting of: Candida albicans, Candida glabrata and Candida tropicalis” naturally results from performing the recited method steps in the claim, and therefore, the inhibiting effect is considered inherent to the claimed method. As such, modified Nivoliez’s teachings would implicitly result in the same or similar pathogen inhibition. It is further noted that since Nivoliez teaches complete removal of a starting concentration of about 106 CFU/mL of C. albicans in the presence of a Lactobacillus strain and thiosulfate within 24 hours (see Example 7A on page 17, lines 4-12; see Fig. 6), and further discloses the synergistic effect of Lactobacillus combined with thiosulfate (see page 17, lines 16-17), the recited technical effect would not be considered unexpected.
Applicant states that “[the skilled person] would not have expected a synergistic inhibition of the pathogen of at least 3log10 in less than 20 hours such as set forth in the present technology” (remarks, page 7, paragraph 5).
The Examiner responds that the feature upon which applicant relies (i.e. inhibition of the pathogen of at least 3log10 in less than 20 hours) is not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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/SANDRA ZINGARELLI/Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
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