DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 19, 2026 has been entered.
Claim Amendments
3. The amendment filed March 6, 2026 has been entered. Claims 1, 29-32 and 36 has been amended. Claims 2-21, 24-26 and 33 are canceled. Claim 37 has been newly added. Claims 1, 22-23, 27-32 and 34-37 are under consideration in this Office Action.
Withdrawal of Rejections
4. The rejection of claims 29-32 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of Applicants claim amendments to claims 29-32.
5. The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Flavell et al., as evidenced by Bunker et al., in view of Sampaio et al. is withdrawn in view of Applicants claim amendments to claim 3.
New Grounds of Rejection Necessitated by Applicants Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 1, 22-23, 27-32 and 34-37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1(d) recites selecting the milk sample to be administered to an infant to provide protection against NEC, wherein the infant is less than four weeks old.
However, the claim fails to recite the criteria for milk selection. Thus the metes and bounds of the claim are unclear, because claim 1 does not require the sIgA antibody is present at a minimum concentration. Currently, the instant claims recite every milk sample is selected for administration. Therefore, clarification is required to overcome the rejection.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
7. Claims 1, 22-23, 29-32 and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Flavell et al., (WO 2016033439 published March 3, 2016; priority to Aug 28, 2015) as evidenced by Bunker et al., (Science 28 Sep 2017. Vol 358. Issue 6361) in view of Sampaio et al., (BRPI0404861 published June 2006; priority to Nov. 2004).
The claims are drawn to a method of detecting an secretory IgA antibody for providing protection against necrotizing enterocolitis (NEC) in a milk sample, the method comprising: (a) isolating from the milk sample an antibody repertoire comprising the sIgA antibody; (b) contacting a bacterial array comprising bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof with the antibody repertoire, wherein the bacterial array comprises bacteria affixed to a substrate, wherein the bacteria are associated with NEC; and (c) detecting binding of the sIgA antibody to the bacterial array.
Flavell et al., teach IgA is the predominant antibody isotype produced at mucosal surfaces and is a critical mediator of intestinal immunity. Recognition of enteric pathogens by pathogen-specific IgA, is transcytosed into the intestinal lumen. In the lumen, these antibodies can bind and 'coat' offending pathogens, and provide protection against infection through neutralization and exclusion. Thus, relative levels of bacterial coating with IgA might be predicted to correlate with the magnitude of the inflammatory response triggered by a specific intestinal bacterial species [Background]. There is a need in the art to identify the specific bacteria (e.g., genus, species, strain, sub-strain, etc.) [Background]. Flavell et al., teach secretory antibodies can be used to detect and identify microbes that influence susceptibility to or contribute to the development or progression of inflammatory diseases and disorders [Summary of Invention].
The methods specifically describe binding secretory IgA, produced by the subject, serve as a marker and a means for isolating and identifying disease-causing bacteria. The detection and identification of secretory antibody-coated constituents of the microbiota of the subject are used to diagnose the subject as having, or as at risk of developing, an inflammatory disease, such as colitis or disorder [Methods of Identifying]. It is noted that, NEC is a specific, severe condition that includes inflammation of the colon, making it a type of colitis, but with added tissue death.
The presence of secretory antibody-coated constituents, can be detected using various methods [Methods of Identifying]. The subject is diagnosed as having an inflammatory disease or disorder when particular types of secretory antibody-coated bacteria are determined to be present in the biological sample derived from the subject [Methods of Identifying]. Enrichment of the bacteria bound by secretory IgA, may be accomplished using separation technique. For example, using affinity separation techniques. Techniques for affinity separation may include magnetic separation using magnetic beads conjugated with an affinity reagent [Methods of Identifying]. Labels include magnetic beads, which allow for direct separation; biotin, which can be removed with avidin or streptavidin bound to a support [Methods of Identifying]. The bacteria in the contacted population that become labeled by the affinity reagent are selected for by any convenient affinity separation technique, e.g. as described elsewhere herein or as known in the art [Methods of Identifying]. The term "microarray" refers broadly to both "DNA microarrays" and "DNA chip(s)," and encompasses all art-recognized solid supports, and all art-recognized methods [Definitions].Flavell et al., teach claim 1. Flavell et al., teach methods that combine flow cytometry-based microbial cell sorting and genetic analyses to detect, to isolate and to identify secretory IgA-coated microbes of a subject [Detailed Description]. Thereby teaching claims 2 and 34.
