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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23, 2026 has been entered.
Claim Amendment
3. The amendment March 23, 2025 has been entered. Claim 8 has been amended. Claims 1-7, 9-10, 13 and 15-18 are cancelled. Claims 8, 11-12 and 14 are under consideration in this Office Action.
Withdrawal of Rejections
4. The following rejections have been withdrawn in view of applicants amendments:
a) The deposit rejection of claims 8-12, and 14 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of Applicants amendments, filed Declaration and arguments.
b) The scope of rejection of claims 8-12 and 14 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants amendments and arguments.
c) The rejection of claims 8-9 and 14 rejected under 35 U.S.C. 103 as being unpatentable over Dinleyici et al., in view of Grande et al., and Wook et al., is withdrawn in view of applicants amendments.
Rejection Necessitated By Applicants Amendment
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.
5. Claims 8, 11-12 and 14 are rejected under 35 U.S.C.103 as being unpatentable over Savino et al., (Pediatrics. 2010 Sep;126(3):e526-33. Epub 2010 Aug 16) and Grande et al., (Front. Microbiol. 12 June 2018. Vol 8-2017) in view of Kim et al., (US20190209628 published July 7, 2019; priority to Aug. 9, 2017).
The claims are drawn to a method of treating colic and discomforts related to
colic, in a patient in need thereof comprising administering to the patient a therapeutically effective amount of therapeutic microvesicles isolated from bacteria of a probiotic bacterial strain, wherein the probiotic bacterial strain is selected from L. reuteri DSM 17938, L. reuteri DSM 32846, and a combination thereof.
Savino et al., teach Lactobacillus reuteri DSM 17938 in the treatment of infantile colic. Responders with 50% reduction in crying time from baseline were significantly higher in the L reuteri group versus placebo group [results]. L. reuteri DSM 17938 at a dose of 108 colony-forming units per day in early breastfed infants improved symptoms of infantile colic and was well tolerated and safe. Gut microbiota changes induced by the probiotic could be involved in the observed clinical improvement. Therefore, Savino et al., teach a method of treating colic and discomforts related to colic, in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a probiotic bacterial strain, wherein the probiotic bacterial strain is selected from L. reuteri DSM 17938, L. reuteri DSM 32846, and a combination thereof. However Savino et al., does not teach administering the therapeutic microvesicles isolated from the L. reuteri DSM 17938 probiotic bacteria.
Grande et al., teach Membrane vesicles (MVs) produced from L. reuteri DSM 17938 [abstract]. The probiotic L. reuteri forms biofilm in vitro, generates immunomodulatory factors and demonstrates a specific activity against infantile colic, eczema and Helicobacter pylori colonization [Introduction]. Grande et al., teach membrane vesicles production [Evaluation of Biofilm Formation and MVs Production]. The microbiota vesicles represent a suitable strategy to communicate between beneficial bacteria and intestinal mucosa cells; and MVs could shuttle mediators, that modulate the host immune and defense responses. The MVs of L. reuteri in the gut microflora are involved in the transport of factors that interact with the host, stimulate the immune system, and activate some factors with antimicrobial activity [Conclusion]. The MVs from probiotic strain L. reuteri DSM 17938, has been suggested to be effective against infantile colic, alleviation of eczema and H. pylori colonization to provide preliminary information about the use of MVs for biotechnological applications. While, Savino et al., teach treating colic with DSM 17938 and Grande et al., teach producing MVs from DSM 17938, neither teach administering the microvesicles isolated from the DSM 17938 bacteria.
Kim et al., describe preventing, improving or treating a mental disorder, the composition containing a Lactobacillus sp. bacteria-derived vesicle as an active ingredient. Recently, it has been revealed that mental disorders including depression, autism, schizophrenia, etc. are deeply associated with colic. It has been revealed that colic is accompanied by diarrhea and constipation, results in irritable bowel syndrome if repeated, and is associated with gut microbial dysbiosis [para 6]. The mental disorder may be one or more diseases selected from the group consisting of stress [para 9]. General symptoms caused by stress vary, and included physical symptoms such as stomach pain, abdominal pain and vomiting [para 46]. Thus, stress, stomach pain, abdominal pain, vomiting, diarrhea and constipation are discomforts related to colic, just as instantly recited by the rejected claims. Kim et al., teach administrations as granule formulations [para 53].
