DETAILED ACTION
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 .
Status of the Application
Claims 1-2, 4-8, 11-14, 18-19, and 22-23 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 06/03/2026 are acknowledged. Claims 18-19 remain withdrawn, as being drawn to an unelected invention or specie. Claims under consideration in the instant office action are claims 1-2, 4-8, 11-14, and 22-23.
Applicants' arguments, filed 06/03/2026, have been fully considered but they are not deemed to be persuasive. The rejection of claims 1-2, 4-8, 11-14, and 22-23 under 35 U.S.C. 112 is withdrawn due to Applicant’s amendments. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4-6, 8, 11-14, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Ruseler-van Embden et al. (US 6,723,354, as disclosed in IDS) in view of Vidal et al. (Crohn associated mcrobial communities associated to colonic mucosal biopsies in patients of the western Mediterranean, Systematic and Applied Microbiology, 2015, 38, pp. 442-452) and Denadai-Souza et al. (Functional Proteomic Profiling of Secreted Serine Proteases in Health and Inflammatory Bowel Disease, Scientific reports, 2018, 8(1), pp. 1-9, already of record).
Ruseler-van Embden et al. teaches methods for treating or reducing inflammation by inhibiting proteolytic activity (see abstract). Ruseler-van Embden et al. teaches that “treatment is provided for an inflammation which is intestinal, perineal or peristomal, as is, for instance, seen with babies or infants with diaper rash, with children or adults with diarrhoea or fecal incontinence, with patients with inflammatory bowel syndrome and with stoma patients, which all suffer from the effects of proteolytic activity which is mainly fecal.” (col. 3, lines 21-27), which thus demonstrates a method of treating inflammatory bowel disease. Ruseler-van Embden et al. teaches “Fecal samples from twenty-seven patients with Chron's disease (CD) were studied. Twelve patients, aged 27-58 years, had undergone intestinal surgery 3---12 years previously; locations of the resections were terminal ileum, ileum and cecum, and colon. A second group of patients was not operated; the principal sites of inflammation were ileum, ileum and colon, and colon. The diagnosis CD was established with the usual clinical, radiological and histopathological criteria.” (col. 8, lines 33-41). Ruseler-van Embden et al. teaches providing treatment comprising administering a protease inhibitor (col. 3, lines 51-55), which target proteases caused by bacteria (col. 5, lines 29-37). Regarding claim 8, Ruseler-van Embden et al. teaches “Table 1 shows that patients with CD, ileostomy patients and patients with a pouch (with and without pouchitis) have a high proteolytic activity. “Regarding claims 11-13, Ruseler-van Embden et al. teaches that “Treatment of fecal proteolytic activity can occur by applying the inhibitor in an ointment, cream, gel, powder, or any other suitable form, to the perineal or peristomal location of the inflammation. Intestinal inflammations, such as seen with IBD or pouchitis, can be treated by rinsing the affected location in the digestive tract by, for example, administering an enema, or can be administered orally, preferably in a pharmaceutical composition such as a draught or mixture pill, that can pass relatively unaffected through the esophagus and stomach.” (col. 3, lines 29-37).
Ruseler-van Embden et al. does not teach administering a protease inhibitor that targets a protease expressed by a pathogenic bacterium selected from Bacteroides vulgatus and Bacteroides dorei.
Vidal et al. is drawn towards Crohn associated microbial communities (see abstract). Vidal et al. teaches that Bacteroides vulgatus and Bacteroides dorei were present in abundance in Crohn’s disease patients (see abstract; pg. 446, 1st and 3rd paragraph).
Denadai-Souza et al. is drawn towards the profiling of serine proteases in inflammatory bowel disease (pg. 1, first paragraph). Denadai-Souza et al. teaches “in intestinal pathophysiological contexts such as inflammatory bowel disease (IBD), proteolytic homeostasis can be disrupted in tissues. Increased serine protease activity has been demonstrated in colonic tissues from Crohn’s disease (CD) or Ulcerative Colitis (UC) patients” (pg. 1, third paragraph). Denadai-Souza et al. teaches AEBSF as a broad spectrum protease inhibitor (Fig. 1).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to administer a protease inhibitor that targets a protease expressed by a pathogenic bacterium selected from Bacteroides vulgatus and Bacteroides dorei, as suggested by Vidal et al. and Denadai-Souza et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Denadai-Souza et al. teaches that increased serine protease activity is present in IBD’s such as CD and UC, and Vidal et al. teaches Bacteroides vulgatus and Bacteroides dorei as the most prominent bacterioides in CD (pg. 446, 1st paragraph), with a reasonable expectation of success absent evidence of criticality of the particular steps.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ruseler-van Embden et al. (US 6,723,354), Vidal et al. (Crohn associated mcrobial communities associated to colonic mucosal biopsies in patients of the western Mediterranean, Systematic and Applied Microbiology, 2015, 38, pp. 442-452), and Denadai-Souza et al. (Functional Proteomic Profiling of Secreted Serine Proteases in Health and Inflammatory Bowel Disease, Scientific reports, 2018, 8(1), pp. 1-9) as applied to claims 1-2, 4-6, 8, 11-14, and 22-23 above, and further in view of Kozuch (Treatment of inflammatory bowel disease: A review of medical therapy, World Journal of Gastroenterology, 2008, 14(3), pp. 354-377).