Flavell et al., teach a method of identifying a type (e.g., genus, species, strain, sub-strain, etc.) of bacteria that contributes to the development or progression of an inflammatory disease or disorder in the subject, including the steps of: isolating secretory antibody-bound bacteria from the subject's biological sample, amplifying bacterial nucleic acid from secretory antibody-bound bacteria so isolated, determining the sequences of the amplicons, identifying the type (e.g., genus, species, strain, sub-strain, etc.) of antibody-bound bacteria present in the subject's biological sample by identifying nucleic acid sequences that are indicative of particular types (e.g., genus, species, strain, sub-strain, etc.) of bacteria [Summary of Invention]. Thus teaching claim 2. In some embodiments, the biological sample is a breast milk sample [Summary of Invention]; thereby teaching claims 21-23. The inflammatory disease or disorder is at least one inflammatory disease or disorder includes inflammatory bowel disease and colitis [Summary of Invention].
A method of treating an inflammatory disease or disorder associated with a secretory antibody-bound bacteria in a subject in need thereof, comprises administering to the subject passive immunotherapy [Summary of Invention]. This is achieved by administering to a subject in need thereof a therapeutically effective amount of a passive immunotherapy or passive vaccine, such as by the administration of immunoglobulin, e.g., IgA. In some embodiments, the immunoglobulin is administered orally [Passive Immunotherapy].
The pathogenic effects of at least one type of bacteria associated with an inflammatory disease includes Citrobacter spp., Enterobacteriaceae Other, Enterobacteriaceae spp., Proteus spp., [Summary of Invention]. It is noted that UC Enterobacteriaceae is a large family of gram negative bacteria that includes, familiar pathogens, such as Escherichia coli, Enterobacter, Citrobacter, Proteus Klebsiella, Shigella and other species. Thus claims 29-32.
Thus Flavell et al., teach a method of detecting an sIgA antibody in a milk sample, comprising contacting a bacterial array with the sample, wherein the bacteria array comprises bacteria that are associated with colitis which includes NEC; and detecting binding of an antibody of the sample to a bacterium of the bacterial array wherein the sIgA is administered and wherein the IgA antibody binds to bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof; wherein the milk provides protection against NEC.
It is noted that Bunker et al., evidences that an antibody will bind to bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof. Bunker et al. discovered that antibodies produced by naïve small intestinal plasma cells are recirculated and enriched within Peyer's patches, independently of exogenous antigen and T cell help. The resulting polyreactive IgAs are released into the gut lumen and bind to microbial surface glycans, thus innately recognizing the gut microbiota. Polyreactive IgAs appear to be a product of the coevolution of host and microbiota to maintain symbiotic homeostasis [abstract]. Bunker et al., asked whether IgAs might bind microbial glycans by screening mAbs against a microbial glycan microarray. Numerous glycan reactivities were observed among microbiota-reactive mAbs from IgA PCs (Fig. 2E and fig. S11, A and B). Notably, microbiota-reactive IgA mAbs typically bound multiple distinct microbial glycans. For example, an antibody showed affinity binding interactions with glycans from Proteus penneri, Proteus mirabilis and various strains of Escherichia coli. These findings support the conclusion that microbial surface glycans are common targets of microbiota-reactive IgAs [Microbiota reactive antibodies bind a diverse subset of commensal bacteria].
