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 .
DETAILED ACTION
Applicant’s amendment filed on 25 March 2026 is entered. Claim 18 is amended. Claims 18-19, 21-31, 36-37, and 39-40 are pending and under examination.
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.
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.
(Maintained) Claims 18, 21-28, 31, 36-37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (WO 2018169296 A1, 20 September 2018) in view of de la Zerda et al. (EP 2734557 B1, 28 May 2014) and Gomez-Gullen et al. (Enhancement of oral bioavailability of natural compounds and probiotics by mucoadhesive tailored biopolymer-based nanoparticles: A review, Food Hydrocolloids 118 (available online 23 March 2021) 106772).
Regarding 18, 21-22, 26, 36-37, and 39, Kim teaches mucoadhesive devices for the release of probiotics and for the maintenance of their enzyme activities (Kim title) wherein the mucoadhesive films comprise one or more bacterial strains of lactic bacteria and Bifidobacteria (Kim claim 1; p. 6, [31]), and the mucoadhesive film has the ability to maintain vitality of the bacterial strains during processing and storage such that the mucoadhesive polymer can release the living bacteria in vivo (p. 6, [29]). Kim’s phrase “maintain vitality” implies that the bacterial strains are alive or vital. “Viability” or “viable” is an art recognized term for living bacteria cells of which vitality is maintained. Thus, the terms “vitality” and “viability” are interpreted as equivalents, meaning that the bacteria are alive. The bacteria used are selected from a list including L. reuteri (Kim claim 3) and can be used to treat oral mucositis to increase compliance in patients treated with chemotherapy (Kim claim 10). The composition of the films contains carboxymethylcellulose (p. 8, [43]) and polyalkylene oxides (Kim claims 5-6) and may also be prepared using natural and synthetic gelatins, agarose gel, agarose-xanthan gel, and other mucoadhesive polymers (p. 8, [42]-[44]). The data relating to the tests on healthy volunteers using mucoadhesive gel with the side containing probiotic towards the gum (p. 11, [63]) are shown in Table 4. Kim teaches the gel is mixed and dried into a thin film and between 102 and 1012 CFU/cm2 of lyophilized bacteria is distributed on said film (Kim claims 2 and 13).
Kim does not teach the mucoadhesive composition comprises a stabilizer such as sucrose, nor the administration of the composition to a patient in need thereof in the form of a gel.
Zerda teaches a method for production of thermoreversible hydrogels for therapeutic applications (Zerda title), wherein said components comprise between 18% and 40% (w/w) ethylene oxide/propylene oxide block copolymer, between 0.05% and 2% (w/w) HPMC or CMC (carboxymethylcellulose) (Zerda claim 1) and polyoxamer 407 (Pluronic® F-127) is recognized as a [ethylene oxide/propylene oxide block copolymer] suitable for pharmaceutical use (Zerda page 7, paragraph [0051], lines 1-2). Additionally, Zerda teaches further including a step of adding an effective amount of therapeutic agent (Zerda claim 4) and at least one sugar chosen from the group consisting of sucrose (Zerda claim 10).
Zerda does not teach L. reuteri as the therapeutic agent within the gel.
Gomez teaches the encapsulation of probiotics in food-grade biopolymers with mucoadhesive potential, in order to allow for greater penetration of the mucous layer, as well as promote lower and longer acting dosages (Gomez abstract) by providing controlled and constant delivery of living cells (Gomez Pg. 2 para. 6 sentences 3-4), and encapsulation can promote higher survival rates (Gomez Pg. 13 para. 6 sentence 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to incorporate the viable L. reuteri probiotic of Kim in the mucoadhesive polymer gel taught by Kim and Zerda because it was known in the art that doing so would allow for greater penetration of the composition into the mucous layer, as well as promote lower and longer acting dosages by providing controlled and constant delivery of living cells, and promote higher survival rates of the L. reuteri probiotic. One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Gomez teaches the incorporation of probiotic strains into a mucoadhesive polymer gels. One of ordinary skill in the art would then understand that the resultant gel mucoadhesive composition comprising the L. reuteri probiotic would then be suitable for use in a method of treating oral mucositis because the active ingredient of L. reuteri taught by Kim would be more effectively administered into the subject in need thereof.
