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 .
Priority
This application, filed 11/18/2022 is a Continuation of 16486464, filed 08/15/2019, now U.S. Patent # 11534424. 16486464 is a National Stage entry of PCT/US2018/000091, International Filing Date: 02/16/2018. PCT/US2018/000091 Claims Priority from Provisional Application 62459916, filed 02/16/2017; Priority from Provisional Application 62502129, filed 05/05/2017; and Priority from Provisional Application 62506906, filed 05/16/2017.
Status of Claims
Claims 1, 3-4, 6-7, 15, 17-24, 32, and 41-46 are currently pending. Claims 2, 5, 8-14, 16, 25-31, and 33-40 have been canceled.
Claims 1, 3-4, 6-7, 15, 17-24, 32, and 41-46 were examined and are rejected.
Claim Objections
Claims 32, 42-43, and 46 are objected to because of the following informalities: the biomarker “anti-splOO” should be “anti-sp100”. Appropriate correction is required.
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.
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) 1, 3-4, 6-7, 15, 17-24, 32, 41-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et. al., US 20110130409 (publ 6/2/2011), in view of Kaneko et. al., US 20090253802 (publ. 10/8/2009); and further in view of Cheung et. al., Aliment. Pharmacol. Ther., vol. 43, pp. 283-293, publ. online 11/12/2015. All references were cited in the IDS.
Jones teaches substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives and pharmaceutical salts thereof as agonists of the S1P1 receptor, for treating S1P1-associated disorders (see Title; Abstract; para [0001]). The 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivative S1P1 agonists, or pharmaceutical salts, hydrates, or solvates thereof are taught to have the following structural formula (para [0030-0036]):
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. Jones discloses the compound (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid (p. 15, Table A, see compound 3; p. 17, see compound 12), and exemplifies this compound, including as the L-arginine salt (p. 20, see para [0342-0343]). 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid as the L-arginine salt in crystalline form is taught (para [0154]). S1P1 associated disorders to be treated include biliary cirrhosis and autoimmune diseases (Title; p. 4, para [0045]; p. 6, para [0074], [0100]; p. 7, para [0128]). Tablets and capsules, with suitable excipients, for oral administration are taught (p. 21, para [0347]). Effective doses are taught to range from about 0.001-5000 mg., with a range of 0.001-25 mg exemplified, in one or multiple doses per day (p. 21, para [0355]; p. 22, para [0357]). As Jones teaches the compound can be solvated or hydrated, it would have been prima facie obvious that Jones also encompasses the compound in non-solvated or anhydrous form, including anhydrous, non-solvated crystalline (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid as the L-arginine salt.
Jones doesn’t explicitly teach treating primary biliary cholangitis or primary biliary cirrhosis, previous or concurrent treatment with UDCA, or assessment of one or more of the recited biomarkers.
Kaneko teaches S1P1 receptor agonists for treating liver diseases such as primary biliary cirrhosis (Abstract; para [0018], [0049]).
It would have been prima facie obvious to one of ordinary skill in the art, at the time of the invention, to have treated an individual in need of treatment for primary biliary cholangitis or primary biliary cirrhosis, in view of the teachings of Jones and Kaneko. Jones teaches the compound of the instant claims as a S1P1 agonist and in the form of the L-arginine salt, including crystalline, hydrated or solvated forms, for treating autoimmune diseases and biliary cirrhosis, while Kaneko teaches different S1P1 agonists for treating primary biliary cirrhosis. As (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid, or otherwise known as compound 1 is taught as an S1P1 agonist, it would have been prima facie obvious to one of ordinary skill in the art to have administered an effective amount of this compound to a subject in need of treatment for primary biliary cirrhosis or primary biliary cholangitis, with a reasonable expectation of success.
Neither Jones nor Kaneko explicitly teach previous or concurrent treatment with UDCA, or assessment of one or more of the recited biomarkers.
