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 Rejections - 35 USC § 103
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.
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.
Claim(s) 1-8 and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (US 2019/0105275 A1) in view of Gao et al (“Indirubin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice through the inhibition of inflammation and the induction of Foxp3-expressing regulatory T cells”, Acta Histochemica, vol.118(6) (July 2016), pg.606-614) and Wu (US 2017/0014383 A1).
Liang teaches ([0003]) that mesalazine (5-amino-2-hydroxybenzoic acid, 5-ASA or mesalamine) is used to treat inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and mild-to-moderate Crohn’s disease. Liang teaches ([0004]) that there is a need for pharmaceutical compositions for the oral administration of mesalazine with different release profiles because patients suffering from IBD exhibit gastrointestinal tract symptoms that vary in location and degree. In its claim 42, Liang teaches the following:
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As shown above, Liang’s unit orally-administrable dosage form of mesalazine comprises (a) a plurality of delayed-immediate release minitablets (“DR/IR minitablets”) and (b) a plurality of delayed-extended release minitablets (“DR/ER minitablets”). Specifically, in Example 11, Liang teaches a unit dosage form of mesalazine having (a) DR/IR minitablets prepared in its Example 1 and (b) DR/ER minitablets prepared in its Example 7 combined in a 30:70 ratio: in Example 1, Liang teaches delayed-immediate release minitablets (a) containing a compressed matrix having mesalazine provided with Eudragit® L30D-55 (instant methacrylic acid and ethyl acrylate copolymer 1:1 dispersion – see [0068] in Liang) as the pH-dependent enteric coating; in Example 7, Liang teaches delayed-extended release minitablets (b) containing a compressed matrix containing mesalazine provided with ethylcellulose and hypromellose as the inner pH-independent extended release coating and with Eudragit® S 100 (instant methacrylic acid and methyl methacrylate copolymer 1:2 – see [0068] of Liang) as the outer pH-dependent enteric coating. As shown above in claim 42, Liang teaches that its delayed-immediate release minitablets (a) selectively release mesalazine in the distal ileum (small intestine) and that its delayed-extended release minitablets (b) selectively release mesalazine in the colon (large intestine).
Liang does not teach instant limitation “wherein the AhR agonist is an at least 20-fold more potent activator of AhR than Indigo naturalis on a gram for gram basis”. Gao teaches (see under Introduction, 1st paragraph in the right-hand column) that although many therapeutic drugs, such as 5-aminosalicylic acid (5-ASA) (which was used in Liang), are commonly used for ulcerative colitis (UC) clinically, such drugs show limited benefits and severe side effects or high cost and thus it is necessary to discover novel therapeutic drugs with high efficacy and low toxicity for the treatment of UC. Gao teaches (abstract) that its study on the therapeutic efficacy of indirubin on DSS-induced UC in mice showed significant anti-UC effect of indirubin: “indirubin treatment could obviously ameliorate DSS-induced inflammation and immune responses in UC mice, with minimal signs of toxicity, suggesting that indirubin may serve as a potential drug for the treatment of UC.” (1st paragraph under Fig.3 on pg.611). Gao thus concludes (see Conclusion) that its results suggest that indirubin can be a promising candidate for the treatment of UC. Besides, as evidenced by Wu (see abstract and [0014]), it is known in the art that indirubin is compatible with acrylate or methacrylate copolymers (such as methacrylic acid and methyl methacrylate copolymer (Eudragit)). Based on the teachings of Gao and Wu, it would have been obvious to one skilled in the art to use indirubin (instant indigo derivative of claim 8 and instant AhR agonist of claim 13) instead of 5-ASA in Liang with a reasonable expectation of avoiding limited benefits, severe side effects or high cost of many commonly used drugs for UC and instead achieving high efficacy and low toxicity in treating UC. Indirubin is instant indigo derivative of claim 8 and thus teaches instant AhR agonist which is an at least 20-fold more potent activator of AhR than Indigo naturalis on a gram for gram basis in vivo (see also [0112] and Fig.4 of present specification). Thus, Liang in view of Gao and Wu renders obvious instant claims 1, 4-8 and 10-12.
With respect to instant claim 3, Liang in view of Gao and Wu does not explicitly teach instant range for the weight percentage of the aryl hydrocarbon receptor agonist (indirubin) which is necessary for treating IBD, such as ulcerative colitis (UC). However, Liang teaches (claim 42) that the total amount of mesalazine in the unit dose form is from about 0.4 to 6 g. Furthermore, Gao teaches or suggests (see abstract) that giving 10 mg/kg per day of indirubin was successful in treating UC in mice. Under such guidelines, instant range for the wt.% of indirubin (for human) would have been obvious to one skilled in the art before the effective filing date of the claimed invention because it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Thus, Liang in view of Gao and Wu renders obvious instant claim 3.