Regarding claims 23-24 and 31, Kim teaches the use of between 102 and 1012 CFU/cm2 administered on the films, but fails to teach the concentrations of the polyoxy-alkylene copolymer or the mucoadhesive polymer in the gel. Zerda teaches the same polyoxy-alkylene copolymer described in the specification, Pluronic® F127, can be between 18 and 40% (w/w), the carboxymethylcellulose can be between 0.05% and 2% (w/w) when creating the therapeutic gel.
Kim, Zerda, and Gomez do not disclose the concentration of sucrose in the obvious composition above.
MPEP §2144.05(II)(A) states “[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. "[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)”.
The selection of specific concentrations of the sucrose stabilizer would have been a matter of routine optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the efficacy of the treatment would have been affected by these concentrations.
Regarding claim 25, Zerda teaches the use of a central hydrophobic chain of polyoxypropylene flanked by two hydrophobic chains of polyoxyethylene (Zerda page 7, lines 2-3) with the following formula:
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189
1051
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wherein “(a) and (b) are equal to 95-105 and 54-60, respectively” (Zerda page 7, paragraph [0051]). One of ordinary skill in the art would recognize Zerda was describing a compound with a chemical formula that has close chemical structural similarity to the compound recited in instant claim 25. The main difference between the formula of the compound taught by Zerda as compared to the compound recited in instant claim 25 is that prior art Zerda teaches that b=54-60, which does not overlap with the y=67 as recited in instant claim 25. However, MPEP 2144.09(I) states “a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979)”. Due to the close similarity in structure between the compound taught by Zerda and the compound recited in instant claim 25, a prima facie case of obviousness exists because the compounds would be recognized by a person of ordinary skill in the art to have similar properties and utilities.
Regarding claim 27, Kim teaches chemotherapy and radiotherapy can quite frequently give rise to oral mucositis, which comprises the rapid death of cells in the most superficial layers of the buccal mucosa, with the appearance of very painful inflammation and ulceration that becomes an easy target for bacterial and viral infections (Kim page 1, paragraph [4]).
One of ordinary skill in the art would have been motivated to use the method taught by Kim, Zerda, and Gomez to treat radio-induced oral mucositis with a reasonable expectation of success because both radio- and chemotherapy induce oral mucositis with similar display of symptoms, and the method of Kim, Zerda, and Gomez would have been effective to treat those same symptoms.
Regarding claim 28, Although Kim does not explicitly teach the use of PBS, Kim does teach “studies were carried out in aqueous buffer (33.87 mM KH2PO4, 46.79 mM Na2HPO4 12H2O)” (Kim page 16, paragraph 95). Zerda does not specifically teach the liquid component is PBS (consisting of NaCl, KCI, Na2HPO4, and KH2PO4), however, claim 7 recites phosphate salts as a pH-modifying substance and claim 10 lists sodium chloride and potassium chloride as salts in the water-soluble substance of the composition. So in combination, Kim teaches potassium and sodium phosphate salts as a buffer, and Zerda teaches buffered saline (i.e., sodium chloride and potassium chloride); this combination constitutes, or at least clearly suggests, PBS.
It would have been obvious to one of ordinary skill to account for osmotic stressors and to use an isotonic, phosphate-based solution as taught by Kim and Zerda such as PBS to ensure the patients in need thereof would be treated for oral mucositis with living L. reuteri.
(Maintained) Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Kim, Zerda, and Gomez as applied to claims 18, 21-28, 31, 36-37, and 39 above, and further in view of Gupta et al. (Scientific Reports 2020; 10:16189. pp. 1-11) and Shin et al. (Molec and Cell Bio 2007; 27(20): 7188-7197).
Kim, Zerda, and Gomez differ from claim 19 insofar as they do not teach the monitoring of a response following the treatment with the therapeutic gels.
