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
Claims 1-2, 4, 9, 14-15, 21, 31-33, 35-36, 42, 51, 58 and 61-64 are pending in the current application.
Claims 1-2, 4, 9, 14-15, 21 and 31-33 are withdrawn for being directed to non-elected inventions and species.
Claims 35-36, 42, 51, 58 and 61-64 are under examination.
The rejection of claim 36 under 35 U.S.C. 112(d) is withdrawn in light of the claim amendment 8/22/2025 further limiting the coating to a complete biofilm coating on the microsphere.
Priority
This application is a 371 of PCT/US2019/044998 filed on August 2, 2019 which claims domestic benefit of 62/714,589 filed on August 2, 2018.
Claim Objections
Claim 64 is objected to because of the following informalities: missing an article “a” in front of “microsphere” in the limitation “comprising: microsphere comprising cross-linked dextran” in line 4. Appropriate correction is required.
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.
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.
Modified rejection necessitated by amendment: Claims 35-36, 42, 51, 58 and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Goodman et al. (WO 2015/134808 A2, published September 11, 2015; previously cited) in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited). The rejection of claim 58 is further evidenced by Navarro et al. (“Enhanced Probiotic Potential of Lactobacillus reuteri When Delivered as a Biofilm on Dextranomer Microspheres that contain Beneficial Cargo”, Frontiers in Microbiology, 2017, Vol. 8, Article 489, 15 pages; previously cited).
Regarding claim 35, the limitation “wherein the prebiotic comprises a nutritional supplementation for the probiotic bacterium” is being interpreted as requiring the prebiotic (structure) to confer nutritional supplementation (function). Based on the instant specification paragraph [0074], a prebiotic is intended as a nutritional supplement for the probiotic bacterium. Thus, this limitation is being interpreted to mean that any prebiotic is capable of serving the function of comprising a nutritional supplementation for the probiotic bacterium.
Regarding claims 35 and 64, Goodman teaches a method for treating or preventing a disease suitable [to be] treated by a biofilm in a subject, such as necrotizing enterocolitis NEC (description p.7, [0026]). Goodman teaches administering to a subject in need thereof, an effective amount of a composition as described (description p.7, [0026]). Goodman teaches a composition comprising a biocompatible microsphere, a biofilm-generating probiotic bacterium, a prebiotic, and/or a prebiofilmic (abstract). Goodman teaches the microsphere can be a biodegradable polymer selected from acetalated dextran and Sephadex® copolymers (made from dextran cross-linked with epicholorhydine, commercially available from Sigma-Aldrich) (description p.22, [0103]). Goodman teaches the biofilm-generating probiotic bacterium may comprise Lactobacillus reuteri “L. reuteri”) (description p.25, [0110]). Goodman teaches the prebiotic substances help stimulate the exclusive growth of the probiotic species and provide the bacteria in the form of a biofilm on a biocompatible microsphere (description p. 4, [0016]). Goodman teaches the prebiotic can comprise a water-soluble carbohydrate selected from maltose, sucrose, and combinations thereof (relevant to claim 64) (description p.24, [0104]).
Goodman teaches an “effective amount” refers to a quantity sufficient to achieve a beneficial or desired result or effect (description p.19, [0090]). Goodman teaches the composition of the method is administered to provide from about 1 x 107 to about 1 x 109 CFU/ml of the biofilm-generating probiotic bacterium (description p.29, [0124]). Goodman further teaches the skilled artisan will be able to determine the effective amount based on the size and nature of the application in question (description p.19, [0091]).
Goodman is silent on administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system for the prevention of necrotizing enterocolitis (title). Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri were grown on MRS-loaded Sephadex microspheres (p.937, 2nd column – 1.3. Histologic evaluation of experimental NEC injury). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a pregnant female carrying a fetus taught by Buddington as the subject in need thereof in the method of Goodman. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the microsphere system of Goodman to comprise the L. reuteri bacterium as a biofilm coating the microsphere surface taught by Olson, because Olson teaches L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC. One of ordinary skill in the art would have found it beneficial to administer L. reuteri as a biofilm coating on the microsphere because Olson teaches a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity.
Regarding claim 36, Goodman teaches the biofilm-generating probiotic bacterium adheres to the surface of the biocompatible microsphere and generates a biofilm (description p.5, [0021]).
Goodman is silent as to whether the biofilm is a complete biofilm coating on an external surface of the microsphere.
However, Olson teaches that allowing L. reuteri to form a biofilm on the surface of biocompatible microspheres increases its ability to survive in acidic environments such as the stomach and adhere to intestinal tissue (p.937, 1st column 1st full paragraph). Olson further teaches that bacteria within the biofilm state are more resistant to harsh conditions, antimicrobial agents and host immune defenses, and resemble the natural gut reservoir (p.937, 1st column 1st full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to allow a complete biofilm coating taught by Olson to form on the external surface of the microsphere of Goodman, because Olson teaches that allowing the L. reuteri to form a biofilm on the microsphere surface increases its ability to survive in acidic environments such as the stomach. One of ordinary skill in the art would have found it beneficial to improve the microsphere’s ability to resist harsh conditions and resemble the natural gut reservoir.
