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 .
Current Status of 17/755,164
This Office Action is responsive to the amended claims and Applicant remarks of 09/29/2025. Claims 1-6, 8, and 13-18 are pending in this application and have been considered on the merits.
Priority
The instant application is a national stage entry of PCT/CN2020/123330, filed 10/23/2020, which claims foreign priority to Chinese Patent Application No. 201911019555.X, filed 10/24/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
A review of the file wrapper indicates Chinese language foreign priority documents. However, since it is not in English, a judgement cannot be made as to whether it supports the instant claims, which is required to prefect foreign priority. The conditions of 35 U.S.C. §119(a)-(d) or (f) are not met.
Therefore, the effective filing date of the instant claims is the international filing date of 10/23/20202.
Response to Arguments
Objection to Specification: Applicants have addressed the minor informalities of the specification through amendment. These amendments render the previous objection moot, and the objection is withdrawn.
Claim rejections 35 U.S.C. §112: Applicants have amended claims 1 and 13 to remove the term “resonator” and the phrase “preferably 1-4” from the claims. These amendments render the previous rejection moot, the §112(b) rejection is withdrawn.
Applicants’ amendment addresses the portion of the claim directed to preventing and/or treating a disease. However, the claim continues to recited “preventing and/or treating a disease related to decreased thyroid hormone receptor activity,” which was previously rejected under 35 U.S.C. §112(a). Applicants have not amended this portion of the claim or provided arguments or evidence demonstrating that the specification enables this subject matter. Accordingly, the rejection is maintained. This rejection can be rendered moot by removal of “preventing” from the claim.
Claim rejections 35 U.S.C. §103: Applicants allege that the amended compounds of (I) and (Ia) are non-obvious over the references cited in the Non-Final rejection mailed 05/28/2025. Applicants argue that the combined teachings of the references fail to disclose compounds in which both X and Y are simultaneously substituents other than hydrogen. Applicants further contend that the references do not teach or suggest that X is -CR(R17R18)-OC(O)-R5. Applicants acknowledge that Roughley teaches amine modification as a routine strategy for modulating pharmacokinetic and pharmacodynamic properties; however, Applicants assert that this reference does not suggest the specific substitution at X as presently claimed. These arguments have been fully considered and are found persuasive, the previous rejections are withdrawn.
Applicants have also presented arguments comparing the pharmacokinetic (PK) properties of MGL-3196 to Example 5 of WO 2009037172 A1 and rely on these comparisons to support conclusions regarding the effect and purported essentiality of specific structural substitutions. However, the comparative AUC and Cmax values presented in Table 2 of the Applicants’ Remarks for Example 5 differ significantly from the values reported for this same compound in the reference under similar experimental conditions (see Table 3 of Example 24 of WO 2009037172 A1, pg. 42-43), and Applicants have not provided an explanation reconciling these discrepancies. Because these PK values serve as the baseline for Applicants’ comparative analyses, the reliability of the underlying comparisons is not established. In the absence of a consistent and reliable reference point, the asserted structure-property relationships, the attribution of observed PK differences to particular substitutions (Y, X, R17, and R18), and the conclusions regarding the essentiality of those substitutions are not persuasively supported. Accordingly, the probative value of Applicants’ PK arguments is limited.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating diseases associated with decreased thyroid hormone receptor activity, does not reasonably provide enablement for “preventing a disease related to decreased thyroid hormone receptor activity.” The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating and/or preventing a disease related to a decreased thyroid hormone receptor activity. The method uses a therapeutically effective amount of a compound of formula (I) or (Ia), broadly reading on all compounds embraced by (I) and (Ia), including those not found within the disclosure. Preventing diseases requires identifying those patients who will acquire the diseases before the disease occurs. This would require extensive and potentially open-ended clinical research on healthy subjects. The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases. Thus, the claims are extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from disease related to a decreased thyroid hormone receptor activity before the fact. The state of the art is that cardiovascular disease (Yusuf, Salim et al. “Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.” Lancet (London, England) vol. 364,9438 (2004): 937-52. doi:10.1016/S0140-6736(04)17018-9), and metabolic disease (Franks, P.W. Gene × Environment Interactions in Type 2 Diabetes. Curr Diab Rep 11, 552–561 (2011). https://doi.org/10.1007/s11892-011-0224-9) are not preventable.