Gupta teaches of a 5-FU treated chemotherapy-induced oral mucositis mouse model wherein the expression of nuclear factor E2-related factor-2 (Nrf-2), a key transcription factor regulating the expression of cytoprotective genes important in mitigating oxidative stress, was significantly higher in the L. reuteri-treated group of mice leading to the conclusion that Lactobacillus reuteri mediates cytoprotection via Nrf-2 in chemo-induced oral mucositis (Gupta page 2, Results, paragraph 3).
Shin teaches NRF2 regulates expression of Ahr and subsequently modulates several downstream events of the AHR signaling cascade, including (i) transcriptional control of the xenobiotic metabolism genes Cyp1a1 and Cyp1b1 (Shin abstract). Shin teaches that in mice fibroblasts, chemical activation of NRF2 signaling leads to significant increases in Ahr and Cyp1a1 expression, but minimal changes in the Nrf2-knockdown fibroblasts (Shin page 7190, Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to analyze the immune response in patients treated with the obvious method of Kim, Zerda, and Gomez because reactive oxygen species are responsible for much of the symptoms and pathologies of oral mucositis, and treatment with L. reuteri mitigates the oxidative stress through upregulation of Nrf-2. As NrF-2 and indole-3-aldehyde (3-IALD or I3A) both activate the same receptor, Ahr, one of ordinary skill in the art would have had a reasonable expectations of success that analysis of the components involved in 3-IALD signaling, particularly downstream of AhR would be an effective measure of the efficacy of L. reuteri-mediated treatment of oral mucositis.
(Maintained) Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Kim, Zerda, and Gomez as applied to claims 18, 21-28, 31, 36-37, and 39 above, and further in view of Desrosiers (US 20200138878 A1, 07 May 2020).
Kim, Zerda, and Gomez do not teach lyophilization of the composition.
Desrosiers teaches the lyophilization of a composition comprising Lactobacillus reuteri and mucoadhesive polymers (Desrosiers [0052], [0065], and [0066]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to lyophilize the composition of Kim, Zerda, and Gomez to maintain the stability, longevity, and viability of the L. reuteri in the composition. One of ordinary skill in the art would have had a reasonable expectation of success because lyophilization processes of a L. reuteri and mucoadhesive containing composition were already known in the art according to Desrosiers.
(Maintained) Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Kim, Zerda, and Gomez as applied to claims 18, 21-28, 31, 36-37, and 39 above, and further in view of Zelante et al. (Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22, Immunity, 2013 Aug 22, 39(2):372-85. doi: 10.1016/j.immuni.2013.08.003).
Kim, Zerda, and Gomez do not teach the stabilizer to be tryptophan.
Zelante teaches that tryptophan metabolites from microbiota can balance mucosal reactivity, and that switching from sugar to tryptophan as an energy source can adapt Lactobacillus spp. to produce an aryl hydrocarbon receptor (AhR) ligand that contributes to Il-22 transcription, which results in a balanced mucosal response that allows for survival of microbial communities in a mucosal environment (Zelante Abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to use tryptophan in the composition of Kim, Zerda, and Gomez in order to promote the survival of the L. reuteri probiotic component in a mucosal environment. One of ordinary skill in the art would have had a reasonable expectation of success because Zelante teaches that using tryptophan as an energy source adapts Lactobacillus spp. to produce an aryl hydrocarbon receptor (AhR) ligand that contributes to Il-22 transcription, which results in the advantageous effect of balancing mucosal reactivity and promotion of the survival of microbial communities.
(Maintained) Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Kim, Zerda, and Gomez as applied to claims 18, 21-28, 31, 36-37, and 39 above, and further as evidenced by Fiorillo et al. (Gels in Medicine and Surgery: Current Trends and Future Perspectives, Gels 2020, 6, 48; published 03 December 2020).
The gel taught by the combination of Kim, Zerda, and Gomez above is a two-phase elastic colloidal material consisting of dispersed liquid that is incorporated into a solid phase, as evidenced by Fiorillo (Fiorillo first sentence). Accordingly, the gel taught by the combination of Kim, Zerda, and Gomez meets the limitations of claim 40 because the obvious gel is inherently a two-phase elastic colloidal material consisting of dispersed liquid that is incorporated into a solid phase according to Fiorillo.
