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
Claims 1-10 are pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Instant application is continuation of PCT/CN2022/088752, filed 04/24/2022. PCT/CN2022/088752 claims priority of foreign application CN202110684539.3, filed 06/21/2021. Therefore, the effective filing date is 06/21/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1-4 and 6 are objected to because of the following informalities:
Claim 1 reads “…R1 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-C6 alkyl hydroxyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; or R1 is morpholinyl, tetrahydropyrrolyl, morpholinyl substituted by one or more hydroxyl or C1-C6 alkyl, or tetrahydropyrrolyl substituted by one or more hydroxyl or C1-C6 alkyl; or R1 is
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;”. For clarity and brevity, and to correct the missing subscript, this should instead read “…R1 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-C6 alkyl hydroxyl, C1-C6 alkoxy, C3-C8 cycloalkyl, morpholinyl, tetrahydropyrrolyl, or
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, wherein the morpholinyl and tetrahydropyrrolyl are optionally substituted with one or more hydroxyl or C1-C6 alkyl;”.
Claim 1 reads “…R2 is selected from hydrogen, C1-6 alkyl, or C3-C8 cycloalkyl; C1-6 alkyl and C3-C8 cycloalkyl can be substituted by one or more halogen;” and should read ““…R2 is selected from hydrogen, C1-6 alkyl, or C3-C8 cycloalkyl, wherein the C1-6 alkyl and C3-C8 cycloalkyl are optionally substituted by one or more halogen;”.
Claims 2 and 3 read “…R1 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; or R1 is
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”. For clarity and brevity, this should instead read “…R1 is selected from hydrogen, cyano, halogen, C1-6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl,
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”.
Claim 4 reads “…wherein the structure of the sulfoximide substituted indazole compound is shown in the table below:…” and should read “…wherein the structure of the sulfoximide substituted indazole compound is selected from the table below:…”.
Claim 6 reads “…prevention or treatment of IRAK4-related disease.” and should read “…prevention or treatment of an IRAK4-related disease.”
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 6-9 are rejected under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
For the sake of compact prosecution, claims 6-9 will be interpreted as a method of preventing or treating those diseases or conditions listed in claims 6-9 comprising administering a compound of claim 1.
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.
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 compounds of formula (I) where Ar is phenyl, naphthyl, or 5-10 membered heteroaryl, does not reasonably provide enablement for compounds of formula (I) and isomers 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 make the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful as IRAK4 kinase inhibitors. This invention is also directed to compositions comprising said compounds.
Predictability of the art
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. 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).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
4. The breadth of the claims
The scope of the claims involves compounds of formula (I), shown below, and isomers thereof.
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Claim 1 is very broad in the options of substituents for Ar and in the recitation of isomers of compounds of formula (I). There is an indefinite amount of hypothetical compounds included in claim 1.
5. The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary
The specification only provides the synthesis of 36 compounds. In all of the compounds synthesized, Ar is phenyl or a 5-10 membered heterocycle. However, it would be assumed that the inventors are also enabled for Ar to be naphthyl, since this substituent would be similar in size and reactivity to others taught. There are no examples of isomers of compounds of formula (I).
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. It would be expected that the varying ring sizes and heteroatoms in the rings of Ar would change the reactivity of the compounds, and therefore may require alternate synthesis methods. Synthesis methods are not provided for any isomers of compounds of formula (I). It would require one skilled in the art, such as a chemist, to perform an indefinite number of reactions to determine which compounds of formula (I) and isomers thereof can be prepared and would require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 6-9 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 method of inhibiting IRAK4 kinase activity, TNF-α secretion, and hERG potassium channel current comprising administering a compound of formula (I), does not reasonably provide enablement for the treatment of any IRAK4 related disease or condition comprising a compound of formula (I) or an isomer 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.
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. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
Breadth of the claims
The breadth of the claim includes a method of treating a disease related to IRAK4 in a patient, comprising administering a compound of the formula (I) or an isomer thereof.
Nature of the invention
The nature of the invention is performance of a method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof.
