Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
Claims 1, 11, 15, 21 and 26 are pending.
Claims 2-10, 12, 16-20, and 22-25 have been canceled.
Claims 1, 11, and 21 have been amended.
Claims included in the prosecution are claims 1, 11, 15, 21 and 26.
The Examiner notes that the status identifier for claim 21 should be “(Currently Amended)”. For the manner of making amendments and the required format, see the applicable U.S. regulations, in particular 37 CFR 1.121 and 1.125.
New Rejections
Applicants’ amendments have necessitated the following grounds of rejection:
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. § 103 (a) are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 11, 15, 21 and 26 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Lichtenstein (Approach to corticosteroid-dependent and corticosteroid-refractory Crohn’s disease. Inflammatory Bowel Diseases. Vol. 7, Suppl. 1:S23-S29, May 2001), Harty (US 20050159396 A1), and Furuta (Rebamipide Enema Therapy as a Treatment for Patients with Active Distal Ulcerative Colitis. Journal of Gastroenterology and Hepatology, 22 (2007) 261–267, previously cited) herein referenced Lichtenstein, Harty, and Furuta.
Lichtenstein teaches corticosteroids are a drug of choice for the treatment of patients with moderately to severely active Crohn's disease (CD), an inflammatory bowel disease characterized by chronic recurrent flares of disease activity (summary). However, among patients receiving corticosteroid therapy for induction of remission, 20% have corticosteroid-refractory disease and 36% of those with an initial response develop corticosteroid dependency within l year (summary). Chronic corticosteroid exposure in patients who are dependent on corticosteroids increases the risk for serious drug-related adverse effects (summary). Withdrawal or reduction of corticosteroid therapy without exacerbation of symptoms is therefore recognized as an important goal of treatment (summary). To emphasize, corticosteroid therapies are associated with high risk of dependence, lack of maintenance benefits, toxicities (see Table 1), and adverse effects (see Table 2). The tapering of corticosteroid therapy is “steroid sparing” and can result in relapse (page S23, column 1, paragraph 1). Lichenstein discusses the use of immunomodulators to prevent relapses in patients with temporarily inactive CD (page S24, column 2, paragraph 1). Lichtenstein warns that although conventional corticosteroid therapy effectively induces remission of moderately to severely active CD, its benefits should be weighed against the high risk of dependence, toxicity and ineffectiveness as maintenance therapy (bridging pages S27-S28). While Lichtenstein draws attention to specific immunomodulators, the prior art suggests that they be used as alternative agents in the replacement of corticosteroids, i.e., steroid sparing (page S28, column 1, paragraph 1).
Lichtenstein differs from the claimed invention insofar rebamipide is not mentioned.
However, Harty is provided to show that it is known to administer rebamipide for treatment of Crohn’s disease (CD).
Harty discloses a composition for the inhibition or treatment of inflammatory bowel diseases (IBD) or other inflammatory diseases comprising 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt or ester thereof; at least one antioxidant; and a pharmaceutically acceptable carrier (claim 1) wherein the antioxidant is selected from the group consisting of amino salicylates including rebamipide (see composition, claim 4; method of treating, claim 8). Harty aims to reduce inflammation and promote healing ([0006]) by providing a combination of 5-ASA with an antioxidant ([0057]). Although Harty is focused on N-acetylcysteine (NAC), rebamipide is taught as an antioxidant ([0058]). The combination therapies can be delivered orally ([0055]) or directly to the colon ([0014]). Harty discloses that the combination acts synergistically to cause a significant reduction in macroscopic injury ([0036]), reduce the degree of epithelial damage, the extent of mucosal ulceration and the amount of mononuclear cell infiltration ([0041]), and produce a significantly greater degree of healing than either NAC or 5-ASA alone ([0043]). As the disease involves multiple pathways being affected (see Table 2), the prior art aptly suggests a combination-therapy approach. As such, one skilled in the art knowing the synergistic effects that result and harm reduction is not a singular pathway, one would have been motivated to utilize rebamipide in such combination therapies.
While Harty teaches that there is a need for a reduction in the use of corticosteroids, e.g., prednisolone, as anti-inflammatory agents, because they are costly and can bring about drug-induced toxicity ([0013]) does not explicitly teach a method in reducing the corticosteroid.
However, Furuta is provided to show that it would be useful in reducing and then eliminating the corticosteroid.
Furuta discloses immunomodulators in the tapering of corticosteroids for patients with IBD, specifically UC. Furuta states, “Immunomodulatory treatment is now accepted as corticosteroid-sparing therapy for UC patients. Rebamipide {2-(4-chlorobenzoylamino)-3[2-(1H)-quinolinon-4-yl] propionic acid}, a cytoprotective agent originally used for the treatment of gastritis and gastroduodenal ulcers, has been suggested to suppress immune responses and neutrophil activation in vitro, and has been shown to be effective in alleviating intestinal inflammation in animal colitis models,” (see page 262, column 1, paragraph 2). Furuta conducts a study in which topical application (via an enema) of rebamipide to persistently inflamed mucosa in patients with UC that had received corticosteroids for more than 2 weeks without success. In order to determine the clinical efficacy of rebamipide, the study looked at histological parameters and inflammatory cytokine levels in the rectal mucosa before and after treatment (page 262, see the last paragraph of Introduction section).
