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 .
Priority
This application, filed on 9 August 2024, is a National Stage entry from International Application No. PCT/US2023/062351, filed on 10 February 2023, which claims benefit under 35 U.S.C. 120 to US Provisional Application Nos. 63/419,790 and 63/308,709, filed on 27 October 2022 and 10 February 2022, respectively.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 17 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 9 recites: “The compound of claim 1, wherein each Rc and Rc is H.” Rc is recited twice. Further, Rc is a subgroup substituent making up R3, R5, R7 and another subgroup Ru of claim 1. It is unclear if all the substituents within R3, R5, R7, and Ru are now all Rc and Rc is H, or if the substituents having the subgroup Rc are all H, exemplified in instant claim 11 for Rb.
Regarding claim 17, the written description and the claims are separate statutory requirements. Under modern claim practice, claims must stand alone to define an invention. Ex parte Fressola, 27 USPQ2d 1608 (BPAI 1993) (MPEP §2173.05(s). Claim 17 includes reference to “Table I” without providing a chemical structure or chemical name for each compound. As a result, one of ordinary skill in the art must refer back to the specification to understand what the claimed invention is.
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.
Claims 1-9, 11, and 13-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020123827 (“Yu”) in view of WO2019240938 (“Bohan”), evidenced by Brown et al., Bioisosteres in Medicinal Chemistry, First Edition, pp. 1-14. First published: 3 August 2012 (“Brown”).
Yu teaches the compounds of Formula (III) (p. 5), wherein compounds 9-11 and 15 are species of Formula (III), which maintain good agonistic activity towards thyroid hormone receptor (THR) β and offer the beneficial therapeutic effects of thyroid hormones, but also avoid side effects affecting the heart (¶[0009]; p. 7 and claim 14). The compounds were compared with MGL-3196,
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the comparative compound, for selectivity towards THRβ, wherein compound 9,
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, showed the best selectivity towards THRβ with a selectivity factor of >58.8 versus MGL-3196 with a selectivity factor of 19.2 (¶[0010]; ¶[0187], Table 1). Yu states: “The pharmacokinetic properties of some preferred compounds are significantly better than those of the comparative compound [MGL-3196], thus improving the properties of the finished drug.” (¶[0010]). Yu also teaches; a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable salt thereof as an active ingredient (¶[0026]); a formulation including the disclosed compounds and a carrier, excipient, or a diluent (¶[0041]); and a method of treating a metabolism-related disease. The metabolism-related disease is selected from the group consisting of hyperlipidemia, hypercholesterolemia, non-alcoholic steatohepatitis, etc. The method includes administering to the subject an effective amount of a compound or a pharmaceutical composition comprising the compound and pharmaceutically acceptable salt thereof as an active ingredient (¶¶[0027]-[0029]). Activation of THRβ was demonstrated by treating HEK293-LUC cells with the disclosed compounds, and testing for activity through a chemiluminescence assay, which showed Embodiments 4, 9, 12, and 13 can activate the downstream signal of THRβ (pp. 47-49, ¶[0192]).
Yu does not teach compounds wherein the cyanoazauracil moiety is substituted with a cyanouracil moiety.
Bohan teaches compounds that are selective THR agonists which suppress the cardiac side effects of nonspecific THR agonists while retaining the potential beneficial effects of THR activation (¶[0058]). Bohan teaches compounds of Formula (X) (p. 46), wherein in one of the compounds of Formula (X) is compound 12 (Table 1),
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, the cyanouracil analog of MGL-3196 (vide supra). Bohan teaches modification of the lead compound MGL-3196, to improve selectivity of THR agonists, by modifying the azauracil ring to an uracil ring (i.e., replacing a N with a CH).
Brown provides further evidence of the modification taught in Bohan through the concept of isosterism. Brown states:
“In 1925, H.G. Grimm [3] extended the concept of isosterism, introduced by Langmuir, with Grimm’s hydride displacement law:
‘Atoms anywhere up to four places in the periodic system before an inert gas
change their properties by uniting with one to four hydrogen atoms, in such
a manner that the resulting combinations behave like pseudoatoms, which
are similar to elements in the groups one to four places, respectively, to
their right.’
Therefore, according to this law, the addition of hydrogen to an atom will result in a pseudoatom with similar properties to the atom of the next highest atomic number. So, CH is isosteric with N and NH is isosteric with O and so on.” (p.5).
Yu and Bohan are considered analogous art to the claimed invention because they are in the same field of optimizing THRβ ligands to improve potency, selectivity, and limit cardiac side effects. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), before the effective filing date of the claimed invention, to combine the prior art elements to arrive at the claimed compounds with predictable results (MPEP §2143(B)). It would have been prima facie obvious to a PHOSITA to choose compound 9 as a lead compound because it has greater selectivity towards THRβ than MGL-3196, as taught by Yu, and one of skill in the art would have been motivated to modify compound 9 by substituting the cyanoazauracil moiety for the cyanouracil moiety, based on the teachings of Bohan, because Bohan teaches modifying the lead compound MGL-3196 by substituting the cyanoazauracil moiety for the cyanouracil moiety to give compound 12 (vide supra). In the instant case, the claimed genus, i.e. Formula I, encompasses compounds of sufficiently similar structure to the compounds of Formula (III) taught by Yu (MPEP §2144.08(II)(A)(4)(c)). The deficiency in Yu, wherein it is lacking an uracil ring, is rectified by the teachings of Bohan which provides motivation to modify a lead agonist of THRβ, e.g., MGL-3196, to have an uracil as opposed to an azauracil moiety. More specifically, the difference between the claimed compounds and the compounds of Yu is the replacement of an N atom for a CH group which are isosteres, as evidenced by Brown, and would be considered structurally similar for the purpose of binding to the THRβ receptor. See. In re Merck & Co., 800 F.2d 1091, 1096-97, 231 USPQ 375, 378-79 (Fed. Cir. 1986). Accordingly, claims 1, 3-8, and 13-16 are prima facie obvious.
