DETAILED ACTION
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, 2, 4, 6, 9, 11, 14, 17, 19, 22, 25, 26, 30, 32-35, 37, 38, and 41 are pending. Claims 3, 5, 7, 8, 10, 12, 13, 15, 16, 18, 20, 21, 23, 24, 27-29, 31, 36, 39, and 40 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2021/064666, filed on December 21, 2021. This application also claims the benefits of U.S. Patent Application No. 63/128,964, filed on December 22, 2020.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The abstract is further objected to as it does not accurately reflect the enabled subject matter of the application. An example amended abstract is provided below:
The present invention relates to imidazo[1,2-a]pyridinyl derivatives of formula (I):
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, or pharmaceutically acceptable salts thereof, that are capable of modulating the activity of interleukin-1 receptor-associated kinase-4 (IRAK4). The variables X, Y, Z, R1, R2, R3, R4, R5, R6, R7, and R8 of formula (I) are as defined herein. The present invention also provides methods for preparing the imidazo[1,2-a]pyridinyl derivatives of formula (I).
In the current version of the abstract, it states:
“The disclosure further provides methods… to their medical use, in particular to their use in the treatment and management of diseases or disorders including inflammatory disease, autoimmune disease, cancer, cardiovascular disease, a disease of the central nervous system, disease of the skin, an ophthalmic disease and condition, and a bone disease.”
This sentence is not present in the amended abstract example as shown above because the instant specification does not include sufficient disclosure demonstrating treatment of the aforementioned diseases or disorders. The instant specification only provides data that the instant compounds can inhibit IRAK4 activity in vitro.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 9, 38, and 41 are objected to because of the following informalities:
For claim 1:
The “and” that follows “is optionally substituted with 1 to 3 halo” and precedes “R3, R4, R5, R6 and R7 are each independently selected from” should be deleted.
“two heteroatoms independently selected O, N, and S” should read “two heteroatoms independently selected from O, N, and S”.
For claim 9:
Formulas IIA and IIB combined is equivalent to Formula II. Therefore, to avoid repetition, Formula II can be removed from claim 9 and Formulas IIA and IIB can remain.
Likewise, Formulas IIIA and IIIB combined is equivalent to Formula III. Therefore, to avoid repetition, Formula III can be removed from claim 9 and Formulas IIIA and IIIB can remain.
There should be a space between “(IIIA),” and “or”
For claim 38:
“ophthalmology” should read “ophthalmic diseases”
For claim 41:
“is selected from the group consisting from is selected from…” should read “is selected from the group consisting from…”
Appropriate correction is required.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Hopkins et al. (Hopkins) (WO2020150626A1; published July 23, 2020).
Novelty:
Hopkins teaches imidazo[1,2-a]pyridinyl derivatives of the formula (I’):
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as compounds capable of modulating the activity of interleukin-1 receptor-associated kinase 4 (i.e., IRAK4) (abstract). The variables of formula (I’) are defined in claim 1 of Hopkins. The IRAK4 inhibitors represented by formula (I’) as disclosed in Hopkins differ from those presently claimed in that all the compounds of Hopkins have a reversed amido group attached to the central bicyclic ring. Moreover, none of the exemplified compounds of Hopkins possess a cyclopropyl ring attached to the pyridinone (see compound 496 on pg. 63 of Hopkins as an example):
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.
Thus, the instant invention is considered novel.
Nonobviousness:
Both Hopkins and the present invention disclose IRAK4 inhibitors. Although a POSITA would have considered it obvious to further explore derivatives of the compounds disclosed in Hopkins (such as the compounds of the present invention) as IRAK4 inhibitors, Hopkins does not teach nor suggest both reversing the amido linker orientation and attaching a cyclopropyl substituent to, specifically, the pyridinone ring of the formula (I’) compounds to arrive at the instantly claimed compounds.
Thus, the instant invention is considered nonobvious.
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 38 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 38 recites “The method of claim 37, wherein the IRAK4 mediated disease is selected from the group consisting from ophthalmology, uveitis…” The instant specification does not mention “uveitis”. Thus, claim 38 fails to comply with the written description requirement.
Claims 1, 2, 4, 6, 9, 11, 14, 17, 19, 22, 25, 26, 30, 32-35, 37, 38, and 41 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 the following list of enabling elements, does not reasonably provide enablement for any compound that does not meet the enabling requirements listed below.