Zerda teaches the same polyoxy-alkylene copolymer as exemplified in the instant specification, Pluronic® F127, can be between 18 and 40% (w/w), the carboxymethylcellulose can be between 0.05% and 2% (w/w) when creating the therapeutic gel.
Kim, Zerda, and Gomez do not disclose the concentration of sucrose in the obvious composition.
MPEP §2144.05(II)(A) states “[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. "[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)”.
The selection of specific concentrations of the sucrose stabilizer would have been a matter of routine optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the efficacy of the treatment would have been affected by these concentrations.
Response to Arguments
Applicant's arguments filed 25 March 2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that Kim expects difficulties in survival of cells in a gel, Zerda only discloses chemical compounds, and Gomez teaches encapsulation in a nanofiber not a gel so one of ordinary skill in the art would encapsule their bacteria in a nanofiber, not a gel (Remarks pgs. 7-9), Kim does teach that other studies showed difficulty in keeping bacteria alive in/on oral thin films (OTF), but does not disclose that the bacteria would not survive in hydrogels. As acknowledged in the rejection, Kim does not teach administration of a gel form. This deficiency is cured by Zerda, which teaches pharmaceutical use of hydrogels comprising much of the same components of Kim's film, and Gomez teaches encapsulation of bacterial cells in mucoadhesive biopolymers is advantageous. Although Gomez teaches their specific encapsulation is with mucoadhesive polymer nanoparticles, the nanoparticle structure taught by Gomez is not being used in the rejection, and furthermore the claimed composition does not exclude nanoparticles. Gomez teaches that encapsulation in mucoadhesive biopolymers is advantageous, and thus provides a motivation for one of ordinary skill in the art to encapsulate probiotic bacteria in mucoadhesive biopolymers, just like the one taught by Kim in view of Zerda, because doing so would allow for greater penetration of the bacteria into the mucous layer and promotes lower and longer acting doses by providing controlled and constant delivery of living cells.
Although Zerda alone may only refer to classical chemical active ingredients and not to living organisms, the rejection also includes the teachings of Kim. Kim and Zerda teach a film and a hydrogel, respectively, that comprise many of the same components, particularly carboxymethylcellulose and polyalkylene oxides such as polyoxy-ethylene-propylene copolymer (Pluronic® F-127). Since Kim teaches that probiotic L. reuteri can be viable in/on films comprising carboxymethylcellulose and polyalkylene oxides, one of skill in the art would reasonably expect that same L. reuteri to survive in a hydrogel with those same components, such as the one taught by Zerda. Therefore, the combination of Kim and Zerda teach that living organisms can be delivered using a hydrogel comprising a mucoadhesive polymer such as carboxymethylcellulose and a polyoxy-alkylene copolymer.
Gomez was incorporated into the rejection because it taught that there is a motivation to encapsulating probiotic bacteria into mucoadhesive biopolymers, such as the one taught collectively by Kim and Zerda. Although Gomez does refer to nanofibers instead of hydrogels, Gomez does teach that encapsulation of probiotics into food-grade biopolymers of mucoadhesive potential allows for greater penetration of the mucous layer and promote lower and longer acting dosages by providing controlled and constant delivery of living cells. When taken together with Kim and Zerda, both of whom teach mucoadhesive biopolymers namely those comprising the mucoadhesive polymer carboxymethylcellulose, one of ordinary skill in the art would have recognized the advantages of incorporating the L. reuteri probiotic of Kim into the mucoadhesive gel taught by the combination of Kim and Zerda, namely because mucoadhesive biopolymers (such as those containing carboxymethylcellulose like Kim and Zerda) would provide the benefits of allowing for greater penetration of the mucous layer and promoting lower and longer acting dosages by providing controlled and constant delivery of living cells, as taught by Gomez.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander M Duryee whose telephone number is (571)272-9377. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/Alexander M Duryee/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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