DETAILED ACTION
This Office Action is in response to Applicant’s Remarks filed on 19 March 2026.
Claims 13-17 and 20-24 are pending in the current application. Claim 23 remains withdrawn. Claims 13-17, 20-22 and 24 are examined on the merits herein.
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 .
Response to Arguments
Applicant's arguments filed 19 March 2026 have been fully considered but they are not persuasive.
Applicant contends the proposed modification of Jing is improper, because Jing is directed to the development and use of a controlled microfluidic gut-on-chip model to evaluate the mechanistic effects of COS on intestinal barrier function under inflammatory conditions. Applicant argues the system is intentionally designed to minimize confounding variables. Applicant argues Jing is not directed to therapeutic compositions or combination treatments.
The above arguments are not found persuasive. Applicant’s reasoning would render any combination of references that rely on in vitro and in vivo testing to be improper.
Jing et al. is expressly concerned with the study of COS because of its observed protective effects in treating inflammatory bowel disease. The gut-on-chip model was established to avoid the disadvantages of animal models, wherein animal models cannot accurately mimic human intestinal physiology. Jing et al. teach the gut-on-chip model is intended to allow researchers to quickly screen drugs in addition to COS to treat human IBD.
Additionally, Santos-Moriano et al. was cited for teaching the structure-function relationship of COS having different degrees of deacetylation/acetylation. Their anti-inflammatory activity was measured using in vitro models.
Rizzo et al. teach orally administering pomegranate extract to treat colitis and promote intestinal healing. Furthermore, Jing et al. cited their previous work Zheng 2018b, wherein they orally administered COS to mice (see Jing et al., first paragraph and Zheng 2018b, section 2.3).
Thus, while Jing et al. and Santos-Moriano et al. focus on in vitro testing, the ordinary artisan would have been motivated to formulate COS with pomegranate extract together in an oral dosage form, because Rizzo et al. teach treating inflammatory bowel disease with an oral composition and Jing et al. acknowledge the administration of COS in mice was effective in reversing dysbiosis of gut microbiota and protecting the barrier function. Thus, the ordinary artisan would have had a reasonable expectation of success.
Applicant contends the cited references use different biological pathways.
The above arguments are not found persuasive, since each component was individually known for treating inflammatory bowel disease, and improving gastrointestinal health.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
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).
For the above stated reasons, said claims are properly rejected under 35 U.S.C. 103(a). Thus, the rejection is hereby maintained.
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.
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.
Claim(s) 13, 14 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jing et al. (Frontiers in Cell and Developmental Biology, published 26 April 2022, vol.10, cited in previous Office Action) as evidenced by Zheng et al., 2018b (Carbohydrate Polymers, 2018, vol.190, pp.77-86, cited in previous Office Action) in view of Santos-Moriano et al. (Catalysts, 2019, vol. 9, 405, 12 pages, cited in previous Office Action), and further in view of Rizzo et al. (Nutrients, April 2023, vol. 15, no. 1771, 22 pages, cited in previous Office Action) and Valero-Cases et al. (Journal of Agricultural and Food Chemistry, 2017, vol. 65, pp. 6488-6496, cited in previous Office Action).
Jing et al. acknowledge chitosan oligosaccharides (COS) has a known protective effect on inflammatory bowel disease (IBD), (abstract). In an IBD model, Jing et al. found chitosan oligosaccharides (COS) can reduce intestinal epithelial injury by promoting the expression of the mucous layer (abstract). They found COS can protect the intestinal epithelial barrier and vascular endothelial glycocalyx barrier by inhibiting the adhesion and invasion of E. coli 11775 (abstract, p.6, first para). COS can also decrease inflammatory response by reducing the expression of toll-like receptor 4 protein (TLR4) and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein. Jing et al. disclose preparing COS by enzymatic hydrolysis and membrane separation as described by Zheng et al., 2018b (p.2, Preparation of COS). Jing et al. tested COS at a concentration of 10, 100, 500 and 1,000 µg/mL (fig. 4). Jing et al. also disclose COS at a concentration of 10-20 mg/kg/day can reduce the damage and inflammation of enteritis caused by DSS (p.2, first para).