Regarding claim 42, Goodman teaches a composition comprising one or more biofilm-generating probiotic bacterium comprising at least Lactobacillus reuteri (“L. reuteri”) (description p.6, [0025]).
Regarding claim 51, Goodman teaches the microsphere can also carry an agent which is selective against the growth or proliferation of a pathogen (description 21, [0099]; claim 15).
Regarding claim 58, Goodman teaches using L reuteri strain ATCC23272 (description p.36, [0146]). Goodman is silent on whether the probiotic L. reuteri produces glucosyltransferase (GTF).
The current specification discusses the use of L. reuteri (ATCC23272), also known as DSM 20016 (specification p.93, [0319]). The current specification identifies L. reuteri strain DSM20016 as containing extracellular glucosyltransferase protein GTFW encoded by gtfW (specification p.70, [0267]).
However, as evidenced by Navarro, the L. reuteri strain ATCC 23272 taught by Goodman corresponds to L. reuteri strain DSM20016 (p.12, 2nd column 1st paragraph), which is identical to the strain identified as producing glucosyltransferase as discussed in the current specification. Thus, as evidenced by Navarro, the L. reuteri strain ATCC23272 taught by Goodman would necessarily produce glucosyltransferase.
Regarding claim 61, Goodman teaches that a novel probiotic formulation can also contain a prebiofilmic, which is a substance that supports biofilm formation and/or durability (description p.6, [0021]). Goodman further teaches admixing a biocompatible microsphere with a biofilm-generating probiotic bacterium, a prebiotic, and further admixing a prebiofilmic (description p.6, [0024]).
Regarding claim 62, Goodman teaches probiotics are any type of micro-organisms that have health benefits, including L. acidophilus, L. crispatus, L. gasseri, L. delbrueckii, L. salivarius, L. casei, L. paracasei, L. plantarum, L. rhamnosus, L. reuteri, L. brevis, L. buchneri, L. fermentum, L. rhamnosus, B. adolescentis, B. angulation, B. bifidum, B. breve, B. catenulatum, B. infantis, B. lactis, B. longum, B. pseudocatenulatum, and S. thermophiles) (description p.22, [0101]).
Regarding claim 63, Goodman teaches the biocompatible microsphere can be one or more of Sephadex® copolymers (made from dextran cross-linked with epicholorhydine, commercially available from Sigma-Aldrich) (description p.22, [0103]).
Response to Arguments
Applicant has provided statements that the result of administering biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere resulted in significantly improved conferred resistance to necrotizing enterocolitis (NEC) that is transferred from the pregnant female to its offspring, which is both surprising and unexpected (Declaration dated 8/22/2025, item 4). Applicant identifies the experimental conditions and results of an in vivo experimental mouse model of NEC to evaluate the potential effects of maternal-to-infant transfer of immunity to NEC (Declaration dated 8/22/2025, items 6-7). Applicant states that their results demonstrate surprisingly and unexpectedly that dextran microspheres coated with L. reuteri dramatically increase resistance to NEC, which is surprising because to the inventor’s knowledge, this is the first study to show probiotic administration to a pregnant female can confer disease resistance to her offspring; and the dramatic improvement of biofilmic L. reuteri adhered to microspheres over planktonic administration was surprising given that dextran microspheres are quickly passed through the gastrointestinal tract of the subjects following administration, with Exhibit A – Schmitt et al. reference submitted as support (Declaration dated 8/22/2025, items 8-10). Applicant further submits Exhibit B, which contains data in coordination with the inventors and scientists at Scioto Biosciences, to provide additional support that there is rapid excretion of dextranomer microspheres following administration to rats (Declaration dated 8/22/2025, item 11). Applicant further argues that based on data provided in Exhibits A and B, the skilled artisan would have no reason to expect that adhering L. reuteri to a microsphere would increase therapeutic efficacy; no prior art suggested that administering probiotics to pregnant females could result in transfer of bacteria to the fetal gastrointestinal tract nor that such transfer could confer disease resistance including resistance to NEC; and therefore applicant’s discovery is both surprising and unexpected in view of the cited references (Declaration dated 8/22/2025, items 12-14).
Declaration under 37 C.F.R. 1.132
A Declaration is due full consideration and weight for all that it discloses. Declarations are reviewed for the following considerations:
1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996));
2) whether the Declaration presents a comparison to the closest art;
3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990));
4) whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance (Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)); and
5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339 (Fed. Cir. 2007)).