The teachings of Ruseler-van Embden et al., Vidal et al., and Denadai-Souza et al. above.
Ruseler-van Embden et al., Vidal et al., and Denadai-Souza et al. do not teach further administering a non-specific immunosuppressive agent, such as a steroid.
Kozuch is drawn towards various treatment for inflammatory bowel diseases (pg. 354, Introduction). Kozuch teaches that “Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; nonsystemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease.” (see abstract).
It would have been obvious to one of ordinary skill in the art to further administer a non-specific immunosuppressive agent, such as a steroid, as suggested by Kozuch, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[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).
Therefore, it would have been prima facie obvious to combine a protease inhibitor and a steroid in a composition cojointly to treat inflammatory bowel disease.
Response to Arguments
Applicant's arguments filed 06/03/2026 have been fully considered but they are not persuasive.
Applicant argues that “It does not motivate the artisan to inhibit proteases expressed by a specific bacterial genus or species that none of the references implicates as relevant. The Office's reasoning therefore impermissibly relies on hindsight, using claim 1 as a roadmap to weave together Ruseler-van Embden's generic teaching about fecal proteolytic activity, Denadai-Souza's host-protease profiling, and Paszti-Gere's host-matriptase mechanistic study to arrive at the bacterial-target limitation that none of the references discloses, suggests, or contemplates… none of the cited references - Ruseler-van Embden, PasztiGere, or Denadai-Souza - teaches or suggests that proteases secreted by B. vulgatus or B. dorei are drivers of UC or CD pathology, which is the essential bacterial-target limitation now recited in amended independent Claim 1.” The Examiner respectfully disagrees since Fujita et al. is drawn towards an analysis of bacterial DNA in tissue samples from patients with inflammatory diseases, and teaches B. vulgatus as a prominent Bacteroide in inflammatory bowel diseases (see abstract).
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).
Applicant also argues that “the alleged motivation to combine these references is legally insufficient because, at most, it would have led one of ordinary skill to inhibit the host derived proteases catalogued by Denadai-Souza (thrombin, cathepsin G, plasma kallikrein, plasmin, tryptase, and others), not the bacterial proteases that Applicant was the first to identify as pathologically relevant.” The Examiner respectfully disagrees since Vidal et al. teaches that Bacteroides vulgatus and Bacteroides dorei were present in abundance in Crohn’s disease patients (see abstract; pg. 446, 1st and 3rd paragraph). Given that Ruseler-van Embden teaches that “Bacteria, either as primary causal agent or during a secondary infection, and other pathogenic microorganisms, secrete proteases that damage the surrounding tissue for their purposes.” (col. 1, lines 32-35), one of ordinary skill in the art would have been motivated to administer a serine protease inhibitor that targets a protease expressed by a pathogenic bacterium selected from Bacteroides vulgatus and Bacteroides dorei.
Applicant also argues that “Far from motivating one of ordinary skill to administer AEBSF ( or any serine protease inhibitor) to treat UC or CD, Paszti-Gere would have discouraged such use, because it teaches that serine protease inhibition compromises intestinal barrier function. The Office's selective citation of a single sentence in the bridging paragraph at pp. 739-740 of Paszti-Gere - taken out of the context of an article whose central message is that matriptase activity is required for barrier integrity-cannot supply the requisite motivation to combine.” The Examiner respectfully disagrees since Denadai-Souza et al. teaches AEBSF as a broad spectrum protease inhibitor (Fig. 1).
Applicant also argues that “Applicant's Specification documents unexpected results: the discovery that approximately 40% of UC patients are "overproducers" of Bacteroides proteases, that B. vulgatus and B. dorei are uniquely pathogenic among Bacteroides species, and that protease inhibition rescues barrier function and attenuates disease severity both in vitro and in vivo. These unexpected findings flow from a mechanism that none of the cited references contemplated or suggested.” The Examiner respectfully disagrees since Ruseler-van Embden teaches that “Bacteria, either as primary causal agent or during a secondary infection, and other pathogenic microorganisms, secrete proteases that damage the surrounding tissue for their purposes.” (col. 1, lines 32-35). Vidal et al. teaches that Bacteroides vulgatus and Bacteroides dorei were present in abundance in Crohn’s disease patients (see abstract; pg. 446, 1st and 3rd paragraph). One of ordinary skill in the art would thus expect that inhibition of the proteases produced by Bacteroides such as Bacteroides vulgatus and Bacteroides dorei
Conclusion
1-2, 4-8, 11-14, and 22-23 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