Sampaio et al., teach obtaining secretory immunoglobulin extracted from human breast milk and human colostrum, for oral administration with clinical indications for cases of primary or secondary immunodeficiency, immunosuppression, intoxications, infections by toxigenic microorganisms or pathogenic, in addition to premature and newborn babies with very low weight, aiming to confer passive immunization to these individuals [abstract]. Thus teaching claims 22-23 and 36-37. Sampaio et al., teach a method to test the obtained sIgA [para 35] thereby teaching claims 24-26. Breast milk and human colostrum, from which immunoglobulins were extracted was performed by different methods. The analysis of the results of this standardization step allowed the choice of the extraction method that presented the best yield, highest purity of immunoglobulins whose biological characteristics of the antibody were preserved [para 37]. Thus teaching isolating from the milk sample an antibody repertoire comprising the antibody. Immunological tests revealed high reactivity of IgA to various bacteria in all preparations as well as high levels of anti-bacteria antibodies and neutralizing activity for tetanus and diphtheria toxins. Despite the reductions observed in both IgA dosages and anti-bacterial antibody titers, the immunoblotting tests confirmed the maintenance of the EPEC (E. coli) and E. coli enterotoxigenic antigen recognition capabilities [para 38]. Thereby teaching claims 29-31. Tests to inhibit EPEC adhesion to human cells showed that sIgA's ability to block adhesion remained unchanged in virtually all samples, at the same levels observed in untreated samples, as well as in relation to the original pools [para 38]. The evaluation of the reactivity of the antibodies obtained was verified through immunoblotting (IB) tests with total antigenic preparations (crude extracts) from different bacterial strains; and the ELISA technique for determining specific IgA for EPEC [para 69]. Different bacterial strains were used including E. coli 0111: H-, eae +, eaf + and bfp + (EPEC); E. coli producing Shiga toxin, O111ac: H- producing Stx1 (STEC); E. coli enterotoxigenic (ETEC); E. coli enteroinvasive O28ac: H- (EIEC) with the objective of identifying the presence of reactivity of the immunoglobulins isolated against the microorganisms tested [para 70]. Thus teaching contacting a bacterial array with the antibody repertoire, wherein the bacterial array comprises bacteria affixed to a substrate, wherein the bacteria are associated with necrotizing enterocolitis (NEC).
Literary reports teach in order to prevent acute infections and necrotizing enterocolitis the use of fresh colostrum and human milk in passive immunization for human use [para 22]. Thus teaching the milk provides protection against NEC. Sampaio et al., explained good results in the prevention of infectious diarrhea and necrotizing enterocolitis in nurseries using colostrum nursing babies and children [para 25]. Thereby teaching claim 3. Thus Sampaio et al., teach the milk as a body fluid provides protection against NEC wherein the sIgA was isolated from the milk sample and contacted with an immunoblot or ELISA substrate fixed with an array of bacteria to detect binding of the antibody to the bacterial array.
Accordingly, Sampaio et al., teaches a milk sample which contains sIgA known to provide protection against NEC upon administration wherein the sIgA was isolated from the milk sample and contacted with an immunoblot or ELISA substrate fixed with an array of bacteria to detect binding of the sIgA antibody to the bacterial array.
Moreover, it would have been prima facie obvious at the time of applicants’ invention to apply Sampaio et al’s administration of sIgA to infants to Flavell’s method in order to reduce the severity of necrotizing enterocolitis in infants when Sampaio and Flavell both teach sIgA administration to infants. Additionally, Bunker et al., evidences that an antibody binds to bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof.
One of ordinary skill in the art would have a reasonable expectation of success by detecting sIgA antibody in a milk sample, because sIgA triggers efficient protective host defense reactions via passive immunotherapy for cases of primary or secondary immunodeficiency, immunosuppression, intoxications, infections by toxigenic or pathogenic microorganisms.