The Declaration under 37 CFR 1.132 filed on August 22, 2025 is insufficient to overcome the rejection of claims 35-36, 42, 51, 58 and 61-63 under 35 U.S.C. 103 because: while applicant presents information identifying the unexpected discovery that dextran microspheres coated with L. reuteri dramatically increase resistance to NEC, this is an outcome that results from the active method step of administering to a pregnant female an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic. The active method step and the composition are taught in the prior art, as discussed in the rejection above. Goodman teaches a composition comprising a biocompatible microsphere, a biofilm-generating probiotic bacterium, a prebiotic, and/or a prebiofilmic. Goodman teaches the microsphere can be a biodegradable polymer selected from acetalated dextran and Sephadex® copolymers. Buddington teaches maternal-to-infant transmission of probiotics, and that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis. Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC. Therefore, one of ordinary skill in the art would reasonably expect that performing the same active method step taught in the prior art of administering to a pregnant female the same composition taught in the prior art of a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely covering a surface of the microsphere and a prebiotic would predictably result in conferring necrotizing enterocolitis resistance or immunity to a fetus.
Applicant summarizes the 103 rejection and argues that the cited references fail to provide any reasonable likelihood of successfully conferring NEC resistance to a fetus when administered to a pregnant female (See Remarks dated 8/22/2025, p.8 last paragraph). Applicant argues that the administration of the claimed composition to pregnant females transfers immunity to or prevents the development of NEC to offspring as supported by the specification [0324] and [0328] (See Remarks dated 8/22/2025, p.9, 1st paragraph). Applicant argues that administration of microspheres coated with a biofilm-generating L. reuteri bacterium to pregnant females surprisingly and unexpectedly results in significantly improved conferred resistance to necrotizing enterocolitis that is transferred from the pregnant female to its offspring (See Remarks dated 8/22/2025, p.9 – 1st paragraph).
Applicant argues that the dramatic increase in efficacy between planktonic bacteria administration and biofilmic L. reuteri adhered to a surface of a microsphere was further surprising considering the microspheres are completely cleared from the GI track following treatment discontinuation and the administration did not result in the presence of a bacteria in the blook, and refers to applicant-supplied reference “Schmitt” and Exhibit B of Goodman Declaration (See Remarks dated 8/22/2025 p.9 2nd paragraph).
Applicant argues that in contrast, Buddington discloses that probiotic bacteria administered to pregnant females prior to giving birth were detected in the feces and vaginal swabs of the mothers, but such findings do not provide evidence that administering bacteria to pregnant females results in acquired immunity or health benefits for the offspring; and therefore there is no basis in Buddington for the proposition that maternal administration of probiotics as performed in that study confers immunity to offspring (See Remarks dated 8/22/2025, p.9 last paragraph – p.10 top paragraph). Applicant argues that moreover there is no teaching or suggestion in Buddington that the composition of Goodman would significantly improve NEC resistance in offspring over non-biofilmic bacteria administration when administered to a pregnant female (See Remarks dated 8/22/2025, p.10, 2nd paragraph). Applicant argues that Buddington offers no evidence or suggestion that [probiotic administration to a pregnant female] is capable of conferring any measurable or meaningful resistance to disease, let alone robust NEC resistance achieved by the present invention, and neither Goodman nor Olson cures these deficiencies (See Remarks dated 8/22/2025, p.10 last paragraph).
Applicant argues that applicant has demonstrated that administration of a composition comprising a microsphere including a biofilm-generating L. reuteri partially or completely coating a surface of the microsphere to a pregnant female surprisingly results in significantly improved conferred NEC resistance and survival in offspring, and even if Goodman teaches the administration of the claimed composition, the skilled artisan would not expect the surprisingly improved properties when administered to the claimed patient population (See Remarks dated 8/22/2025, p.11 3rd paragraph).
Applicant argues that the Goodman Declaration provides additional evidence that the claimed method demonstrates surprising results in view of the prior art, and the administration of L. reuteri as disclosed by Buddington without adherence to a microsphere does not exhibit the same degree of surprising efficacy as the claimed probiotic compositions (See Remarks dated 8/22/2025, p.12 top paragraph). Applicant points to Exhibit A of the Goodman Declaration demonstrating that microspheres are completely cleared from the gastrointestinal tract following treatment discontinuation; the exposure to the microspheres is limited to the gastrointestinal lumen following administration to the subject, and the rapid excretion of microspheres is further validated by Exhibit B of the Goodman Declaration demonstrating that dextranomer microspheres are rapidly excreted from the gastrointestinal tract within 2-3 days; suggesting that maternal-to-infant probiotic transfer would not be expected (See Remarks dated 8/22/2025, p.12 middle paragraph).