Enabling elements:
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, or a pharmaceutically acceptable salt thereof, wherein:
X is CH, CF or N;
Y is CH or N;
Z is ring A or -CH2-ring A-*, wherein -* indicates the point of connection to R1;
Ring A is
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wherein n is 1 or 2;
W is absent, CH2 or O, and -* indicates the point of connection to R1;
R1 is H, -CN, C1-3alkoxy or C1-3alkyl optionally substituted with 1 substituent independently selected from halo and C1-3alkoxy;
R2 is C3-6cycloalkyl or C1-4alkyl, wherein the C1-4alkyl is optionally substituted with 1 to 2 halo; and
R3, R4, R5, R6 and R7 are each independently selected from H, halo, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy or any two of R3, R4, R5, R6 and R7 together with the carbon atoms from which they are attached form a C3-6cycloalkyl; and
R8 is H.
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 and use the invention commensurate in scope with these claims.
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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims imidazo[1,2-a]pyridinyl derivatives of formula (I):
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, or pharmaceutically acceptable salts thereof, that are capable of modulating the activity of interleukin-1 receptor-associated kinase-4 (IRAK4). The variables X, Y, Z, R1, R2, R3, R4, R5, R6, R7, and R8 of formula (I) are as defined in the instant specification. The present invention also provides methods for preparing the imidazo[1,2-a]pyridinyl derivatives of formula (I).
State of the prior art
The teachings of Hopkins as discussed above in the “Examiner’s note on novelty and nonobviousness” section are incorporated herein.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
The instant specification discloses nearly 200 examples (see Examples 1-192 on pg. 112-243 which correspond to the compounds listed in instant claim 34) of compounds represented by formula (I) as disclosed in instant claim 1. However, these examples only teach a subset of the claimed embodiments. Therefore, the specification is not enabling for the remaining, non-exemplified substituent combinations recited in instant claim 1.
Accordingly, claim 1 is not fully enabled by the specification. Claims 2, 4, 6, 9, 11, 14, 17, 19, 22, 25, 26, 30, 32-35, 37, 38, and 41, which are dependent on claim 1, are also rejected for further requiring and/or reciting the non-enabling elements listed above.
The breadth of the claims
The claims are broad insofar as the instant claims recite an IRAK4 inhibitor of formula (I) wherein the compound can possess a structurally diverse range of chemical groups.
Claims 37, 38, and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims imidazo[1,2-a]pyridinyl derivatives of formula (I):
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, or pharmaceutically acceptable salts thereof, that are capable of modulating the activity of interleukin-1 receptor-associated kinase-4 (IRAK4). The variables X, Y, Z, R1, R2, R3, R4, R5, R6, R7, and R8 of formula (I) are as defined in the instant specification. The present invention also provides methods for preparing the imidazo[1,2-a]pyridinyl derivatives of formula (I).
State of the prior art
The teachings of Hopkins as discussed above in the “Examiner’s note on novelty and nonobviousness” section are incorporated herein.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The amount of direction or guidance present and quantity of experimentation necessary
According to the instant specification, “the term “treat”, “treating” or “treatment” of any disease, condition or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder” (pg. 39, “Definitions” section, 3rd paragraph).
The prior art only provides in vitro biochemical assay data (which indicates the IRAK4 inhibitory activity of the compounds of Hopkins: see the Potency Data Table in Hopkins, pg. 363-373). The instant specification also only provides in vitro data from biochemical, MDR1-MDCK, solubility, and Kpuu assays. In both the prior art and the instant specification, there is no disclosure on a reasonably predictive correlation between the reported assay datapoints and, for example, clinical symptom amelioration/improvement in patients having any of the IRAK4 mediated diseases as listed in instant claims 38 and 41. In the absence of such a correlation or additional in vivo/clinical data, a POSITA would require undue experimentation to practice the claimed therapeutic method across its scope.
Even though the in vitro data of the instant specification show that the instant compounds can inhibit IRAK4 (which is a desired pharmacological effect), this inhibitory activity is not demonstrated in patients.
Thus, instant claims 37, 38, and 41 fail to comply with the enablement requirement.
The breadth of the claims
The claims are broad insofar as the instant claims recite an IRAK4 inhibitor of formula (I) wherein the compound can possess a structurally diverse range of chemical groups.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624