Kim et al., confirmed that, when a Lactobacillus sp. bacteria-derived vesicle is administered to a stress and depression animal model, resistance to stress efficiently increases, and an effect of treating chronically persisting long-term depression behavior is exhibited, and thus the Lactobacillus sp. bacteria-derived vesicle, according to the present invention, is expected to be capable of being usefully employed in developing a medicine or a functional health food, etc., for preventing, reducing the symptoms [abstract]. The mental disorder may be stress [para 16]. When Lactobacillus-derived vesicles were administered to stress and depression animal models, resistance to stress is effectively increased, and treatment of long-term, chronic depressive behavior is effective, and therefore, the Lactobacillus sp. bacteria-derived vesicles according to the present invention can be effectively used in developing a medicine or health functional food for preventing, a mental disease such as stress [para 25]. General symptoms caused by stress vary, and are classified into four categories including physical symptoms such as fatigue, headaches, insomnia, stomach pain, abdominal pain and vomiting [para 46].
Therefore, it would have been prima facie obvious at the time of applicants’ invention to treat colic and its associated symptoms with DSM 17938 of Savino et al., when Grande teach producing MVs from DSM 17938 for administration to treat colic as taught by Kim et al. Kim et al., clearly teach the administration of MVs, while Savino et al., teach the DSM 17398 is known to treat colic and Grande et al., produced MVs from DSM 17398 which could be used to treat colic. Thus the MVs from a strain known to treat colic is obvious. Furthermore, Kim et al., teach MVs are known to treat colic, stomach and abdominal pain which are discomforts related to colic. One of ordinary skill in the art would have a reasonable expectation of success by incorporating MVs as taught by Grande et al., into Savino et al, colic treatment in order to reduce stress, physical pain and thereby treat colic.
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 treatment where there is no change in the respective function of the membrane vesicles, 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
6. Applicant's arguments filed March 23, 2026 have been fully considered but they are not persuasive.
Applicants acknowledge that Savino et al., does teach a method of treating colic and discomforts related to colic, in a patient in need thereof comprising administering to the patient a therapeutically effective amount of L. reuteri DSM 17938; but Savino et al., does not teach administering the therapeutic microvesicles isolated from the L. reuteri DSM 17938 probiotic bacteria. Next Applicants acknowledge that Grande et al., teach Membrane vesicles (MVs) produced from L. reuteri DSM 17938. Therefore, Grande et al., clearly teach producing membrane vesicles from L. reuteri DSM 17938 to be effective against infantile colic, and Savino et al., taught treating colic with DSM 17938. Finally, Kim et al., teach the administration of Lactobacillus MV to treat colic and discomforts related to colic such as abdominal pain, stomach pain, stress, vomiting and diarrhea.
Applicants argue that Kim et al., only teach the genus of Lactobacillus species and does not specifically recite DSM 17938. However both Savino and Grande already taught the DSM 17938 being known to treat colic and its related discomforts. In response to applicant's arguments against the Kim et al., reference 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). In this case, it would have been prima facie obvious at the time of applicants’ invention to treat colic and its associated symptoms with DSM 17938 of Savino et al., when Grande teach producing MVs from DSM 17938 for administration to treat colic and its related discomforts such as physical pain, stomach pain, abdominal pain, and stress all taught by Kim et al.
Applicants acknowledge that Grande et al., "has been suggested to be effective against infantile colic,"; but argue that the passage does not teach that the MVs from the strain are effective against infantile colic. Applicants are remined that reduction to practice is not a requirement for a prior art reference to teach a principle. Applicants attention is directed to MPEP section 2123 stating that patents are relevant as prior art for all they contain, “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir.1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Therefore applicant’s argument is not persuasive especially when Grande et al., suggest the MVs as being effective against infantile colic. Additionally, Savino et al., taught DSM 17938 is effective against colic and Kim et al., teach administered MVs are effective to treat colic and the physical manifestations associated with the discomforts of colic.
Applicants assert that Kim does not teach "administration to treat colic" or that "MVs are known to treat colic." However, Applicants are reminded that the amended claims are not limited to only the treatment of colic, but instead to the treatment of discomforts related to colic. It is noted, that the specification does not provide a definition or limit to the symptoms defined by “discomfort.” Kim et al., state that was revealed that mental disorders including depression, autism, schizophrenia, are deeply associated with colic. It has been revealed that colic is accompanied by diarrhea and constipation, results in irritable bowel syndrome if repeated, and is associated with gut microbial dysbiosis [para 6]. Therefore Kim et al., treatment of colic and its related discomforts by administering Lactobacillus MVs. Moreover, the broadest reasonable interpretation of discomforts related to colic would include manifestations such as stress, anxiety, pain, abdominal pain, stomach pain, diarrhea and vomiting. Applicants have provided no evidence to the contrary regarding the teaching of Kim et al. In this case, Kim et al., is relevant for all it contains. , The use of references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.