Applicant's arguments filed August 22, 2025 have been fully considered but they are not persuasive. Goodman teaches a method for treating or preventing a disease such as NEC; teaching administration to a subject in need thereof, a composition comprising a biocompatible microsphere, a biofilm-generating probiotic bacterium coating the surface of the microsphere, a prebiotic, and/or a prebiofilmic (abstract). Buddington teaches the instantly required subject of a pregnant female, which one of ordinary skill in the art would recognize as a specific “subject in need thereof” in the method of Goodman. Olson teaches the delivery of L. reuteri as a biofilm coating on a microsphere, and teaches that this formulation significantly reduced NEC incidence and severity. The recitation of “conferring necrotizing enterocolitis (NEC) resistance or immunity to a fetus” is the intended outcome or desired outcome of the method. However, the single required active method step of the instant claims does not differ from the active method step recited in the prior art, and thus does not distinguish over the prior art. Therefore the instant claims are obvious over prior art for the reasons discussed in the rejection above.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., planktonic bacteria administration; microsphere clearance from the gastrointestinal tract) are not recited in the rejected claims. 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). The instant claims require that the L. reuteri bacteria is a partial or complete coating a surface of the microsphere, which is taught in the prior art by Goodman and Olson. The instant claims do not recite any requirement of clearance of the microspheres from the gastrointestinal tract.
Regarding Applicant’s arguments that Buddington does not teach conferring immunity to offspring or would improve NEC resistance in offspring over non-biofilmic bacteria administration, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The use of non-biofilmic bacteria is not a feature of the claimed invention. Buddington is relied upon for teaching maternal-to-infant transmission of probiotics; that probiotics enhance disease resistance in infants, and of particular benefit to infants with or at risk of necrotizing enterocolitis; and that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence assemblages of GIT bacteria.
Olson teaches a novel probiotic delivery system for the prevention of necrotizing enterocolitis in which probiotics are grown as a biofilm on microspheres. Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC, and that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity.
The Goodman Declaration is discussed above. The instant claims require a single active method step of administering to a pregnant female a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri partially or completely coating a surface of the microsphere, and a prebiotic. This active method step, the subject of a pregnant female, and a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri coating and a prebiotic are taught in the prior art, and do not distinguish from the instantly claimed invention, as discussed in the rejection above. The desired effect of conferring NEC resistance or immunity to a fetus is a result/outcome of the administration of the composition to a pregnant female subject, and is therefore not an unexpected result.
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).
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.
Modified rejection to include new claim 64: Claims 35-36, 42, 51, and 61-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 25 of U.S. Patent No. 10,624,934 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Patented claim 1 is directed towards a microsphere composition comprising: a plurality of microspheres each comprising cross-linked dextran, and a prebiotic water-soluble carbohydrate selected from the group consisting of maltose, sucrose and combinations thereof; L. reuteri; and a pharmaceutically acceptable carrier.
Patented claim 25 is directed towards the microsphere composition of claim 1, wherein the L. reuteri is adhered to the microspheres.
Patented claim 12 is directed towards a method of one or more of preventing necrotizing enterocolitis (NEC), each suitably treated by the formation or enhancement of a biofilm in a subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 1, and optionally wherein the surface of the microsphere is porous and/or semi-permeable and the prebiotic is released by diffusion or the microsphere slowly degrades causing leaks and diffusion from the microsphere.
Patented claim 12 does not recite administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 12 to select a pregnant female carrying a fetus taught by Buddington as the subject in need thereof. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 12 to administer microspheres having Lactobacillus grown as biofilms on microspheres as taught by Olson. One of ordinary skill in the art would have been motivated to select microspheres coated with L. reuteri biofilm because Olson teaches that this novel method allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium and thereby providing longer-acting benefits to the developing gut. One of ordinary skill in the art would have found it beneficial to administer the probiotic in a formulation that preserved its efficacy and significantly reduced NEC incidence and severity with a single dose.
Patented claim 13 is directed towards a method of administering a probiotic to a subject comprising administering a dose of a composition of claim 1 to the subject, thereby administering the probiotic.
Patented claim 1 is directed towards a microsphere composition comprising: a plurality of microspheres each comprising cross-linked dextran, and a prebiotic water-soluble carbohydrate selected from the group consisting of maltose, sucrose and combinations thereof; L. reuteri; and a pharmaceutically acceptable carrier.
Patented claim 25 is directed towards the microsphere composition of claim 1, wherein the L. reuteri is adhered to the microspheres.
Patented claim 13 does not recite administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claims 1 and 13 to select a pregnant female carrying a fetus taught by Buddington as the subject in need thereof. The reasons for doing so are the same as discussed regarding Patented claim 12 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 modified the method of patented claims 1 and 13 to select the microsphere composition of claim 25 where L. reuteri partially coat the microsphere surface. The reasons for doing so are the same as discussed regarding Patented claim 12 above.
Patented claims 2-10 recite methods of preparing the microsphere composition of patented claim 1, which render obvious the limitations recited in instant claims 36, 42, 51, 58 and 61-62. Patented claims 14-16 recite administration conditions that render obvious the limitation “an effective amount” recited in instant claim 35.