Cheung teaches primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, as a chronic, autoimmune cholestatic liver disease that causes progressive inflammation and fibrosis of the interlobular bile ducts (Abstract; p. 284, 1st para of Intro). Symptoms of PBC include fatigue and pruritis (p. 285, left col., 2nd para from top; p. 288, right col.). Cheung teaches PBC is treated with ursodeoxycholic acid (UDCA) which improves biochemistry and transplant-free survival, however, 30-40% of PBC patients have an incomplete response to this therapy; as such, there is an urgent need for novel PBC therapies (p. 284, 1st 2 para of Intro). Cheung teaches criteria for PBC diagnosis includes ALP >1.5 times the upper limit of normal (ULN); a positive anti-mitochondria antibody titer >1:80, and liver biopsy findings consistent with PBC (p. 284, left col., last para-right col., top para); additional biomarkers of PBC patients includes elevated AST and ALT levels (p. 285, right col., first full para; p. 286, Table 1). Cheung further teaches PBC patients that exhibited an incomplete response to previous UDCA therapy were treated with a combination of fenofibrate and UDCA (Abstract; p. 284, left col., last para before Materials & Methods section; p. 284, right col., see Treatment para). Cheung teaches that patients receiving the combination therapy had significantly improved decompensation-free and transplant-free survival compared to patients receiving UDCA alone as evidenced by significantly reduced ALT and AST levels (p. 286, beginning with para before Table 1-p. 287, left col., next to last para-p. 288, Fig. 2).
It would have been prima facie obvious to have treated a patient having PBC comprising measuring one or more biomarkers from a sample in the patient such as AMA, ALT, and AST prior to administering compound 1 to obtain baseline levels of these markers; administering an effective amount of compound 1; obtaining a second measurement level of the biomarkers AMA, ALT, and AST after administering compound 1, and continuing to administer compound 1 if the levels of the biomarkers have decreased after administration of compound 1, in view of the combined prior art. Jones and Kaneko teach as discussed previously, while Cheung teaches PBC is typically treated with UDCA, however, between 30-40% of patients lack a full response to this therapy, thus additional therapies are desired. Cheung further teaches biomarkers of PBC include positive AMA and elevated ALT and AST levels, and that a combination therapy of fenofibrate and UDCA, administered to patients that previously had an incomplete response to UDCA, significantly improved decompensation-free and transplant-free survival compared to patients receiving UDCA alone. As such, it would have been prima facie obvious to have treated a patient with PBC and fatigue and/or pruritis comprising administering an effective amount of compound 1, (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid in combination with current UDCA therapy, including patients that were previously treated with UDCA and had an inadequate response to treatment, with a reasonable expectation of success because Cheung teaches combination therapy with UDCA improved patient survival compared to UDCA monotherapy. As S1P1 agonists such as (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acetic acid are taught to treat PBC, one of ordinary skill in the art would have been motivated to have administered a therapeutically effective amount of this compound, along with a therapeutically effective amount of UDCA, with a reasonable expectation that patient survival would have been improved. Furthermore, one of ordinary skill in the art would have been motivated to have measured the levels of biomarkers AMA, ALT, and ASP in the PBC patients before and after administration of compound 1, as these biomarkers are characteristic of PBC. One of ordinary skill in the art would have further continued administration of compound 1 to PBC patients after confirmation that the biomarker levels had decreased after an initial treatment with compound 1, as this would have been evidence of the efficacy of the therapy.
Regarding the recitation of instant claim 41, wherein the second level of the biomarker in step (c) is 2% less, 5% less, or up to >50% less than the corresponding first level of the biomarker measured in step (a), although this limitation is not explicitly taught, Kaneko teaches S1P1 agonists for treating PBC, and compound 1 is a S1P1 agonist. As discussed above, it would have been prima facie obvious to have administered a therapeutically effective amount of compound 1 to treat a subject with PBC, along with measurement of the biomarkers of this condition prior to and after treatment with compound 1. As such, it would have been prima facie obvious treatment of the same patient population as claimed with the same compound as recited in the instant claims would have provided the same decrease in biomarkers such as AMA, ALT, and AST as recited by instant claim 41.
Information Disclosure Statement
The IDS filed on 1/5/23 has been considered. However, numerous foreign applications and non-patent literature cited on the IDS have not been considered, as copies of these references have not been provided. The publications not considered have a strikethrough as shown on the annotated IDS.
Correspondence
Claims 1, 3-4, 6-7, 15, 17-24, 32, and 41-46 were examined and are rejected.
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627