State of the prior art
No single drug has been discovered that is effective in treating the myriad of IRAK4-related diseases in a patient, including, but not limited to, autoimmune disease, inflammatory disease, pain disease, respiratory and lung disease, gastrointestinal disease, allergic disease, infectious disease, trauma and tissue injury disease, fibrotic disease, eye disease, joint, muscle and bone disease, skin disease, kidney disease, hematopoietic system disease, liver disease, oral disease, metabolic disease, heart disease, vascular disease, neuroinflammatory disease, neurodegenerative disease, sepsis, genetic disease, and cancer. See In re Hokum, 226 USPQ 353 (ComrPats 1985).
Since the compounds synthesized in the instant specification appear novel, there is no prior art teaching that these compounds are enabled for the treatment of any specific disease or condition.
Level of one of ordinary skill in the art
The artisans performing the inventor’s or joint inventor’s method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
Level of predictability in the art
Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ at 367 ¶3. Similarly, it is well established that “[T]he 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). Since the claims include any isomer of a compound of formula (I), there would be no predictability that these isomers would share any significant structural similarity with formula (I) or have the same properties as compounds of formula (I).
Amount of direction provided by the inventor
The invention lacks direction with respect to making and/or using (performing) a method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof.
Existence of working examples
The disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof.
Similarly, according to the specification, compounds of formula (I) and isomers thereof are capable of treating a variety of diseases in a patient, including, but not limited to, autoimmune disease, inflammatory disease, pain disease, respiratory and lung disease, gastrointestinal disease, allergic disease, infectious disease, trauma and tissue injury disease, fibrotic disease, eye disease, joint, muscle and bone disease, skin disease, kidney disease, hematopoietic system disease, liver disease, oral disease, metabolic disease, heart disease, vascular disease, neuroinflammatory disease, neurodegenerative disease, sepsis, genetic disease, and cancer.
However, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any of the aforementioned diseases. The specification only provides examples for inhibiting IRAK4 kinase activity, TNF-α secretion, and hERG potassium channel current comprising administering specific compounds of formula (I). There is insufficient disclosure to reasonably conclude that the method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof, as recited, would contribute to treatment of any the aforementioned diseases. No examples are provided for the treatment of any specific IRAK4-related disease. The inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claim.
Quantity of experimentation needed
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
One skilled in the art, such as a medical doctor, would be required to perform hundreds of clinical trials and in vivo or in vitro assays in order to determine which of the infinite number of compounds of formula (I) and isomers thereof would be capable of treating which IRAK4-related diseases. Even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404. These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for a method of treating an IRAK4-related disease in a patient, comprising administering a compound of formula (I) or an isomer thereof, is clearly justified.
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 6-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the administration of the compound of claim 1. For the sake of compact prosecution, claim 6-9 will be interpreted as described above in the 35 U.S.C. 101 rejection.
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 claims 1-10, the phrase "an isomer thereof" renders the claims indefinite because the claims includes elements not actually disclosed (those encompassed by "an isomer thereof"), thereby rendering the scope of the claims unascertainable. Neither the specification nor the claims specify what type of isomer is included in this definition. If the claims are referencing, for example, a constitutional isomer, this would result in an indefinite number of compounds, since the compounds need only share a molecular formula with any hypothetical compound of formula (I), and would not need to share a structural feature with formula (I). This rejection would be overcome by removing “an isomer thereof” from the claims.
The inventor or joint inventor should note that claim 6 is a reach-through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented. Similarly, the metes and bounds of the preventable or treatable IRAK4-related diseases or conditions are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification and claims teach treatable or preventable IRAK4-related diseases or conditions to include, but are not limited to, “autoimmune disease, inflammatory disease, pain disease, respiratory and lung disease, gastrointestinal disease, allergic disease, infectious disease, trauma and tissue injury disease, fibrotic disease, eye disease, joint, muscle and bone disease, skin disease, kidney disease, hematopoietic system disease, liver disease, oral disease, metabolic disease, heart disease, vascular disease, neuroinflammatory disease, neurodegenerative disease, sepsis, genetic disease, and cancer”. However, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments, including, but not limited to, the above listed conditions and diseases. Consequently, the method for the treatment or prophylaxis of an IRAK4-related disease or condition, the method comprising administering a compound of formula (I) or an isomer thereof has been rendered indefinite by the use of the reach-through protocol.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Rejections - 35 U.S.C. § 112(a), to overcome this rejection.
Conclusion
Claims 1-10 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 7-3.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624