Modified rejection to include new claim 64: Claims 35-36, 42, 51, and 61-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 20-26 of U.S. Patent No. 10,369,176 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Patented claim 1 is directed towards a composition comprising a biocompatible microsphere, a prebiotic, and a biofilm-generating probiotic bacterium that releases a DNABII protein, wherein the prebiotic comprises an effective amount of a nutritional supplementation for the probiotic bacterium to support the formation of a biofilm, and wherein the prebiotic comprises an effective amount of a nutritional supplementation for the probiotic bacterium to support the formation of a biofilm, and wherein the prebiotic diffuses from within the microsphere.
Patented claim 15 is directed towards the composition of claim 14, wherein the biodegradable polymer is one or more of Sephadex, Sephadex G-25, which is cross-linked dextran (relevant to claims 35 and 63).
Patented claim 20 is directed towards a method for treating a disease suitably treated by a biofilm in a subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 1 or 2.
Patented claim 20 does not recite administering to a pregnant female carrying a fetus, or a biofilm-generating L. reuteri partially or completely coating a surface of the microsphere.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 1 to select a pregnant female carrying a fetus taught by Buddington as the subject in need thereof. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 12 to administer microspheres having Lactobacillus grown as biofilms on microspheres as taught by Olson. One of ordinary skill in the art would have been motivated to select microspheres coated with L. reuteri biofilm because Olson teaches that this novel method allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium and thereby providing longer-acting benefits to the developing gut. One of ordinary skill in the art would have found it beneficial to administer the probiotic in a formulation that preserved its efficacy and significantly reduced NEC incidence and severity with a single dose.
Patented claims 2-17 are directed towards additional limitations of the composition that render obvious the limitations of claims 36, 42, 51 and 61-63.
Modified rejection to include new claim 64: Claims 35-36, 42, 51, and 61-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, and 11-12 of U.S. Patent No. 11,452,748 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Patented claim 1 is directed towards a microsphere composition comprising:
a plurality of microspheres, each microsphere comprising dextran cross-linked with epichlorohydrin;
a water-soluble carbohydrate that diffuses from within the microsphere selected from the group consisting of maltose, sucrose, and combinations thereof;
L. reuteri strain ATCC 23272, wherein the L. reuteri is adhered to the surface of each microsphere; and
a pharmaceutically acceptable carrier.
Patented claim 11 is directed towards a method of treating necrotizing enterocolitis in an infant in thereof, comprising administering to the infant in need thereof the composition of claim 1 [a composition comprising: about 1×107 and 1×109 CFU/ml of L. reuteri plurality of microspheres each comprising: cross-linked dextran and a water-soluble carbohydrate selected from the group consisting of maltose, sucrose, and combinations thereof].
Patented claim 11 does not recite administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 1 to replace the infant in need thereof with a pregnant female carrying a fetus taught by Buddington. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria, which could prevent the infant from developing NEC. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
Patented claims 4-5 and 12 render obvious the limitation of “an effective amount” in instant claim 35.
Modified rejection to include new claim 64: Claims 35-36, 42, 58 and 62-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 11,497,780 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Patented claim 1 is directed towards a composition comprising:
a microsphere comprising dextran cross-linked with epichlorohydrin;
a prebiotic; and
a strain of Lactobacillus reuteri (“L. reuteri”) that expresses glucosyltransferase (GTF) protein, wherein the prebiotic comprises an effective amount of a nutritional supplementation for the L. reuteri strain to support the formation of a biofilm.
Patented claim 9 is directed towards a method of treating a disease selected from the group consisting of inflammatory bowel disease (IBD), colitis, enteric infectious disease, necrotizing enterocolitis (NEC), infection-induced colitis, traveler's diarrhea, and psychological disorders in a subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 1.
Patented claim 9 does not recite administering to a pregnant female carrying a fetus, or a biofilm-generating L. reuteri partially or completely coating a surface of the microsphere.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 1 to select a pregnant female carrying a fetus taught by Buddington as the subject in need thereof. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 12 to administer microspheres having Lactobacillus grown as biofilms on microspheres as taught by Olson. One of ordinary skill in the art would have been motivated to select microspheres coated with L. reuteri biofilm because Olson teaches that this novel method allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium and thereby providing longer-acting benefits to the developing gut. One of ordinary skill in the art would have found it beneficial to administer the probiotic in a formulation that preserved its efficacy and significantly reduced NEC incidence and severity with a single dose.
Modified rejection necessitated by amendment: Claims 35-36, 42 and 61-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 24 and 26 of previously copending Application No. 16/961,910, now U.S. patent 12,453,747, in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Patented claim 1 is directed towards a method of necrotizing enterocolitis (NEC)-induced neurodevelopmental deficiencies in a subject suffering from or has suffered from necrotizing enterocolitis (NEC), comprising administering to the subject an effective amount of a composition comprising a microsphere comprising a biofilm-generating probiotic L. reuteri bacterium and a prebiotic, wherein the bacterium forms a biofilm partially or completely coating the surface of the microsphere, and wherein the prebiotic comprises a nutritional supplementation for the probiotic L. reuteri bacterium.