With respect to instant claims 13 and 14, as discussed above, Liang’s oral dosage form containing mesalazine is used in treating ulcerative colitis. However, (i) since Gao teaches using indirubin instead of drugs commonly used for UC (such as 5-aminosalicylic acid (5-ASA)) by stating that such common drugs show limited benefits and severe side effects and teaching indirubin as a new candidate for UC with high efficacy and low toxicity, and (ii) since it is known in the art, as evidenced by Wu, that indirubin is compatible with acrylate or methacrylate copolymers (such as methacrylic acid and methyl methacrylate copolymer (Eudragit)), it would have been obvious to one skilled in the art to administer Liang’s dosage form where the mesalazine is replaced with indirubin to a patient refractory or intolerant to a known therapy such as mesalazine (5-aminosalicylic acid) with a reasonable expectation of avoiding limited benefits and severe side effects and instead achieving high efficacy and low toxicity for the treatment of UC. Thus, Liang in view of Gao and Wu renders obvious instant claims 13 and 14.
Claims 2 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over LIANG et al (US 2019/0105275 A1) in view of Gao et al (“Indirubin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice through the inhibition of inflammation and the induction of Foxp3-expressing regulatory T cells”, Acta Histochemica, vol.118(6) (July 2016), pg.606-614), Wu (US 2017/9914383 A1) and Phelps (“The Emergence of Prodrugs: A Proficient Pathway to New Drug Development through the 505(b)(2) Pathway”, an internet article (published on April 4, 2014) obtained from the website: https://www.outsourcedpharma.com/doc/the-emergence-of-prodrugs-a-proficient-pathway-to-new-drug-development-through-the-b-pathway-0001#:~:text=Prodrugs%20can%20improve%20how%20an,enzymatic%20cleavage%20or%20chemical%20reaction.).
As discussed above in Paragraph 5, Liang in view of Gao and Wu teaches or renders obvious using indirubin (an indigo derivative) instead of 5-ASA in Liang. Furthermore, as evidenced by Phelps (see under “Conclusion”), it is already known in the art that prodrugs maximize the amount of active drug that reaches its site of action and thus have become a powerful instrument in optimizing the value of therapeutic drug agents. It would have been obvious to one skilled in the art to use a prodrug of indirubin ( instant prodrug of an indigo derivative of claims 2 and 9) in Liang so as to maximize the amount of indirubin that reaches its site of action and thus optimize the value of indirubin. Therefore, Liang in view of Gao, Wu and Phelps renders obvious instant claims 2 and 9.
Claims 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over LIANG et al (US 2019/0105275 A1) in view of Sahoo et al (“Solvent-free Hot Melt Extrusion Technique in Improving Mesalamine Release for Better Management of Inflammatory Bowel Disease”, Indian Journal of Pharmaceutical Education and Research, vol.53(4), pg.S554-S562 (Oct-Dec, 2019)), Gao et al (“Indirubin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice through the inhibition of inflammation and the induction of Foxp3-expressing regulatory T cells”, Acta Histochemica, vol.118(6) (July 2016), pg.606-614) and Wu (US 2017/0014383 A1).
As already discussed above in Paragraph 5, in Example 11, Liang teaches a unit dosage form of mesalazine having (a) DR/IR minitablets prepared in its Example 1 and (b) DR/ER minitablets prepared in its Example 7 combined in a 30:70 ratio: in Example 1, Liang teaches delayed-immediate release minitablets (a) containing a compressed matrix having mesalazine provided with Eudragit® L30D-55 dispersion (instant poly(methacrylic acid-co-ethyl acrylate) 1:1 of claim 17 (instant pH-sensitive polymer of claim 15) – see [0068] in Liang) as the pH-dependent enteric coating; in Example 7, Liang teaches delayed-extended release minitablets (b) containing a compressed matrix containing mesalazine provided with ethylcellulose (instant cellulosic polymer of claim 20) and hypromellose (instant cellulosic polymer of claim 20 (hydroxypropyl methylcellulose)) as the inner pH-independent extended release coating and with Eudragit® S 100 (instant methacrylic acid and methyl methacrylate copolymer 1:2 of claim 17 (instant pH-sensitive polymer of claim 15) – see [0068] of Liang) as the outer pH-dependent enteric coating. Liang further teaches that its delayed-immediate release minitablets (a) selectively release mesalazine in the distal ileum (small intestine) and that its delayed-extended release minitablets (b) selectively release mesalazine in the colon (large intestine).