As evidenced by Zheng et al., 2018b, the COS of Jing et al. has a polymerization degree, MW and degree of deacetylation that lies in the range of claim 14, alternative b. The COS has a MW < 1 kDa, a degree of deacetylation of 88%, and a degree of polymerization from 2-6. As evidenced by Zheng et al., 2018b, COS was prepared by enzymatic hydrolysis and separated with a membrane (p.78, 2.2. Preparation of COS). The chitosan was degraded by chitosanases in acetate buffer at pH 6 and at 40 °C. The reaction was terminated by decreasing the pH to 2.5 with HCl. COS less than 1 kDa were retained by semipermeable membrane. The deacetylation degree was 88%, and the degree of polymerization ranged from 2-6.
Jing et al. do not expressly disclose the degree of deacetylation (present claim 13). Jing et al. do not expressly disclose fermented pomegranate (present amended claim 13). Jing et al. do not expressly disclose a pharmaceutical oral dosage form comprising COS (present claims 20 and 22).
Santos-Moriano et al. disclose preparing three types of chitosan oligosaccharides (COS) with molecular weight (MW) between 200-1,200 Da (abstract): fully deacetylated (fdCOS), partially acetylated (paCOS), and fully acetylated (faCOS), (abstract). The size of COS (degree of polymerization), degree of deacetylation (DD), and pattern of acetylation (PA) affect their properties (p.1-2, bridging para). The bioactivity of COS is well reported, in particular their anti-inflammatory, neuroprotective, antibacterial, antiviral, antihypertensive, antiangiogenic and antitumor properties (p.1, last para). The fdCOS was determined to have a DD of between 95 and 100% (p.3, last para). The faCOS has a DD of between 0 and 5% (p.6, 2.2. Enzymatic Production and Characterization of faCOS). While Santos-Moriano et al. was not able to fully characterize the DD of paCOS, it was known that the paCOS was prepared from chitosan having a DD of 81% (p.5, 2.3. Enzymatic Production and Characterization of paCOS). Furthermore, Santos-Moriano et al. reference the work of another group who similarly tested the properties of COS having a DD of 50%, “50-COS, more related to paCOS” (p.8, first para). Anti-inflammatory activity was determined by preparing three concentrations of each compound: 500, 250, and 100 ng/well (p.9, 3.5. Anti-Inflammatory Activity of COS). The three types of COS were able to decrease the production of TNF-α at 6 h after stimulation with LPS (p.6, last para). Santos-Moriano et al. note fdCOS exhibited a negligible anti-inflammatory effect. “In contrast, paCOS (except for 100 ng/well) and faCOS displayed a more stable effect between 2 and 6 h. These results could be indicating a critical role of the acetamide group of COS in their properties” (p.6, last para).
Rizzo et al. teach pomegranate extract promotes mucosal homeostasis in patients with inflammatory bowel disease (IBD) “by affecting pathogen biofilm formation and favoring the regeneration of the intestinal barrier through the regulation of the crosstalk between epithelial and stromal cells” (abstract). Pomegranate functions as a prebiotic, as well as an antioxidant, bactericide, anticarcinogenic, and anti-inflammatory agent (p.2, first para). Rizzo et al. teach using 200 mg/kg whole extract of Punica granatum (PG), (section 3.1). The extract significantly reduced biofilm formation ability by S. epidermidis (p.11-12). Rizzo et al. attribute the bio-affective properties to the polyphenols present in pomegranate (p.17).
Valero-Cases et al. teach fermented pomegranate juices increased the bioavailability of phenolic compounds, ensuring the survival of lactic acid bacteria (LAB) after simulated gastrointestinal digestion, suggesting a possible prebiotic effect of phenolic compounds on LAB (abstract). Valero-Cases et al. found increased levels of phenolic compounds in the fermented juices (p.6490). A total of nine compounds were found, eight of which were the same as in the control juices. Microbial metabolites derived from fermented pomegranate juices and the high viability of microorganisms reaching the colon may contribute to the maintenance of gut health (p.6494, last para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine COS with fermented pomegranate.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, pomegranate extract promotes mucosal homeostasis in patients with inflammatory bowel disease (IBD), while COS can reduce intestinal epithelial injury by promoting the expression of the mucous layer in an IBD model.
Pomegranate extract, and fermented pomegranate are both rich in polyphenols, and are known to have a positive impact on gastrointestinal health. While Valero-Cases et al. only identified the prebiotic effect of fermented pomegranate, one having ordinary skill in the art would have expected it to have the same/similar properties of pomegranate extract as recognized by Rizzo et al. Specifically, one having ordinary skill in the art would have expected fermented pomegranate to also be useful in treating patients with IBD, by promoting mucosal homeostasis “by affecting pathogen biofilm formation and favoring the regeneration of the intestinal barrier through the regulation of the crosstalk between epithelial and stromal cells”.
