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 .
Claim Status
Claims 1, 11, 13-21 and 26 are pending.
Claims 1, 11, 13-20 and 26 are currently amended.
Claims 2-10, 12 and 22-25 have been canceled.
Claims 1, 11, 13-21 and 26 are currently under consideration.
Claims 1, 11, 13-21 and 26 are rejected.
Acknowledgement of Receipt
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/26/2025 has been entered.
Withdrawn Objections/Rejections
The objections to claim 20 for the use of an acronym is withdrawn.
In light of the new amendments, the rejection of claim 13 under 35 U.S.C. § 112(b) as being indefinite is withdrawn.
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 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.
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. Applicants are 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.
Applicant Claims
The instant claims are directed to a method of treating or preventing Crohn’s disease comprising the administration of a therapeutically effective amount of rebamipide and at least one other drug effective against Crohn’s disease, wherein the method further comprises: (a) initiating administration of rebamipide while the subject is receiving said at least one other drug; (b) decreasing the dose of said at least one other drug, either concurrently with the initiation of rebamipide administration or subsequent to the observation of clinical symptom improvement in the subject; and (c) discontinuing administration of said at least one other drug upon reaching disease remission in the subject (instant claim 1). The said at least one other drug is a corticosteroid, 20 to 60 mg (instant claim 15), wherein rebamipide is used in a subject suffering from or is at risk of increased intestinal permeability (instant claim 16) and wherein rebamipide is administered in an oral pharmaceutical form (instant claim 21) in a daily dose of 300-600 mg (instant claim 26).
Claim(s) 1, 11, 13-20 and 26 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Furuta et al. (Rebamipide Enema Therapy as a Treatment for Patients with Active Distal Ulcerative Colitis. Journal of Gastroenterology and Hepatology 22 (2007) 261–267) in view of Rutgeerts et al. (A Comparison of Budesonide with Prednisolone for Active Crohn’s Disease. The New England Journal of Medicine, 331(13):842-845, 09/29/1994) and further in view of Phillips et al. (US 2019/0224324 A1, filed 04/02/2019), herein referenced Furuta, Rutgeerts, and Phillips.
Furuta provides a method comprising rebamipide topically applied to persistently inflamed mucosa in patients with ulcerative colitis (UC) who had received corticosteroids for more than 2 weeks without success (pg. 261, col. 1, para. 3). Furuta discloses a method in which rebamipide {2-(4-chlorobenzoylamino)-3[2-(1H)-quinolinon-4-yl] propionic acid} was obtained as an enema in a pressurized canister suitable for rectal application and contained 150 mg Rebamipide suspended in 60 mL 1.5% carboxymethylcellulose dissolved in saline solution (pg. 262, see Methods). All patients were receiving 5-amino salicylic acid (1.5–2.25 g/day) in combination with prednisolone (20–40 mg/day) at the time of entry (pg. 263, col. 1, para. 1) to read instant claims 13-15. Treatments of rebamipide enema therapy twice a day for 3 weeks, during which prednisolone doses were kept constant (pg. 263, col. 1, para. 1) to read on element (a) of instant claim 1 and on instant claim 26. The clinical activity index (CAI) was measured as a clinical assessment of disease activity before treatment and at 3 weeks after the initiation of Rebamipide enema therapy (pg. 262, col. 1, para. 4). No patients discontinued rebamipide enema therapy because of side-effects, and no hematological toxicity or biochemical changes related to liver or renal function were observed (pg. 263, col. 1, para. 1) to read on instant claim 11.
Furuta provides results to show that the mechanism of action of rebamipide is distinct from the mechanism action of corticosteroids (IL-1/IL-1ra v. IL-8) (pg. 265, col. 2, para. 1) and that when taken together, and as rebamipide affects non-immune cells, it may down-regulate the interplay between immune and non-immune cells and attenuate the chronically perpetuated inflammation to provide an improvement in wound healing and suppression of intestinal inflammation (pb. 266, col. 1, para. 1).