Furthermore, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of detecting an sIgA antibody in a milk sample, wherein NEC is an inflammatory disease and NEC is a type of colitis; when there is no change in the respective function of the antibodies or bacteria, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
8. Applicant's arguments filed March 6, 2026 have been fully considered but they are not persuasive.
First Applicants argue Flavell does not teach the age of infants which are administered treatment for provide protection against NEC. In response to applicant's arguments against the references individually, 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).
Flavell et al., teach a method of detecting an sIgA antibody in a breast milk sample comprising contacting a bacterial array with the sample. Flavell et al., teach a bacteria array comprising at least one of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof. Flavell et al., teach detection of binding of the sIgA antibody to the bacterial array by flow cytometry. Flavell et al., teach orally administering to a subject in need thereof a therapeutically effective amount of the administration of IgA.
Sampaio et al., teach the milk provides protection against NEC and specifically associated bacteria. Sampaio et al., teach administering breast milk containing sIgA to preterm and infants to prevent NEC. Therefore, Flavell et al., as evidenced by Bunker et al., in view of Sampaio et al., teach the isolation step; contact step; detection step and selection step.
Applicants argue that Flavell does not evaluate samples from infants and is silent regarding the timing of treatment to infants. However, the claims do not require milk samples from infants. Instead the claims recite isolating from human breast milk, breast milk or milk sample. Obviously newborns, infants and premature infants do not produce milk. Therefore, the argument is not persuasive. Flavell et al., teach the biological sample is a breast milk sample. Both Flavell et al., and Sampaio et al., teach detection of bacteria. Sampaio et al., teach administering human breast milk and human colostrum. Sampaio et al., teach administering breast milk containing sIgA to preterm and infants to prevent NEC.
Applicants argue that a method of detecting an secretory IgA antibody for providing protection against necrotizing enterocolitis (NEC) in a milk sample; however contrary to Applicants argument, Flavell clearly teach a method of detecting an secretory IgA antibody in a breast milk sample. Flavell teach detection with affixed Citrobacter spp., Enterobacteriaceae Other, Enterobacteriaceae spp., Proteus spp., bacteria. Therefore, Applicants arguments are not found persuasive.
Second, Applicant respectfully disagrees that a skilled person would be motivated by Flavell to select milk samples for provide protection against NEC. Flavell et al., clearly teach that secretory antibodies can be used to detect and identify microbes present in the microbiota. Flavell teach the relative levels of bacterial coating with IgA might be predicted to correlate with the magnitude of the inflammatory response triggered by a specific intestinal bacterial species. Flavell clearly and specifically teach the association with colitis. It is well known that Necrotizing Enterocolitis (NEC) is a severe form of colitis (intestinal inflammation) that involves inflammation, cell damage, and death in the intestines, most often affecting premature infants and leading to tissue necrosis. Contrary to Applicants arguments; Flavell et al., teach detection of bacteria associated with inflammatory diseases and colitis, which both include NEC.
Furthermore, Sampaio et al., reference provide evidence that Literary reports teach in order to prevent acute infections and necrotizing enterocolitis the administration of fresh colostrum and human milk in passive immunization for human use. Sampaio et al., explained good results in the prevention necrotizing enterocolitis in nurseries using colostrum nursing babies. Thus Sampaio et al., teach the milk as a body fluid provides protection against NEC wherein the sIgA was isolated from the milk sample and contacted with an immunoblot or ELISA substrate fixed with an array of bacteria to detect binding of the antibody to the bacterial array. Therefore, contrary to Applicants a skilled person would be motivated by Flavell to select milk samples for provide protection against NEC, because that is exactly what Sampaio et al., teach.