Patented claim 1 does not recite a prenatal method of conferring NEC resistance or immunity to a fetus, or administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri were grown on MRS-loaded Sephadex microspheres (p.937, 2nd column – 1.3. Histologic evaluation of experimental NEC injury). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 1 to replace a subject suffering from or has suffered from necrotizing enterocolitis with a pregnant female carrying a fetus taught by Buddington as the subject. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 1 to administer Sephadex microspheres having Lactobacillus grown as biofilms on the microspheres taught by Olson. One of ordinary skill in the art would have been motivated to select dextran microspheres coated with L. reuteri biofilm because Olson teaches that this novel method allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium and thereby providing longer-acting benefits to the developing gut. One of ordinary skill in the art would have found it beneficial to administer the probiotic in a formulation that preserved its efficacy and significantly reduced NEC incidence and severity with a single dose.
Patented claim 11 recites “wherein the composition further comprises one or more of a prebiofilmic that supports biofilm formation and durability, a therapeutic drug or agent, a chemical reductant, a molecule that promotes adsorption, and a molecule that supports absorption”, which renders instant claim 61 obvious.
Patented claim 15 recites “wherein the microsphere comprises dextranomer, the probiotic comprises L. reuteri and the prebiotic comprises maltose, glycerol or histidine”, which renders instant claims 42 and 62-64 obvious.
Patented claim 24 recites the method of claim 1, “wherein the microsphere comprises dextranomer and the prebiotic comprises maltose”, which renders instant claim 64 obvious.
Patented claim 26 recites “the method of claim 24, wherein the microsphere comprises the complete biofilm coating on an external surface of the microsphere”, which renders instant claim 36 obvious.
Modified rejection necessitated by amendment: Claims 35-36, 42 and 61-64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 9, and 14 of copending Application No. 17/287,481 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Sheretz et al. (“The prevalence of Clostridium difficile and toxin in a nursery population: A comparison between patients with necrotizing enterocolitis and an asymptomatic group”, The Journal of Pediatrics, 1982, Vol. 100, Issue 3, pp.435-439; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Instant claim 64 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising a microsphere comprising cross-linked dextran; a biofilm-generating L. reuteri bacterium forming a biofilm coating on a surface of the microsphere, and a water soluble carbohydrate selected from maltose, sucrose and combinations thereof.
Reference claim 1 is directed towards a method for preventing or treating Clostridium difficile infection caused by antibiotic dysbiosis or reversing antibiotic induced dysbiosis in a patient in need thereof, comprising administering to the subject a composition comprising:
a microsphere comprising cross-linked dextran,
a biofilm-generating probiotic bacterium comprising Lactobacillus reuteri forming a biofilm coating on the surface of the microspheres, and
a water soluble carbohydrate selected from the group consisting of maltose, sucrose and combinations thereof.
Reference claim 1 does not recite a prenatal method of conferring NEC resistance or immunity to a fetus, or administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Sheretz teaches the prevalence of Clostridium difficile and toxin in a nursery population of patients with necrotizing enterocolitis and an asymptomatic group (title). Sheretz teaches that during a period when neonates developed necrotizing enterocolitis, some patients had positive stool samples for C. difficile (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reference claim 1 to replace a patient in need thereof suffering from a C. difficile infection with a pregnant female carrying a fetus taught by Buddington, because Sheretz teaches that neonates with NEC were suffering from a C. difficile infection. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to treat the fetus prior to birth, because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis and Sheretz teaches that neonates with NEC were positive for C. difficile.
Reference claim 3 recites a method for restoring the mucosal layer of the intestine in a subject suffering from Clostridium difficile infection caused by antibiotic induced dysbiosis, comprising administering to the subject an effective amount of a composition comprising:
a microsphere comprising a cross-linked dextran,
a biofilm-generating probiotic bacterium comprising Lactobacillus reuteri forming a biofilm coating on the surface of the microsphere, and
a water-soluble carbohydrate selected from the group consisting of maltose, sucrose and combinations thereof,
wherein the administration of the effective amount of the composition results in the restoration of the protective mucosal layer of the intestine.
Reference claim 3 does not recite a prenatal method of conferring NEC resistance or immunity to a fetus, or administering to a pregnant female carrying a fetus.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Sheretz teaches the prevalence of Clostridium difficile and toxin in a nursery population of patients with necrotizing enterocolitis and an asymptomatic group (title). Sheretz teaches that during a period when neonates developed necrotizing enterocolitis, some patients had positive stool samples for C. difficile (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reference claim 1 to replace a patient in need thereof with a pregnant female carrying a fetus taught by Buddington, because Sheretz teaches that neonates with NEC were suffering from a C. difficile infection. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to treat the fetus prior to birth, because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis and Sheretz teaches that neonates with NEC were positive for C. difficile.
Reference claim 6 recites “wherein the microsphere further comprises a complete biofilm coating on the external surface of the microsphere”, which renders obvious instant claim 36.