Furuta does not mention Crohn’s disease (CD). However, UC and CD are both inflammatory bowel diseases (IBD) that affect the gastrointestinal tract and treatments thereof share the same primary goal which is to reduce inflammation. Furuta explicitly teaches that rebamipide attenuates local inflammatory responses in the gut (pg. 264, col. 2, see Discussion). Thus, one skilled in the art would strongly consider treatment plans that would include rebamipide to address IBD associated inflammation.
Rutgeerts discloses a study in which patients with active Crohn’s disease are treated with 9 mg per day doses of budesonide and 40 mg per day of prednisolone (abstract). Results show that budesonide is particularly suited for topical intestinal therapy because its affinity for the corticosteroid receptor is 15 times that of prednisolone and its systemic bioavailability is low (pg. 8944, col. 2, para. 3). The Crohn's disease activity index decreased more in the prednisolone group than in the budesonide group and suggests that topical therapy is as rapidly effective as systemic therapy (pg. 845, col. 2, para. 1). Rutgeerts shows that prednisolone has a more powerful systemic effect compared to budesonide (pg. 845, col. 2, para. 1). Although budesonide therapy is associated with fewer side effects, Rutgeerts concludes that both controlled-release budesonide and prednisolone are effective in inducing remission in patients with active Crohn's disease (pg. 845, col. 2, last para.).
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 apply the method to treat Crohn’s taught by Rutgeerts in the method to treat UC taught by Furuta with expected results. One would be motivated to do so with a reasonable expectation of success because Rutgeerts shows that the corticosteroid utilized by Furuta, prednisolone, is more effective compared to another corticosteroid in being effective in improving systemic well-being and stimulating weight gain (pg. 845, col. 1, para. 2 – col. 2, para. 1).
Furuta does not teach decreasing or discontinuing dosages of the corticosteroid.
Phillips discloses methods for treating, preventing or alleviating the symptoms of and inflammation associated with inflammatory diseases and conditions of the gastrointestinal tract to include Crohn’s disease ([0114]), in an individual comprising orally administering pharmaceutical compositions comprising a corticosteroid and a mucoadhesive agent (claim 1).
Phillips teaches that initial treatment may continue for a certain length of time and then the patient is taken off the drug for a period before treatment resumes again, and in certain embodiments, patients are given treatment with a higher dose of the composition until a desired reduced disease state is achieved, and then continued on a on a lower dose of the composition ([0078]). Phillips teaches that an at least one additional active agent may be administered in association with or in combination with the corticosteroid being administered ([0132]), is not a second corticosteroid, and can be a proton pump inhibitor (PPI) or a mucosal protectant ([0133]). The corticosteroid and the least one additional active agent can be in single or separate dosage forms; administered simultaneously, sequentially, or at different times, e.g., several doses of a corticosteroid composition are administered over a period of time, after which administration of the corticosteroid composition is discontinued and administration of at least one additional active agent is administered at least once ([0132]).
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 apply the methods taught by Phillips to the teachings of Furuta in view of Rutgeerts with expected results. One would be motivated to do so with a reasonable expectation of success because Philips provides methods that tailor to the patients’ needs with the suggestion that corticosteroids with decreased side effects and complications will enable patients with chronic conditions to receive treatment for longer periods of time ([0106]). This teaching resonates with Furuta’s aim to assess the clinical efficacy and safety of a method and with Rutgeerts’ teaching that fewer side effects are associated with corticosteroids that have low systemic bioavailability (pg. 845, col. 2, para. 1). The prior art teaches and suggests that adaptable methods are important when considering risks and benefits of administering corticosteroids with an active agent (e.g., mucosal protectant, i.e., rebamipide) in order to meet the needs of the patient to ameliorate symptoms and conditions, acute and/or chronic; localized and/or systemic. Further, an artisan would understand mucosal protectant taught by Phillips to indicate the cytoprotective agent taught by Furuta that overlaps with the claimed rebamipide.