Third, Applicant notes that Citrobacter spp. and Proteus spp. are merely provided as part of a large list, however, Flavell provides no evaluation of whether these taxa are actually relevant to colitis. Applicants are reminded that claim 1 only requires one genus. Therefore, Flavell teach the claimed limitation of one genus. Furthermore, reduction to practice is not a requirement for obviousness. In this case, Flavell teach detection with affixed Citrobacter spp., Enterobacteriaceae Other, Enterobacteriaceae spp., Proteus spp., bacteria. No more than routine skill is required to affix the bacteria. Further, Bunker et al., evidences that an antibody will bind to bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof. Thus no more than routine skill was required to affix and detect bacteria. Finally, Sampaio et al., teach affixing E. coli and other bacteria. Therefore, Applicants argument is not persuasive.
Applicants urge that Flavell teach several species are named within the reference. It is noted that MPEP 2131 states that: “A claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference.” Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). Further, MPEP 2131 states: When a claim covers structures or compositions, either generically or as alternatives, the claim is deemed anticipated if any of the structures or compositions within the scope of the claim is known in the prior art. Brown v. 3M, 265 F.3d 1349, 1351, 60 USPQ2d 1375, 1376 (Fed. Cir. 2001). Furthermore, MPEP 2131 states: “when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. Flavell et al., teach a method of detecting an secretory IgA antibody in a milk sample, the method comprising: (a) isolating from the milk sample an antibody repertoire comprising the sIgA antibody; (b) contacting a bacterial array comprising bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella. Sampaio et al., teach a human milk sample which contains sIgA was known to provide protection against NEC upon administration wherein the sIgA was isolated from the milk sample and contacted with an immunoblot or ELISA substrate fixed with an array of bacteria to detect binding of the sIgA antibody to the bacterial array. In this case, it would have been prima facie obvious at the time of applicants’ invention to apply Sampaio et al’s administration of sIgA to infants to Flavell’s method in order to reduce the severity of necrotizing enterocolitis in infants when Sampaio and Flavell both teach sIgA administration to infants. Additionally, Bunker et al., evidences that an antibody binds to bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof.
Applicants are reminded that the method of detection recites the intended use of providing protection against NEC. In response to applicant's argument regarding the intended use of providing protection, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Thus no undue experimentation would be required to detect Citrobacter spp. and Proteus spp.
Finally, Flavell et al., as evidenced by Bunker et al., in view of Sampaio et al., teach a method of detecting an secretory IgA antibody for providing protection against necrotizing enterocolitis (NEC) in a milk sample, the method comprising: (a) isolating from the milk sample an antibody repertoire comprising the sIgA antibody; (b) contacting a bacterial array comprising bacteria of one or more genus selected from the group consisting of Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof with the antibody repertoire, wherein the bacterial array comprises bacteria affixed to a substrate, wherein the bacteria are associated with NEC; (c) detecting binding of the sIgA antibody to bacteria and (d) selecting the milk sample just as instantly claimed. Applicants arguments are not persuasive and the rejection of record is maintained.
Claim Rejections - 35 USC § 103
9. Claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over
Flavell et al., (WO 2016033439 published March 3, 2016; priority to Aug 28, 2015) as evidenced by Bunker et al., (Science 28 Sep 2017. Vol 358. Issue 6361) in view of Sampaio et al., (BRPI0404861 published June 2006; priority to Nov. 2004)
as applied to claims 1, 22-26, 29-32 and 34-36 above, and further in view of Ballabio et al., (Int J Immunopathol Pharmacol. 2007 Jan-Mar;20(1):119-28).
Flavell et al., in view of Sampaio et al, have been discussed above as teaching a method of detecting an sIgA antibody for providing protection against NEC in a milk sample. Flavell et al., and Sampaio et al., both teach sIgA is present in breast milk samples; while Bunker et al., teach the sIgA will bind Enterobacter, Citrobacter, Klebsiella, Proteus and combinations thereof; none teach the sIgA antibody in breast milk having the instantly recited concentrations.