Methods of Furuta provide rebamipide (150 mg) suspended in 60 mL 1.5% carboxymethyl-cellulose dissolved in saline solution (page 262, see Methods) and administers it to patients who were receiving 5-ASA (1.5–2.25 g/day) in combination with prednisolone (20–40 mg/day) at the time of entry (page 263, see Clinical Response). Prednisolone doses are kept constant while twice per day for 3 weeks of administering rebamipide (page 263, column 1, paragraph 1).
With respect a Crohn’s disease activity index (CDAI) of less than 150 points, Lichtenstein teaches with respect to the immunomodulators that a corticosteroid-sparing effect is demonstrated as placebo-controlled studies of patients with moderately to severely active CD demonstrated that related immunomodulators enabled the withdrawal of corticosteroids after induction of remission and increased the rate of maintenance of remission with less corticosteroid use (page S25, column 2, paragraph 1). Throughout the reference Lichtenstein teaches remission being defined as a CDAI score of less than 150 (page S26, column 1, paragraph 1).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to combine the teachings of Lichtenstein, Harty, and Furuta and arrive at a method for treating active severe CD refractory to corticosteroid therapy. One would be motivated to do so because Lichtenstein teaches the replacement of corticosteroids with immunomodulators. Similarly Harty teaches antioxidants e.g., rebamipide, to improve long term health outcomes. Furuta demonstrates that the use of rebamipide, known as a cytoprotective agent, can effectively be used in immunomodulatory treatment (corticosteroid-sparing therapy) as it “attenuates local inflammatory responses in the gut” (page 264, column 2, see Discussion).
Regarding claim 11, Furuta teaches that no patients discontinued rebamipide because of side-effects, and no hematological toxicity or biochemical changes related to liver or renal function were observed (page 263, column 1, paragraph 1). Rebamipide attenuates the chronically perpetuated inflammation to provide an improvement in wound healing and suppression of intestinal inflammation (page 266, column 1, paragraph 1).
Regarding claim 15 (i.e., 20 to 60 mg corticosteroid), as mentioned above Furuta teaches prednisolone 20-40 mg to fall within the claimed range. MPEP 2144.05 states that a prima facie case of obviousness exists in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art.
Regarding clam 21, Harty teaches that for oral administration, the compounds can be formulated into solid or liquid preparations such as tablets ([0072]).
Regarding claim 26 (i.e., 300 to 600 mg), Furuta teaches 150 mg of rebamipide delivered to patients twice a day for 3 weeks (page 263, column 1, paragraph 1) extrapolates to 300 mg thereby falling within the claimed range.
Response to Arguments
Applicants’ arguments are based on newly amended limitations which have been addressed by the new grounds of rejection above.
Applicants’ arguments have been fully considered but they are not persuasive.
Applicants argue that results relating to Ulcerative colitis cannot be extrapolated to Crohn’s disease (Remarks, page 9, number 2); as IL-8 plays a central role in neutrophil recruitment mucosal injury, and maintenance of chronic inflammation in Crohn’s, Furuta reports IL-8 did not change (page 6, paragraphs 3-5). Applicants argue that Rebamipide is not an anti-inflammatory drug. Its principal mechanism of action is associated with mucin production, making its therapeutic profile materially different from that of conventional anti-inflammatory agents (page 10, number 8).
In response to the above arguments, Furuta teaches that mucosal IL-1ra/IL-1β ratio has a significant negative correlation with the degree of inflammation in inflammatory bowel disease (see page 265, column 2, paragraph 1). Furuta provides results with an increased ratio of IL-1 receptor antagonist/IL-1 β (abstract). As evidenced by Strober (Pro-Inflammatory Cytokines Underlying the Inflammation of Crohn’s Disease, Curr Opin Gastroenterol. 2010 July; 26(4): 310–317), IFN-γ (one of the cytokines named by applicant in the remarks) is a major pro-inflammatory cytokine in Crohn’s disease although it may arise from both the Th1 and Th17 cell-mediated responses at different phases of the inflammatory process (abstract). While IL-8 did not change, this is not teaching away from the use of rebamipide in the treatment of Crohn’s.
Applicants argue that Rutgeerts and Phillips do not disclose rebamipide (Remarks, page 10, number 6; page 8, paragraphs 2-3).
Rutgeerts and Phillips are no longer used.
Applicants argue that the claimed invention contributes to clinical development, reduces costs, and already has patent protection in Europe and Japan (bridging pages 11-12).
Applicants’ arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
For these reasons, Applicants’ arguments are found unpersuasive.
Conclusion
All claims under consideration remain rejected; no claims are allowed. Applicants’ amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicants are 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no case, 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 Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 0830-1630.
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/Karen A Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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