It is further noted, COS protects the intestinal epithelial barrier and vascular endothelial glycocalyx barrier by inhibiting the adhesion and invasion of E. coli 11775; it can decrease inflammatory response by decrease the production of TNF-α, reducing the expression of toll-like receptor 4 protein (TLR4) and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein. Thus, the skilled artisan would have been motivated to combine the two drugs wherein they each produce different effects for improving gastrointestinal health.
The paCOS has a MW and DD that reads on the limitations of present claims 13 and 14. The 500, 250, and 100 ng/well of each compound in solution reads on the limitations of claims 20 and 21. One having ordinary skill in the art would have been motivated to formulate the COS and fermented pomegranate as an oral dosage form because they are both intended to exert their therapeutic effect in the gastrointestinal tract.
The ordinary artisan would have been motivated to modify the COS DD of Jing et al., because in the same field of endeavor in preparing COS derivatives having anti-inflammatory properties, Santos-Moriano et al. also teach the anti-inflammatory activity of COS is affected by factors including MW and DD.
Santos-Moriano et al. prepared COS having three different DD: fully acetylated COS, having a DD of 0% (faCOS), partially acetylated COS having a DD of about 50-81% (paCOS) and fully deacetylated COS having a DD of about 100% (fdCOS). While Santos-Moriano et al. were unable to fully characterize the DD of paCOS, the skilled artisan would have known the DD was at least less than 81%, since they started with chitosan having a DD of 81%. Additionally, Santos-Moriano et al. teach “50-COS, more related to paCOS”. Thus, for purposes of brevity, the paFOS will be referred to as having a DD of about 50-81%.
Santos-Moriano et al. found that COS having a DD of 0% (faCOS), about 50-81% (paCOS) and about 100% (fdCOS) were able to decrease the production of TNF-α at 6 h after stimulation with LPS. Additionally, Santos-Moriano et al. note fdCOS exhibited a negligible anti-inflammatory effect, while paCOS and faCOS displayed a more stable effect between 2 and 6 h. These results could be indicating a critical role of the acetamide group of COS in their properties” (p.6, last para).
Thus, one having ordinary skill in the art would have known the DD is a result-effective variable, wherein varying the DD modulates the anti-inflammatory effect of COS. Additionally, partial acetylation appears to be a favorable property. The prior art as a whole suggests an operable range of COS having a DD of about 50-90%, which overlaps with the claimed range.
See MPEP 2144.05 (II)(A) and (B) “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Jing et al., Santos-Moriano et al., Rizzo et al., and Valero-Cases et al. as applied to claims 13, 14 and 20-22 above, and further in view of Daniels et al. (US 2013/0273096, cited in previous Office Action).
Jing et al. teach as discussed above.
Jing et al. do not expressly disclose wherein the composition comprises rhamnan sulfate (claim 15).
Santos-Moriano et al., Rizzo et al. and Valero-Cases et al. teach as discussed above.
Daniels et al. teach a therapeutic dosage form useful for the treatment of a vascular or vessel-related disorder, comprising a sulfated polysaccharide (claim 18). The sulfated polysaccharide is useful for treating a glycocalyx-associated disorder (claim 15). The sulfated polysaccharide is rhamnan sulfate (claims 16 and 17). The polysaccharide can have molecular weights of about 500-500,000 Daltons or higher (para [0071]). And the rhamnan sulfate suppresses degradation of endothelial cells in the glycocalyx (claim 12). The polysaccharides are expected to limit endothelial dysfunction from processes that lead to pathological glycocalyx degradation and ineffective endogenous glycocalyx repair (para [0077]). “Various MWs and chain lengths incorporate into and diffuse within the extracellular matrix and glycocalyx of endothelial and other cells leads to broad effects and applications due to their protective and synergistic effects on the endogenous molecules of the regulatory glycocalyx structure and function” (para [0075]). The composition preferably contains 10-90 wt% rhamnan sulfate (para [0163]). Exemplary excipients include antioxidants, antimicrobial agents (para [0167]; [0169]). The composition can also further comprise vitamin C compounds (i.e. an antioxidant). Compositions comprising rhamnan sulfate can be formulated as oral dosage forms (para [0208]-[0211]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine COS with rhamnan sulfate.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, rhamnan sulfate suppresses glycocalyx degradation in the endothelial cells, while COS can reduce intestinal epithelial injury by promoting the expression of the mucous layer; it protects the intestinal epithelial barrier and vascular endothelial glycocalyx barrier by inhibiting the adhesion and invasion of E. coli 11775; it can decrease inflammatory response by decreasing the production of TNF-α, reducing the expression of toll-like receptor 4 protein (TLR4) and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein. Thus, the skilled artisan would have been motivated to combine the two drugs wherein they each produce different effects for the treatment of glycocalyx disorders.