Ballabio et al., teach Immunoglobulin-A profile in breast milk from mothers delivering full term and preterm infants. Some components of human milk may be critical for survival. Of these, immunoglobulins are important, and in particular secretory immunoglobulins A (sIgA). The concentration of secretory IgA was measured in milk. Of the immunoglobulins found in human milk, the major one is secretory immunoglobulin A (sIgA) (>90%) [page 119]. Ballabio et al., quantified sIgA in human milk. The use of immunoelectrophoretic techniques (SDS-PAGE and immunoblotting) improved, compared to ELISA quantification, the specificity and reliability of the measures [page 120]. Table III teach total protein content in human milk from mother’s where secretory IgAs in colostrum at 19.97 mean value in g/L, mature milk 3.17 mean value in g/L. Therefore, Ballabio et al., teach the sIgA antibody is present in breast milk at a concentration of at least about 0.000001 % w/w of the breast milk and at a concentration of at least about 0.01 ppm of the breast milk as recited by claims 27-28.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Sampaio et al., and Flavell et al’s sIgA to the method wherein Ballabio et al., teach breast milk normally has a sIgA concentration of at least about 0.000001% w/w of the breast milk and at a concentration of at least about 0.01 ppm of the breast milk capable of being quantified using immunoelectrophoretic techniques which have improved quantification, specificity and reliability attributes.
One of ordinary skill in the art would have a reasonable expectation of success by detecting and quantifying sIgA antibody in a milk sample.
It is noted, that while the references recite sensitive detection at very low concentrations they do not specifically state the sIgA antibody is present in breast milk at a concentration of at least about 0.000001 % w/w of the breast milk or at a concentration of at least about 0.01 ppm of the breast milk. Regarding the specific concentrations recited in the instant claims, MPEP 2144.05 states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)."
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of detecting an sIgA antibody in a milk sample, where there is no change in the respective function of the sIgA antibodies, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
10. Applicant's arguments filed March 6, 2026 have been fully considered but they are not persuasive. The rejection claims 27-28 over Sampaio et al., as evidenced by Bunker et al., in view of Flavell et al., as applied to claims 1, 22-23, 29-32 and 34-36 above, and further in view of Ballabio et al.
Applicants argue that Ballabio et al., do not address antibody reactivity. However the claims recite that the sIgA is present in breast milk at a concentration of at least 0.0000001% w/v or 0.01 ppm of the breast milk.
The Office pointed out that Antibody reactivity describes an antibody's ability to bind to its specific target antigen, involving strength (affinity/avidity) and breadth (specificity vs. cross-reactivity); not it’s concentration within the sample. In this case, Ballabio et al., clearly states the concentration of secretory IgA was measured in milk. Ballabio et al., quantified sIgA in human milk. The use of immunoelectrophoretic techniques (SDS-PAGE and immunoblotting) improved, compared to ELISA quantification, the specificity and reliability of the measurements. Where 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. Moreover, Applicants have not provided any scientific evidences that the methods of Ballabio et al., Sampaio et al., and Flavell et al., are incapable of achieving antibody detection. Therefore, Applicants arguments are not found persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case,
it would have been prima facie obvious at the time of applicants’ invention to apply
Pertinent Art
11. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Necrotizing Enterocolitis (NEC) is a severe intestinal disease that involves inflammation (colitis) and tissue death (necrosis) in the intestines, primarily affecting premature infants, and is considered a severe form of enterocolitis. The "colitis" part of NEC specifically refers to the inflammation of the colon (large intestine) and small intestine, which can lead to tissue death, perforation, and serious infection
Carlisle et al., (PLoS One. 2011 Mar 22;6(3):e18084). Carlisle et al., describe gram-negative bacteria are associated with necrotizing enterocolitis. Animals with NEC had more Citrobacter (p<0.01), Klebsiella (p<0.05), than those without NEC. Citrobacter, Klebsiella, and Tatumella are associated with NEC. Gram negative organisms, specifically Gamma-proteobacteria from the Enterobacteriaceae family were associated with the development of NEC.
