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 .
Status of the Claims and Response to Restriction Requirement
Claims 1-18 are pending as of the response filed on 12/22/2025. Applicant’s election of group I claims 1-10 without traverse is acknowledged. Claims 11-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election of the species shown below is acknowledged.
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The elected species is encompassed by claims 1-10. Therefore, claims 1-10 have been examined to the extent to which they are readable on the above identified elected invention and elected species.
Because Applicant did not distinctly and specifically point out the supposed errors in the election of species requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The elected species was examined and found to be free of prior art. Therefore, the examiner has extended the search to include the entire genus of compounds of Formula (I) as in claim 1. The compounds of Formula (I) as in claim 1 was found to be free of prior art.
In view of the pending claims, the following rejections are made, as discussed below.
Priority
This application is a CON of PCT/CN2022/072149 filed 01/14/2022, which claims foreign priority to CHINA 202110056415.0 filed 01/15/2021.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 01/15/2021. It is noted, however, that applicant has not filed a certified copy of the CHINA 202110056415.0 application as required by 37 CFR 1.55.
It is noted that Applicants have not provided an English translation of the certified copy of the foreign priority application as required by 35 U.S.C. 119(b). Without the English translation, one cannot ascertain if the instant invention is supported in the Chinese application. Therefore, art prior to the PCT date, but not before the date of the Chinese application may be cited against the claims. Accordingly, claims 1-10 have been afforded an effective filing date of 01/14/2022, the filing date of the PCT application.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement submitted on 07/13/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claims 1-10 are 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 compound of Formula (I) or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, does not reasonably provide enablement for an isotopically labeled compound thereof, or a prodrug thereof, or a metabolite thereof. 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.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation” would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In re Wands, 8 USPQe2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The breadth of the claims/The nature of the invention
The claims recite substituted indazole compounds of Formula (I) as well as an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.
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The compounds of Formula (I) encompass a vast array of compounds as recited in the definition of the variables R1, R2, R3, R5, R6, L, n, and X and further include potential isotopically labelled compounds, isomers, pharmaceutically acceptable salts, prodrugs and metabolites. The instant specification defines isotopically labelled compounds to include isotopes of hydrogen, 2H (D) and 3H (T), of carbon, such as 11C, 13C and 14C, of chlorine, such as 36Cl, of fluorine, such as 18F, of iodine, such as 123I and 125I, of nitrogen, such as 13N and 15N, of oxygen, such as 15O, 17O and 18O, and of sulphur, such as 35S (Para. [0015]). The instant specification does not have a limiting definition of what constitutes a prodrug or metabolite of the compounds thereof. Therefore, the scope of the claims is extensive. The nature of the invention is the evaluation of these vast array of compounds for their pharmacological activity as inhibitors of FGFR.
The state of the prior art/The level of predictability in the art
Abraham (Burger’s Medicinal Chemistry & Drug Discovery, Sixth Edition, Volume 2: Drug Discovery and Drug Development, Chapter 14, 2003); Haberson et al. (Deuterium Medicinal Chemistry: A New Approach to Drug Discovery and Development, May 2014, hereinafter Haberson).
Abraham teaches the design of prodrugs in a rational manner requires that the underlying causes that necessitate or stimulate the use of the prodrug approach be defined and clearly understood. It may then be possible to identify the means by which the difficulties can be overcome. Abraham teaches the rational design of the prodrug can be divided into three basic steps: 1) Identification of the drug delivery problem, 2) Identification of the physicochemical properties required for optimal delivery, 3) Selection of a prodrug derivative that has the proper physicochemical properties and that will be cleaved in the desired biological compartment (Pg. 524 second column, last paragraph – Pg. 525, first column, continued paragraph). Abraham teaches the consideration of several factors before starting the development of a new prodrug intended for large-scale production reproduced below (Pg. 525, second column, first paragraph – eighth paragraph).
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Abraham teaches the difficulty of extrapolating data from animals to humans encountered during toxicokinetic and toxicologic studies with drugs is amplified with prodrugs because not only might the metabolism of the active moiety differ, but also its availability from the prodrug. As a matter of fact, there is presently no published rationale for the conduct of animal and human pharmacokinetic programs during prodrug research and development (Pg. 526, first column, first full paragraph). Abraham teaches that in most cases prodrug design tends to produce substances that are totally bioactivated by one chemical route. However, this is not necessarily the case and adequate provision must be made for such deviations from the ideal case when planning and interpreting the results in pharmacokinetic and relative bioavailability investigations (Pg. 501 second column, first full paragraph). Thus, it is clear that more studies are clearly needed, especially at early stages of the drug discovery, for prodrugs to achieve the desired state of art and take their place in modern pharmacotherapy.