Reference claim 9 recites “wherein the biocompatible microsphere further comprising one or more of: a prebiofilmic, a therapeutic drug or agent, a chemical reductant, a molecule that promotes adsorption, a molecule that supports absorption”, which renders obvious instant claim 61.
Reference claim 14 recites “wherein the probiotic bacterium further comprises one or more of L. acidophilus, L. crispatus, L. gasseri, group L. delbrueckii, L. salivarius, L. casei, L. paracasei, L. plantarum, L. rhamnosus, L. reuteri , L. brevis, L. buchneri, L. fermentum, L. rhamnosus, B. adolescentis, B. angulation, B. bifidum, B. breve, B. catenulatum, B. infantis, B. lactis, B. longum, B. pseudocatenulatum, S. thermophiles, Pseudomonas fluorescens, P. protegens, P. brassicacearum, P. aeruginosa; Azospirillum. brabrasilense, A. lipferum, A. halopraeferens, A. irakense; Acetobacter diazotrophicus; Herbaspirillum seropedicae; Bacillus subtilis, Pseudomonas stutzeri, fluorescens, P. putida, P. cepacian, P. vesicularis, P. paucimobilis; Bacillus cereus, B. thuringiensis, B. sphaericus; Shewanella oneidensis; Geobacter bemidjiensis, G. metallireducens, G. sulfurreducens, G. uraniireducens, G. lovleyi; Serratia marcescens, Desulfovibrio vulgaris, D. desulfuricans, Dechloromonas aromatic, Deinococcus radiodurans, Methylibium petroleiphilum, Alcanivorax borkumensis, Archaeglobus fulgidus, Haloferax sp., Halobacterium sp., and combinations thereof”, which renders obvious instant claim 62.
This is a provisional nonstatutory double patenting rejection.
Modified rejection necessitated by amendment: Claims 35-36, 42 and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7-8, 16-18, 41-42 and 44 of copending Application No. 19/001,006 in view of Buddington et al. (“Maternal-to-Infant Transmission of Probiotics: Concept Validation in Mice, Rats and Pigs”, Neonatology, 2010, Vol. 97, Issue 3, pp.250-266; previously cited) and Olson et al. (“Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis”, Journal of Pediatric Surgery, 2016, Vol. 51, Issue 6, pp.936-941; previously cited).
Instant claim 35 is directed towards a prenatal method of conferring NEC resistance or immunity to a fetus, the method comprising administering to a pregnant female carrying the fetus an effective amount of a composition comprising microsphere comprising dextran, a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere, and a prebiotic.
Reference claim 1 is directed towards a composition comprising a biocompatible microsphere, a biofilm-generating probiotic bacterium and a prebiotic, wherein the prebiotic comprises a nutritional supplementation for the probiotic bacterium.
Reference claim 8 recites the composition of claim 7, wherein the probiotic bacterium is Lactobacillus reuteri (“L. reuteri”).
Reference claim 16 recites the composition of any one of claims 1-15, wherein the microsphere is a biodegradable polymer.
Reference claim 17 recites the composition of claim 16, wherein the biodegradable polymer is one or more of Sephadex, Sephadex G-25, poly(lactic-co-glycolic acid)(“ PLGA”); polycaprolactone (“PLC”); chitosan; gelatin; DNA hydrogen; acetalated dextran; poly(lactide); poly(glycolide); poly(lactide-co-glycolide); poly(lactic acid); poly(glycolic acid); poly(lactic acid-co-glycolic acid); poly(lactide)/poly(ethylene glycol) copolymers; poly(glycolide)/poly(ethylene glycol) copolymer; poly(lactide-co-glycolide)/poly(ethylene glycol) copolymers; poly(lactic acid)/poly(ethylene glycol) copolymer; poly(glycolic acid)/poly(ethylene glycol) copolymer; poly(lactic acid-co-glycolic acid)/poly(ethylene glycol) copolymer; poly(caprolactone); poly(caprolactone)/poly(ethylene glycol) copolymer; poly(orthoester); poly(phosphazene); poly(hydroxybutyrate); poly(hydroxybutyrate); poly(lactide-co-caprolactone); polycarbonate; polyesteramide; polyanhidride; poly(dioxanone); poly(alkylene alkylate); polyethylene glycol/polyorthoester copolymer; polyurethane; poly(amino acid); polyetherester; polyacetal; polycyanoacrylate; poly(oxyethylene)/poly(oxypropylene) copolymer; and a combination thereof.
Reference claim 18 recites composition of claim 17, wherein the biodegradable is poly(lactic-co-glycolic acid) (“PGLA”) and/or Sephadex.
Reference claim 41 recites a method for treating or preventing a disease suitably treated by a biofilm in a subject in need thereof, comprising administering to the subject an effective amount of the composition of any one of claims 1-23.
Reference claim 42 recites the method of claim 41, wherein the diseases comprises one or more of inflammatory bowel disease (IBD), colitis, enteric infectious disease, diarrheal illness, vaginosis, necrotizing enterocolitis (NEC), wound, burns, psoriasis, dermatitis, tooth decay, periodontitis, sinusitis, infection-induced colitis, traveler’s diarrhea, psychological stress, psychological disorders, or any of chronic or recurrent disease that is caused by pathogenic bacteria displacing healthy bacteria.