One having ordinary skill in the art would have been motivated to formulate the COS and fermented pomegranate as an oral dosage form because they are both intended to exert their therapeutic effect in the gastrointestinal tract. Furthermore, Daniels et al. teach compositions comprising rhamnan sulfate can be formulated as oral dosage forms.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 16 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Jing et al., Santos-Moriano et al., Rizzo et al., and Valero-Cases et al. as applied to claims 13, 14 and 20-22 above, and further in view of Natividad et al. (Nutrients, 2020, vol. 12, no. 3047, 13 pages, cited in previous Office Action).
Jing et al. teach as discussed above.
Jing et al. do not expressly disclose 6’-sialyllactose (6’-SL), (present claims 16 and 24).
Santos-Moriano et al., Rizzo et al. and Valero-Cases et al. teach as discussed above.
Navidad et al. teach 6’-SL and combinations comprising 6’-SL modulate the intestinal barrier, promotes gut health, and protects against intestinal inflammatory disorders (abstract). Navidad et al. found the combination of 6 HMOs (2’FL, 3’SL, 6’SL, LNnT, LNT and DFL) dose-dependently strengthened the barrier to small solutes and ions, as assessed by the trans-epithelial resistance of the cell monolayers (p.9, second para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine COS with hMOs, including 6’SL.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, 6’SL and other major HMOs dose-dependently strengthened the barrier to small solutes and ions, as assessed by the trans-epithelial resistance of the cell monolayers, while COS can reduce intestinal epithelial injury by promoting the expression of the mucous layer; it protects the intestinal epithelial barrier and vascular endothelial glycocalyx barrier by inhibiting the adhesion and invasion of E. coli 11775. While HMOs promotes gut health, and protects against intestinal inflammatory disorders by modulating the intestinal barrier, COS can decrease inflammatory response by decreasing the production of TNF-α, reducing the expression of toll-like receptor 4 protein (TLR4) and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein. Thus, the skilled artisan would have been motivated to combine the two oligosaccharides wherein they each produce different effects on gastrointestinal health and inflammation.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 17 is rejected under 35 U.S.C. 103 as being unpatentable over Jing et al., Santos-Moriano et al., Rizzo et al., and Valero-Cases et al. as applied to claims 13, 14 and 20-22 above, and further in view of Van Dijk et al. (US Patent Application Publication No. 2010/0196539, cited in previous Office Action).
Jing teaches as discussed above.
Jing does not expressly disclose sialic acid (present claim 17).
Santos-Moriano et al., Rizzo et al. and Valero-Cases et al. teach as discussed above.
Van Dijk et al. teach sialic acids comprise a family of about 40 derivatives of neuraminic acid (para [0023]). Sialic acid in combination with other oligosaccharides can be used as prebiotics (para [0027]; para [0113]-[0114]). Free sialic acid is preferably present in an amount of more than 1 wt.% of the total amount of oligosaccharide and free sialic acid (para [0058]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine COS with sialic acid.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, sialic acid containing compositions can function as a prebiotic in combination with oligosaccharides, while COS (an oligosaccharide) can reduce intestinal epithelial injury by promoting the expression of the mucous layer; it protects the intestinal epithelial barrier and vascular endothelial glycocalyx barrier by inhibiting the adhesion and invasion of E. coli 11775; it can decrease inflammatory response by decreasing the production of TNF-α, reducing the expression of toll-like receptor 4 protein (TLR4) and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein. Thus, the skilled artisan would have been motivated to combine the two drugs wherein they each produce different effects for improving gastrointestinal health.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAHAR A CRAIGO whose telephone number is (571)270-1326. The examiner can normally be reached M-F: Noon-8pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
Prosecution Insights