Again, Savino, Grande and Kim are relevant for teaching the treatment of colic with Lactobacillus. Savino and Grande et al., already taught the DSM 17938 strain as treating colic. The rejection is not overcome because a tertiary reference does not specifically state DSM 17938, when the primary and secondary references both teach DSM 17938. In response to applicant's argument that Kim et al., does not teach DSM 17938, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicants argue that Kim does not provide any indication of which parameters were critical or no direction as to which of many possible choices from the Lactobacillus genus would be likely to be successful in treating mental disorders. Contrary to Applicants argument, Savino et al., which specific particularity states Lactobacillus DSM 17938 will treat colic and its associated discomforts. Additionally, Grande et al., teach Lactobacillus DSM 17938 MVs will treat colic. Kim et al., merely provides evidences that upon administration, Lactobacillus MVs will treat colic, and physical discomforts related to colic. Therefore, Savino et al., and Kim et al., in view of Kim et al., provide clear guidance and instructions regarding the choice of Lactobacillus DSM 17938 to treat colic. Thus, Applicants arguments are not persuasive.
Applicants urge that Kim does not provide a reasonable expectation that any of the MVs described therein would be useful for treating colic. Applicants are reminded that Kim et al., is not the only reference within the instant rejection. In this case, Savino et al., teach a method of treating colic and discomforts related to colic, in a patient in need thereof comprising administering to the patient a therapeutically effective amount of L. reuteri DSM 17938. Grande et al., teach Membrane vesicles (MVs) produced from L. reuteri DSM 17938 to be effective against infantile colic. Savino et al., taught treating colic with DSM 17938. Kim et al., teach the administration of Lactobacillus MV to treat colic and discomforts related to colic such as abdominal pain, stomach pain, stress, vomiting and diarrhea.
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, one of ordinary skill in the art would have a reasonable expectation of success by incorporating DSM 17938 MVs capable of being effective against colic as taught by Grande et al., into Savino et al, colic treatment which administered DSM 17938 in order to reduce stress, physical pain, and colic by administering MVs as taught by Kim et al.
Applicants assert that the instant Specification states that the microvesicles were able to recapitulate the same effect as the bacterium, and had an enhanced effect of nerve bundles; yet the prior art references do not show or suggest these recited features. However, Applicant is remined that MPEP 2112.01 states
Where the claimed and prior art products are identical or substantially
identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation
or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195
USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for
believing that the products of the applicant and the prior art are the same,
the applicant has the burden of showing that they are not." In re Spada,
911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the
prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product.
In this case, Grande et al., clearly and specifically teach DSM 17938 MVs; thus both Applicants DSM 17938 MVs and those of the prior art would act in the same manner. Therefore, this argument is not persuasive and the rejection is maintained.
Finally, 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., the effect on nerve bundles or recapitulation 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). Accordingly, Applicants arguments are not persuasive and the rejection is maintained.
Pertinent Art
7. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Huppertz et al., (Lancet. 1997 Jun 7;349(9066):1660-2). Acute and chronic diarrhoea and abdominal colic associated with enteroaggregative Escherichia coli in young children
WO2013098033 Lactobacillus reuteri DSM 17938 for promoting the establishment of healthy and normal cognitive function in young mammals.
454 Pyrosequencing Analysis on Faecal Samples from a Randomized DBPC Trial of Colicky Infants Treated with Lactobacillus reuteri DSM 17938 Roos et al., Feb 2013 Vol. 8, Issue 2; e56710. Roos et al., teach using large-scale DNA sequencing of 16 S rRNA genes, in faecal samples from colicky infants given L. reuteri DSM 17938. However, the increase of Bacteroidetes in the responder infants indicated that a decrease in colicky symptoms was linked to changes of the microbiota.
Microvesicles from Lactobacillus reuteri (DSM-17938) completely reproduce modulation of gut motility by bacteria in mice. West et al., (PloS One. 2020 Jan 7;15(1):e0225481
Lactobacillus reuteri DSM 17938: Review of Evidence in Functional Gastrointestinal Disorders. Srinivasan et al. (Pediatrics & Therapeutics. Review Article - (2018) Volume 8, Issue 3).
Meta-analysis: Lactobacillus reuteri strain DSM 17938 (and the original strain ATCC 55730) for treating acute gastroenteritis in children Szajewska et al., (Beneficial Microbes, 5(3), 285-294).
Protective effect of Lactobacillus reuteri DSM 17938 against experimental necrotizing enterocolitis is mediated by Toll-like receptor 2. Hoang et al., ( American Journal of Physiology-Gastrointestinal and Liver Physiology. Published 2018).
T The Immunomodulatory Properties of Extracellular Vesicles Derived from Probiotics: A Novel Approach for the Management of Gastrointestinal Diseases. Tijeras et al. (Nutrients, 09 May 2019, 11(5):E1038).
Conclusion
8. No claims allowed.
9. 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.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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