Regarding claims 16-20, the prior art is silent regarding the treatment of persons suffering from Crohn’s disease, additional conditions or exposed to substances associated with increased intestinal permeability. However, the treatment of said persons will inevitably flow from the teachings of Furuta, Rutgeerts, and Phillips, since the same compound (rebamipide) is being administered to the same subjects suffering from Crohn’s thus also suffering from increased intestinal permeability. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
Even though the prior art is silent regarding the treatment of a subject suffering from increased intestinal permeability or at risk of increased intestinal permeability, by practicing the method taught by the prior art: “preventing or treating Crohn’s disease comprising administering a therapeutically effective amount of rebamipide," one will also be treating those suffering from conditions associated with increased intestinal permeability. While Applicant express that they have discovered a new property or advantage (treating persons suffering from increased intestinal permeability) of the method taught by (“preventing or treating Crohn’s disease comprising administering a therapeutically effective amount of rebamipide," MPEP 2112(I.) states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.
Claim(s) 21 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Furuta in view of Rutgeerts and Phillips as applied to claims 1, 11, 13-20 and 26 above, further in view of Kinoshita et al. (JP 2010001242 A, pub. 01/07/2010, MT Espacenet) evidenced by Nakashima et al. (Digestive Diseases and Sciences, Vol. 50, Supplement 1 (October 2005), pp. S124-S131), herein referenced Kinoshita and Nakashima, respectively. Citations from Kinoshita are taken from the translation provided.
The teachings of Furuta in view of Rutgeerts and Phillips above are incorporated herein.
Furuta cites pharmacokinetic studies showing the maximum level of rebamipide in gastric mucosal tissue is 10-fold higher than the blood concentration after oral intake of a normal clinical dose (pg. 264, col. 2, see Discussion).
Furuta does not disclose a method wherein the rebamipide is administered in an oral pharmaceutical form selected from any of the species of claim 21 (i.e., tablets).
Kinoshita discloses solid preparation of rebamipide comprising a pharmacologically effective amount of rebamipide and a pharmacologically acceptable additive (abstract, [0001], claim 1). Kinoshita main objective is to provide a solid preparation of rebamipide that contains a high content of rebamipide active ingredient and has excellent disintegration and dissolution properties, in order to realize miniaturization of rebamipide tablets ([0006]). Generally, when the weight and size of a tablet are reduced while keeping the content of the active pharmaceutical ingredient in one tablet the same, it becomes necessary to reduce the amounts of additives such as disintegrants and binders, making it difficult to obtain a tablet that exhibits appropriate disintegration and dissolution properties. For this reason, the rebamipide content in one 176 mg tablet of conventionally available rebamipide tablets has remained at approximately 60% by weight (100 mg) ([0010]). Dosage forms include oral preparations such as effervescent tablets, fast dissolving tablets, matrix tablets, multi-layer tablets, sustained release tablets, pills, capsules, granules or powders in sachets or bottles ([0029]). Kinoshita provides a rebamipide tablet that contains 50 to 500 mg of rebamipide, preferably 90 to 120 mg, and more preferably 100 mg of rebamipide ([0032]).
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 apply the rebamipide table taught by Kinoshita in the method of Furuta in view of Rugeerts and Phillips with expected results. One would be motivated to do so with a reasonable expectation of success because Kinoshita provides rebamipide tablets that are easy to take even for elderly people, patients with swallowing disorders, and patients who take multiple tablets simultaneously, which can contribute to improving patient compliance in the fields of geriatric medicine and pediatric medicine ([0074]). The oral dose of rebamipide, being an easier mode of administration, improves upon Furuta. As mentioned above, Furuta suggests that concentrations are higher in the blood after a clinical dose of oral rebamipide. As evidenced by Nakashima, when compared between oral and enema administration of rebamipide, the intra-rectal dose was more than 10 times lower than oral doses (pg. S128, col. 2, para. 1) to suggest increased delivery.
For the foregoing reasons the instant claims are rendered obvious by the teachings of the prior art.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 11, 13-21 and 26 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Claims 1, 11, 13-21 and 26 are rejected; no claims are currently allowable.
The Examiner asks Applicant to provide support for the amendments in the application disclosure by referencing page numbers, paragraphs, figures, etc. for the sake of compact prosecution.
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 900-500 ET.
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/Karen Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614