Haberson teaches selective deuteration may improve the pharmacokinetic and/or toxicity profile of drugs, which in turn translates to improvements in efficacy and safety profile of a therapeutic agent (Pg. 8, first column, first paragraph). Haberson teaches deuterium incorporation can significantly alter the metabolic profile of a molecule with advantages of improved metabolic stability (Pg. 10, second column, last paragraph, Fig. 1; Pg. 13, first column, last paragraph – second column, continued paragraph). Haberson teaches the cytochrome P450s (CYPs) represent the most important enzymes in drug metabolism and catalyze the Phase 1 metabolism of most drugs. Haberson teaches the complex catalytic cycle of CYP450s in addition to potential alternative clearance mechanisms or sites of metabolism, can result in a number of competing effects that mask the deuterium isotope effect (DIE), thereby making the application of deuterium to drug discovery highly unpredictable and challenging (Pg. 9, second column, last paragraph – Pg. 10, first column, continued paragraph). Haberson teaches that the deuterium effects on the metabolic profile of a therapeutic are not predictable and must be explored for each compound as one would typically approach medicinal chemistry optimization (Pg. 20, second column, continued paragraph).
Therefore, the state of the prior art indicates challenges with respect to the design of prodrugs, as well as unpredictability with respect to deuteration of drugs. The scope of the instant compounds extends beyond deuteration to other isotopically labelled compounds with similar challenges.
Additionally, it is noted that the state of the art with regard to pharmacology is unpredictable. The field of pharmacology involves screening compounds both in vitro and in vivo to determine lead compounds that exhibit the desired pharmacological activity. According to MPEP 2164.03, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).”, with physiological activity being considered to be an unpredictable factor.
Therefore, in consideration of the various challenges with regard to prodrug design/analysis of the metabolites and the high level of unpredictability in the field of isotopic labelling, it is unclear how the instant invention is enabled for the huge genus of compounds being claimed.
The level of one of ordinary skill in the art
The relative level of skill in the art is high, such as, a synthetic organic chemist, healthcare professionals such as, an oncologist or molecular biologist with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally there is significant unpredictability in the art in the field of organic synthesis, prodrug design and isotopic labelling.
The amount of direction provided by the inventor/The existence of working examples
Applicants have provided sufficient guidance for the synthesis of indazole derivatives of Formula (I) as in instant claim 1 (Paras. [00161]-[00335[). However, the disclosure does not provide sufficient guidance to extrapolate the limited examples to making or using the recited isotopically labeled compounds, prodrugs, or metabolites thereof. In fact, there are no examples for the synthesis of an isotopically labelled compound or a prodrug thereof. There is lack of direction or guidance regarding making and using the full scope of compounds being claimed.
The quantity of experimentation needed
Considering the state of the art as discussed in the references above, high degree of unpredictability in the field, and lack of sufficient guidance in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the claims.
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 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claims 1-10, the claims recite the limitation “a prodrug thereof, or a metabolite thereof”. Para. [0024] of the instant specification defines a “prodrug” as “a derivative that is converted into a compound according to the present disclosure by a reaction with enzymes, gastric acid, and the like in a living body under physiological conditions, for example, through oxidation, reduction, hydrolysis, and the like catalyzed by enzymes”. Para. [0025] of the instant specification defines a “metabolite” as “all molecules derived from any compound according to the present disclosure in a cell or organism”.
A prodrug or metabolite is any compound which is pharmaceutically active in vivo when it undergoes metabolic degradation and the specification does not provide any disclosure of what these compounds might be, that transform in vivo into the instantly claimed compounds. Therefore, the specification does not provide a limiting definition of the terms “prodrug” and “metabolite”. The full scope of the compounds – possible prodrugs and metabolites encompassed by the claim has not been defined. Therefore the metes and bounds of the claim are indefinite.
For the purpose of applying prior art, claims 1-10 have been interpreted without the limitation “a prodrug thereof, or a metabolite thereof” appearing in the claims.
Allowable Subject Matter
The compounds of Formula (I) as in claim 1 and the compounds of independent claim 9 have been found to be free of prior art. Except for the 35 U.S.C. 112 rejections, all claims would be allowable.
The following is a statement of reasons for the indication of allowable subject matter:
The instant application relates to a compound of general Formula (I) or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, with variables as defined in instant claim 1, a pharmaceutical composition and a method of treatment thereof of diseases or conditions associated with FGFR.
The closest prior art of record is Lu et al. (CN111606908 A, publication date 09/01/2020, hereinafter Lu, in the IDS). Lu teaches JAK kinase inhibitor compounds of formula (G) (Abstract of English Translation).
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Lu teaches the following exemplary compound, Compound MDI-202 (Para. [0599], Original Chinese document, Pg. 61).
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Compound MDI-202 of Lu overlaps the core structure of instant Formula (I), wherein
L is (C=O);
R6 is H;
n is 1;
R5 is C5 aryl (pyrazol-4-yl) substituted with one R5a, R5a being C1 alkyl (methyl).
Compound MDI-202 of Lu, however, differs from the instant compounds in the group attached to the phenyl ring of the indazole nucleus. It does not contain the
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required by the instant claims. There is no teaching or suggestion in the prior art to arrive at the compounds of the instant invention. Therefore, the instant compounds are novel and non-obvious variants of the compounds taught in the prior art.
Conclusion
Claims 1-10 are rejected.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627