Pharmaceutical compositions bearing the same core molecule (MGL-3196) have demonstrated their efficacy in treating liver diseases and dyslipidemia through thyroid hormone receptor agonism. However, neither the specification nor the cited prior art provides evidence or support for using these compounds in the treatment of cancer, infection, immunological disease, inflammation, or diabetes. MGL-3196 has proven effective in the treatment of metabolic diseases including non-alcoholic fatty liver dieses (NAFLD), non-alcoholic steatohepatitis (NASH), and dyslipidemia (Harrison, Stephen A et al. “Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.” Lancet (London, England) vol. 394,10213 (2019): 2012-2024. doi:10.1016/S0140-6736(19)32517-6). Clinical studies have shown that MGL-3196 can reduce low-density lipoprotein-cholesterol (LDL-C) levels by up to 30%, addressing a key risk factor in cardiovascular disease (Kelly et al., found in IDS submitted 04/22/2022). Therefore, compounds of this class have established utility in the treatment of metabolic disorders and cardiovascular disease. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases.
(5) The relative skill of those in the art, (6) the amount of direction or guidance presented and (7) the presence or absence of working examples:
The artisan is likely one involved in the treatment of one or more of the conditions/diseases and while they might be skilled in treatment, their technical expertise would be insufficient to overcome the art-recognition that the cardiovascular disease and metabolic disease are not preventable (and even might be difficult to treat) or even more than they have no recognition that the thyroid hormone receptor is involved in the disease, and would have no way to know what one will work or not work without experimentation.
Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent cardiovascular disease or metabolic disease. That is, the skill is so low that no compound effective generally against the prevention of cardiovascular disease or metabolic disease.
There is no working example of such a preventative procedure in man or animal in the specification.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to preventing cardiovascular disease and metabolic disease and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-6, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by La Roche (EP 2203441 B1, found in IDS field 01/03/2024).
La Roche discloses compounds of formula (I) which are thyroid hormone receptor agonists useful in treating obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and related disorders and diseases (Title, Abstract). The reference discloses example 20
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(pg. 21, [0078]). Example 20 is a compound of the instantly claimed compounds of formula (I)
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with the following substitutions: R1 is H; R2 and R3 are C1 alkyl (methyl); X is C(R17R18)OZ, R17 and R18 are H, Z is -C(O)OR5, R5 is C2 alkyl; R4, R7, and R9 are H; R6 and R8 are Cl; and Y is H. Example 20 anticipates the structures of III-A, IV-A, and V-A (instant claims 14, 2 and 3).
La Roche discloses the reaction of 1 with 11 in the presence of the base triethyl amine to generate 12.
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(Scheme 7, pg. 11). This reaction corresponds directly to the process of instant claim 5 for preparing (I) from (VI), as the same reactants, reaction conditions, and transformations are employed.
The amended claims limit Y to hydrogen. Accordingly, the claimed process does not require any additional functionalization step at this positions, and the second reaction depicted in the claim is no longer necessary to arrive at the claimed compounds. Therefore, the single reaction disclosed in La Roche anticipates the claimed process of instant claim 5.
La Roche anticipates the limitations of instant claim 6 related to pharmaceutical compositions comprising a therapeutically effective amount of the claimed compounds of (I) or (Ia), and a pharmaceutically acceptable carrier. Claim 12 of La Roche discloses compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
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.
Claims 1,4, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over La Roche in view of Sun (Sun, Shaoyi, and Jianmin Fu. “Methyl-containing pharmaceuticals: Methylation in drug design.” Bioorganic & medicinal chemistry letters vol. 28,20 (2018): 3283-3289. doi:10.1016/j.bmcl.2018.09.016).
The proceeding discussion of La Roche is incorporated by reference into this rejection. La Roche anticipates the claimed compounds of formula (I). La Roche teaches Example 20
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(pg. 21, [0078]), differing from the second disclosed species of instant claim 4 due to the presence of a methyl group at the indicated position
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. Although La Roche is silent on the presence of a methyl group at this position, methylation is a common strategy in modulating PK and PD properties in drug design (see Abstract of Sun). Sun expressly teaches that the replacement of a hydrogen atom with a methyl group can result in profound potency enhancement (pg. 3283, left col, second para). The artisan would be familiar with medicinal chemistry principles and routine structure-activity optimization practices, including common substituent modifications used to evaluate PK and PD properties of small-molecule compounds. In view of the teachings of references La Roche and Sun the artisan would have been motivated to replace the hydrogen atom at the indicated position of Example 20 with a methyl group to arrive at the claimed compound, with a reasonable expectation of success. Therefore, the claimed compounds are obvious over La Roche in view of Sun.