Reference claim 44 recites the method of claim 42, wherein the disease is colitis or NEC.
Reference claims 41 and 44 do not recite a prenatal method of conferring NEC resistance or immunity to a fetus, administering to a pregnant female carrying a fetus, or a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere.
However, Buddington teaches maternal-to-infant transmission of probiotics (title). Buddington teaches that probiotics enhance disease resistance in infants, and may be of particular benefit for infants with or at risk of necrotizing enterocolitis (relevant to conferring NEC resistance or immunity) (p.250, 2nd column last paragraph to p.251, 1st column top paragraph). Buddington teaches that probiotic bacteria administered to mothers during late gestation are transferred to infants born vaginally and influence the assemblages of GIT bacteria (relevant to administering to a pregnant female carrying the fetus) (abstract).
Olson teaches a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres (abstract). Olson teaches that L. reuteri in the biofilm state augments the effectiveness of L. reuteri in preventing NEC (p.938, 2nd column - last paragraph). Olson teaches that this novel method of probiotic administration allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium, thereby providing longer-acting benefits to the developing gut (p.938, 2nd column – last paragraph). Olson further teaches that a single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of reference claim 1 to replace a subject suffering from or has suffered from necrotizing enterocolitis with a pregnant female carrying a fetus taught by Buddington as the subject. One of ordinary skill in the art would have been motivated to select a pregnant female carrying a fetus as the subject in need thereof, because Buddington teaches that administering probiotic bacteria to mothers during late gestation transferred to infants and influenced the assemblages of gastrointestinal bacteria. One of ordinary skill in the art would have found it beneficial to do so because Buddington teaches that probiotic bacteria may be of particular benefit for infants with or at risk of necrotizing enterocolitis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of patented claim 12 to administer microspheres having Lactobacillus grown as biofilms on microspheres as taught by Olson. One of ordinary skill in the art would have been motivated to select microspheres coated with L. reuteri biofilm because Olson teaches that this novel method allows the probiotic to better withstand its transit through the gastrointestinal tract, providing longer-lasting interaction with host intestinal epithelium and thereby providing longer-acting benefits to the developing gut. One of ordinary skill in the art would have found it beneficial to administer the probiotic in a formulation that preserved its efficacy and significantly reduced NEC incidence and severity with a single dose.
Reference claim 2 recites the composition of claim 1, further comprising a prebiofilmic, which renders instant claim 61 obvious.
Reference claim 5 recites the composition of any one of claims 1-4, wherein the prebiotic comprises a water-soluble carbohydrate, wherein the water-soluble carbohydrate comprises one or more of inulin, oligofructose, fructo-oligosaccharide, galacto-oligosaccharide, glucose, maltose, maltodextrins, polydextrose, sucrose, fructose, lactose, isomaltulose, polyols, glycerol, and combination thereof , which renders instant claims 42 and 64 obvious.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues that none of the claims of the cited patents or patent applications teach or suggest the surprising features of improved survival and NEC resistance in offspring when microspheres comprising a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere are administered to pregnant females (See Remarks dated 8/22/2025, p.14, Double Patenting 2nd paragraph). Applicant further argues that the skilled artisan would not expect that administration of any probiotic composition, let alone the composition presently claimed could effectively demonstrate conferred immunity to NEC in a fetus based on the teachings of the cited claim in combination with Buddington, and only through impermissible hindsight reconstruction based on the teachings of Applicant’s own specification could a person of skill arrive at the claimed method (See Remarks dated 8/22/2025, p.14, Double Patenting 2nd paragraph).
Applicant's arguments filed August 22, 2025 have been fully considered but they are not persuasive. A terminal disclaimer is required to overcome a non-statutory double patenting rejection. See MPEP §804.02.
The instant claims require an active method step of administering an effective amount of a microsphere comprising a biofilm-generating L. reuteri bacterium partially or completely coating a surface of the microsphere and a probiotic, wherein the prebiotic comprises a nutritional supplementation for the probiotic bacterium. The reference claims from co-pending applications and patented claims require the same active method step. Buddington teaches the instantly required subject of a pregnant female. Olson teaches a probiotic delivery system in which L. reuteri probiotics are grown as a biofilm on microspheres. The recitation of “conferring necrotizing enterocolitis (NEC) resistance or immunity to a fetus” is the intended or desired outcome of the method. However, the active method step of the instant claims does not differ from the patented or co-pending claims, and thus do not distinguish over the prior art. Therefore the instant claims are obvious over the reference claims and prior art for the reasons discussed in the rejection above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DEEPA MISHRA whose telephone number is (571) 272-6464. The examiner can normally be reached Monday - Friday 9:30am - 3:30pm EST.
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/DEEPA MISHRA/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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