Regarding claims 2, 9 and 11, (R1)m and (R5)n have substituents where Rb and Rc are present in the genus of claim 1 and the m and n integers range from 0-4 and 0-2, respectively. Claim 2 recites, R1 is independently halogen, C1-6 alkyl, etc., and claims 9 and 11 recite Rb and Rc are H but do not further specify if m and/or n are greater than 0. Therefore, the compound that would have been prima facie obvious to a PHOSITA based on the above rationale, reads on these claims in view of Yu and Bohan because the integer 0 for both m and n are incorporated by reference.
Regarding claims 17-18, Yu teaches a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable salt thereof as an active ingredient and a formulation that includes the compound and an excipient (vide supra).
Regarding claims 19-22, Yu teaches the disclosed compounds activate THRβ and can be used in a method of treating a metabolism-related disease such as hyperlipidemia, hypercholesterolemia, non-alcoholic steatohepatitis, etc. The method includes administering to the subject an effective amount of a compound or a pharmaceutical composition comprising the compound and pharmaceutically acceptable salt thereof as an active ingredient (vide supra).
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Yu in view of Bohan evidenced by Brown, further in view of WO2020227549 (“Vandyck”).
The teachings of Yu and Bohan and evidentiary reference are discussed above and are incorporated by reference herein.
Regarding claims 10-11, Yu and Bohan do not teach substituting the azauracil heterocycle with an amide or carboxylic acid functional group.
Vandyck teaches compounds that are effective modulators of THRβ activity that can be used for the treatment of various THRβ related disorders, specifically compounds 8 and 9 are disclosed which are the amide and carboxylic acid derivatives of MGL-3196 (pp. 3 and 76, ¶¶ [0012] and [00185]).
Yu, Bohan, and Vandyck are considered analogous art to the claimed invention because they are in the same field of optimizing THRβ ligands to improve potency and selectivity, for THRβ related disorders. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of the prior art to arrive at the claimed compounds to yield predictable results. It would have been prima facie obvious to a PHOSITA to choose compound 9 as a lead compound because it has greater selectivity towards THRβ than MGL-3196, as taught by Yu, and modify compound 9 by substituting the cyanoazauracil moiety for the cyanouracil moiety, as taught by Bohan because Bohan teaches modifying MGL-3196 by substituting the cyanoazauracil moiety for the cyanouracil moiety to give compound 12 (vide supra). Further replacement of the cyano group of the azauracil heterocycle with an amide and/or a carboxylic acid functional group, would have been prima facie obvious in view of Vandyck, which teaches substituting the cyano group of MGL-3196, with an amide and/or a carboxylic acid. The MPEP states: “It should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound.” See MPEP 2143(B) Example 10 (Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 90 USPQ2d 1947 (Fed. Cir. 2009)). In the instant case, the substitution of the cyano group of the lead compound MGL-3196 for an amide and/or a carboxylic acid, taught by Vandyck, would have provided a PHOSITA with the necessary motivation to further alter compound 9 after replacing the azauracil with an uracil heterocyle, as taught by Yu and Bohan, in a similar manner.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Yu in view of Bohan evidenced by Brown, further in view of McGowan et al., Journal of the American Heart Association, Volume 8, Issue 24, 17 December 2019 (“McGowan”).
The teachings of Yu and Bohan and evidentiary reference are discussed above and are incorporated by reference herein.
Regarding claim 23, Yu and Bohan do not teach a method of treating hypercholesterolemia, whether heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).
McGowan teaches that MGL-3196, a THRβ selective agonist has been studied in a phase II clinical trial in 116 patients with HeFH (p.11, 2nd column).
Yu, Bohan, and McGowan are all analogous art to claimed invention because they are in the same filed of administering THRβ selective agonists to treat lipid disease. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of the prior art to arrive at the instantly claimed method. It would have been prima facie obvious to a PHOSITA to choose compound 9 as a lead compound because it has greater selectivity towards THRβ than MGL-3196, as taught by Yu, and one of skill in the art would have been motivated to modify compound 9 by substituting the cyanoazauracil moiety for the cyanouracil moiety, as taught by Bohan. The modification from cyanoazauracil to cyanouracil would have been expected to improve activity because Bohan teaches modifying MGL-3196 by substituting the cyanoazauracil moiety for the cyanouracil moiety to give compound 12 (vide supra). Therefore, a PHOSITA would have had a reasonable expectation of success in substituting the azauracil moiety in compound 9 taught in Yu, with an uracil moiety to arrive at the compounds in the instantly claimed method. The teachings of McGowan state that the THRβ selective agonist MGL-3196 has been administered to patients having HeFH. Therefore, substituting MGL-3196 with a compound prepared through the collective teachings of Yu and Bohan would have been prima facie obvious because the compounds are recognized as potent and selective THRβ agonists (MPEP §2144.06(II)).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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