Enterobacteriaceae are a large family of Gram-negative bacteria that includes a number of pathogens such as Klebsiella, Enterobacter, Citrobacter, Salmonella, Escherichia coli, Shigella, Proteus, Serratia and other species. These pathogens are present in the human intestinal tract and are a normal part of the gut flora.
https://www.nicd.ac.za/diseases-a-z-index/enterobacteriaceae/
Virnig et al., (Am J Dis Child. Vol 128, Aug 1974) teach organisms isolated from samples from 21 infants with necrotizing enterocolitis from Jan 1, 1964 to April 1, 1972 include E coli, Proteus, Enterobacter, Aerobacter (now classified as Klebsiella).
Coleman et al., (Sci Rep 13, 7893 (2023) teach fecal samples from 10 preterm infants who developed NEC were available for analysis. Figure 1 shows NEC case samples contained Clostridia, Enterobacter, Enterococcus, Escherichia, Klebsiella, Staphylococcus and others. Coleman et al., teach Klebsiella species colonized most preterm infants, were more prevalent in NEC subjects versus controls. Almogren et al., ( Immunology. 2007 Feb;120(2):273–280) A detailed investigation of the binding of secretory component to immunoglobulin A (IgA) in human secretory IgA2 (S-IgA2) was made possible by the development of a new method of purifying S-IgA1, S-IgA2 and free secretory component from human colostrum using thiophilic gel chromatography and chromatography on Jacalin-agarose. Sodium dodecyl sulphate–polyacrylamide gel electrophoresis of unreduced pure S-IgA2 revealed that, unlike in S-IgA1, a significant proportion of the secretory component was bound non-covalently in S-IgA2. When S-IgA1 was incubated with a protease purified from Proteus mirabilis the secretory component, but not the α-chain, was cleaved. This is in contrast to serum IgA1, in which the α-chain was cleaved under the same conditions – direct evidence that secretory component does protect the α-chain from proteolytic cleavage in S-IgA. Comparisons between the products of cleavage with P. mirabilis protease of free secretory component and bound secretory component in S-IgA1 and S-IgA2 also indicated that, contrary to the general assumption, the binding of secretory component to IgA is different in S-IgA2 from that in S-IgA1.
Sterlin et al., (J Exp Med. 2019 Dec 31;217(3):e20181635) IgA are secreted every day in the intestinal lumen. While only one IgA isotype exists in mice, humans secrete IgA1 and IgA2, whose respective relations with the microbiota remain elusive. We compared the binding patterns of both polyclonal IgA subclasses to commensals and glycan arrays and determined the reactivity profile of native human monoclonal IgA antibodies. While most commensals are dually targeted by IgA1 and IgA2 in the small intestine, IgA1+IgA2+ and IgA1−IgA2+ bacteria coexist in the colon lumen, where Bacteroidetes is preferentially targeted by IgA2. We also observed that galactose-α terminated glycans are almost exclusively recognized by IgA2. Although bearing signs of affinity maturation, gut-derived IgA monoclonal antibodies are cross-reactive in the sense that they bind to multiple bacterial targets.
Loomes et al., (Infect Immun. 1990 Jun;58(6):1979–1985) P. mirabilis protease has been found to extend to both subclasses of IgA, IgG, and the nonimmunoglobulin substrates, secretory component and casein.
Mirpuri et al., (Gut Microbes. 2013 Sep 25;5(1):28–39) Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Proteobacteria-specific IgA antibodies may then act to establish the normal microbiota in adult mice by steric hindrance or as a potent neutralizer of mitogenic activity. The precise molecular mechanism of IgA induction to Proteobacteria may be T-cell dependent or independent.
Vincent (J of Immunol. Methods. Vol. 106, Issue 2, 10 Feb 1988, pages 153-160) describe sandwich-type enzyme-linked immunosorbent assays (ELISA) are described for the measurement of free secretory component (SC) and SC bound to IgA (S-IgA).
Conclusion
12. No claims allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/JANA A HINES/Primary Examiner, Art Unit 1645
Prosecution Insights