Claims 15 and 18 further recite that when X is attached to N and Y is hydrogen, both R17 and R18 are not hydrogen at a time, thereby excluding prior-art embodiments in which both positions are unsubstituted. However, as discussed above, replacement of a hydrogen atom with a methyl group at one of these positions represents a routine and predictable modification in medicinal chemistry. In view of the same teachings and rationale applied to the compounds of instant claim 4 above, the artisan would have been motivated to substitute one of the hydrogen atoms at R17 or R18 in the prior-art compound, with a reasonable expectation of success. Accordingly, the subject matter of instant claims 15 and 18 would have been obvious for the same reasons set forth above.
Claims 1, 13, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over La Roche in view of Kelly (Kelly, Martha J et al. “Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia.” Journal of medicinal chemistry vol. 57,10 (2014): 3912-23. doi:10.1021/jm4019299, found in IDS submitted 04/22/2022) and Cable (US 2009/0232879 A1).
The teachings of La Roche are discussed above and teach the compounds of claim 1. The above discussion is incorporated by reference into this rejection. La Roche additionally discloses that the compounds are thyroid hormone receptor agonists and describes their use in treating a broad range of conditions that may be modulated by thyroid hormone analogs, including metabolic diseases and cardiovascular diseases (para [0002]-[0009]). La Roche does not specifically teach methods of treating disease on the basis of decreased thyroid hormone receptor activity. However, reference Kelly further teaches that MGL-3196 binds to both thyroid hormone receptor subtypes (a and b) while exhibiting significantly greater selectivity and potency for the THRb subtype, and discloses a core structure corresponding to that of the instantly claimed compounds (Abstract). Cable teaches the use of thyromimetic compounds for treating fatty liver diseases including non-alcoholic fatty liver disease (NAFLD), which is described as encompassing a spectrum of hepatic disorders associated with dysregulated lipid metabolism and impaired thyroid hormone signaling in the liver ([0039]).
In view of these teachings, the artisan would have been motivated to use compounds of the La Roche, which are derivatives of the MGL-3196 scaffold, in methods for treating metabolic and hepatic diseases associated with decreased thyroid hormone receptor activity. Given the established THRb selectivity of MGL-3196 derived compounds and the recognized role of THRb signaling in hepatic lipid metabolism as taught by Cable, the artisan would have reasonably expected that administration of such compounds would provide therapeutic benefit in the treatment of fatty liver diseases and related metabolic conditions. Accordingly, the claimed methods would have been obvious to the artisan at the time of invention.
Claims 1, 6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over La Roche in view of Sun 2 (Sun, Wei et al. “Drug combination therapy increases successful drug repositioning.” Drug discovery today vol. 21,7 (2016): 1189-95. doi:10.1016/j.drudis.2016.05.015).
The teachings of La Roche are discussed above and teach the compounds and pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers. The above teachings are incorporated by reference into this rejection. The reference teaches instant claims 1 and 6. La Roche does not expressly disclose additional drugs for treating diseases selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immunological disease, metabolic disease, and a combination thereof. However, Sun 2 teaches that drug combinations of two or more drugs with different mechanisms of action are an alternative approach to increase the success of drug repositioning (Abstract).
La Roche teaches compounds and compositions comprising these compounds that are useful in treating diseases mediated by thyroid hormone receptor activity. Sun 2 teaches that it is well known and common in the art to administer additional therapeutic agents in combination with a primary active compound in pharmaceutical compositions. Combination therapies are routinely employed to improve therapeutic outcomes, reduce side effects, or target multiple biological pathways. In the absence of any teaching away or evidence of unexpected results, the artisan would have been motivated to combine the compounds of La Roche with one or more additional drugs of known utility, with a reasonable expectation that each agent would act on its own target. The combination represents a straightforward application of known elements to achieve their expected effects, without yielding any result beyond what the prior art would predict.
Conclusion
No claims are allowable.
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/C.K.E./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625