Liang does not teach that its mesalazine is suspended or dissolved in a matrix made without use of a solvent to form a solid suspension. Sahoo teaches (abstract) improved mesalamine release by hot-melt extrusion (HME) technique could be used for better management of IBD. Sahoo teaches (see CONCLUSION) that stable solid dispersion of mesalamine formulations can be produced utilizing solvent-free continuous hot melt extrusion technique. Sahoo further teaches (pg.S555, left-hand column, 2nd paragraph) that HME technique offers a number of advantages over conventional pharmaceutical processing techniques such as (i) few processing steps, (ii) absence of solvents, (iii) nonstop operation and (iv) improved physiochemical properties of the resultant solid dispersions (Sahoo also teaches that the resultant solid dispersions can be made into tablets (see pg.S555, left-hand column, last 4 lines in the 2nd paragraph. pg.S558, left-hand column, last 3 lines in the 1st paragraph, and pg. S560, left-hand column, last 5 lines in the 1st paragraph)). It would have been obvious to one skilled in the art to use HME technique (with the absence of solvents) to form a solid dispersion (and formulate the solid dispersion into a tablet and then coat the tablet with the pH-dependent enteric coating) in Liang so as to improve mesalamine release, better manage IBD and obtain advantages over conventional pharmaceutical processing techniques as listed above. Thus, Liang in view of Sahoo renders obvious instant limitation, an AhR agonist suspended or dissolved in a matrix made without use of a solvent to form a solid suspension, the solid suspension (in the form of a tablet) coated with a pH-sensitive polymer (see [0152], Examples 8 and 9 of present specification).
With respect to instant limitation “wherein the AhR agonist is an at least 20-fold more potent activator of AhR than Indigo naturalis on a gram for gram basis”, as already discussed above in Paragraph 5, Gao teaches (see under Introduction, 1st paragraph in the right-hand column) that although many therapeutic drugs, such as 5-aminosalicylic acid (5-ASA) (which was used in Liang), are commonly used for ulcerative colitis (UC) clinically, such drugs show limited benefits and severe side effects or high cost and thus it is necessary to discover novel therapeutic drugs with high efficacy and low toxicity for the treatment of UC. Gao teaches (see Conclusion) that its experimental results suggest that indirubin can be a promising candidate for the treatment of UC. Besides, as evidenced by Wu (see abstract and [0014]), it is known in the art that indirubin is compatible with acrylate or methacrylate copolymers (such as methacrylic acid and methyl methacrylate copolymer (Eudragit)). It would have been obvious to one skilled in the art to use indirubin instead of 5-ASA in Liang with a reasonable expectation of avoiding severe side effects and/or high cost and achieving high efficacy and low toxicity for the treatment of UC. Indirubin teaches instant AhR agonist which is an at least 20-fold more potent activator of AhR than Indigo naturalis on a gram for gram basis in vivo (see [0112] and Fig.4 of present specification).
Thus, Liang in view of Sahoo, Gao and Wu renders obvious instant claims 15-17 and 20.
With respect to instant claims 18-19, as shown above, Liang teaches Eudragit® L30D-55 dispersion (methacrylic acid and ethyl acrylate copolymer 1:1) as the pH-dependent enteric coating for the delayed-immediate release minitablets of its Example 1 and teaches Eudragit® S 100 (methacrylic acid and methyl methacrylate copolymer 1:2) as the outer pH-dependent enteric coating for the delayed-extended release minitablets of its Example 7. Furthermore, in its claim 59, Liang teaches the equivalence of the methacrylic acid and ethyl acrylate copolymer 1:1 (as used in the delayed- immediate release minitablets of its Example 1), hypromellose acetate succinate and hypromellose phthalate and also teaches the equivalence of the methacrylic acid and methyl methacrylate copolymer 1:2 (as used in the delayed-extended release minitablets of its Example 7) and hypromellose acetate succinate. Besides, as evidenced by Wu (abstract and [0014]), it is known in the art that indirubin is compatible with cellulosic polymers such as hypromellose acetate succinate and hypromellose phthalate. Thus, it would have been obvious to one skilled in the art to replace the methacrylic acid and ethyl acrylate copolymer 1:1 with hypromellose acetate succinate (instant cellulosic polymer of claim 19, which is instant pH-sensitive polymer of claims 15 and 18) and hypromellose phthalate (instant cellulosic polymer of claim 19, which is instant pH-sensitive polymer of claims 15 and 18) in Liang’s delayed-immediate release minitablets of Example 1 and to replace the methacrylic acid and methyl methacrylate copolymer 1:2 with hypromellose acetate succinate (instant cellulosic polymer of claim 19, which is instant pH-sensitive polymer of claims 15 and 18) in Liang’s delayed-extended release minitablets of Example 7 with a reasonable expectation of success. Thus, Liang in view of Sahoo, Gao and Wu renders obvious instant claims 18-19.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
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/SIN J LEE/Primary Examiner, Art Unit 1613 September 5, 2026
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