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 1-91 are pending as of the response filed on 03/23/2026 and supplemental amendment filed on 03/31/2026. Applicant’s election of Group I claims 1-16, 22-26 and 32-91 without traverse is acknowledged. Claims 17-21 and 27-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 without traverse is acknowledged.
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The elected species is encompassed by claims 1-16, 22-26, 32-33, 39 and 68. Claims 34-38, 40-67 and 69-91 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Therefore, claims 1-16, 22-26, 32-33, 39 and 68 have been examined to the extent to which they are readable on the above identified elected invention and elected species.
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 371 of PCT/JP2022/022306 filed 06/01/2022 and claims foreign priority to JAPAN 2021-092947 filed 06/02/2021.
Acknowledgment is made of Applicant's claim for foreign priority. It is noted, however, that Applicant has not provided an English translation of the certified copy of the application filed in Japan. Without the English translation, one cannot ascertain if the instant invention is supported in the Japanese application. Therefore, art prior to the PCT date, but not before the date of the foreign application may be cited against the claims.
Information Disclosure Statement
The information disclosure statements submitted on 12/29/2025, 04/22/2025, 07/23/2024, 04/26/2024 and 02/13/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
37 C.F.R. 1.121
The following claims have not been provided with the proper status identifier, which is improper.
Claims 34-38, 40-67 and 69-91 are non-compliant. These claims should have the status identifier “Withdrawn”, since they are not encompassed by the elected species.
See MPEP 714(II)(C) for further explanation of the amendment format required by 37 CFR 1.121.
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 7-16 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 therapeutic agent for a disease caused by PAR2 activation, comprising the compound according to claim 1 or a salt thereof OR a therapeutic pharmaceutical composition for a disease caused by PAR2 activation, comprising the compound according to claim 1, does not reasonably provide enablement for a preventative and/or diagnostic agent OR preventative and/or diagnostic pharmaceutical composition for a symptom and/or disease caused by PAR2 activation. 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. This is a scope of enablement rejection.
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 a therapeutic, preventative and/or diagnostic agent for a symptom and/or disease caused by PAR2 activation, comprising the compound of the invention according to claim 1 OR a therapeutic, preventative and/or diagnostic pharmaceutical composition for a symptom and/or disease caused by PAR2 activation, comprising the compound of the invention represented by general formula [I] according to claim 1. The scope of the claims is broad, as they encompass a generic product drawn not only to a therapeutic but also a preventative and/or diagnostic agent/pharmaceutical composition comprising the compound of the invention according to claim 1. The nature of the invention is the provision of compounds having PAR2-inhibitory activity.
The state of the prior art/The level of predictability in the art
Yau et al. (Toward Drugs for Protease-Activated Receptor 2 (PAR2), 30 July 2013, hereinafter Yau); Nowak et al. (Diagnosis and treatment of pruritus, December 2017, hereinafter Nowak).
Yau teaches the activation of PAR2 is associated with many inflammatory, respiratory, gastrointestinal, metabolic, cardiovascular, and neurological diseases, as well as cancers (Pg. 7480, first column, last paragraph). Yau teaches PAR2 activation has also been implicated in different forms of cancer (Pg. 7480, second column, third full paragraph). Yau teaches PAR2 transduces signals to initiate downstream pathways not only through coupling to G proteins, but also trigger G-protein independent pathways, such as through coupling to β-arrestins 1 and 2 (Pg. 7483, first column, last paragraph). Yau teaches development of potent PAR2 ligands has been both challenging and interesting, and emphasize the need for designing robust assays to determine effects of the PAR2 ligands on multiple signaling events (Pg. 7483, second column, third full paragraph). Yau highlights that despite the clear involvement of PAR2 in numerous diseases, the exact mechanisms by which PAR2 signaling leads to specific pathological conditions remains to be fully understood (Pg. 7490, first column, last paragraph).
Nowak teaches pruritus is the most common cutaneous symptom, yet it is difficult to diagnose and manage (Pg. 918, fifth full paragraph). Nowak teaches that the differential diagnosis for generalized pruritus can be challenging and that pruritus may be an early skin manifestation of a more severe systemic disease (Pg. 919, second column, first full paragraph - fourth full paragraph).
Therefore, the state of the prior art indicates unpredictability and complexity with respect to PAR2 signaling pathways and the associated pathological conditions. The state of the prior art highlights the challenges with regard to the design of ligands that act as inhibitors of PAR2 activation. The state of the prior art indicates pruritus is the most common cutaneous symptom, yet it poses considerable difficulty in diagnosis and management. Thus, it is clear that not only diagnosis but also prevention of pruritus (a symptom caused by PAR2 activation) is not well-established or predictable in consideration of the art.
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 high level of unpredictability in the field of PAR2 activation and diagnosis/management of symptoms of PAR2 activation, such as pruritus, it is unclear how the intended products comprising the compound of the invention of general formula [I] according to claim 1, can act as a preventative and/or diagnostic agent/pharmaceutical composition.
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 dermatologist with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally there is significant unpredictability in the art regarding the development of therapies related to PAR2 activation.
The amount of direction provided by the inventor/The existence of working examples
Applicants have provided in vitro assays for the example compounds that exhibit the desired PAR2 inhibitory activity (Paras. [0206]-[0207], Table 3-1, Table 3-2 of the instant specification). However, the disclosure does not provide any data to indicate how these compounds act as a preventative and/or a diagnostic agents for a symptom and/or disease caused by PAR2 activation.
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 1-2, 6, 22-26 and 32-33 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.
1) Regarding claim 1, the claim recites “
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is 5- to 9-membered saturated or partially saturated heterocyclic ring or an oxo thereof”. It is not clear as to what the limitation “or an oxo thereof” refers to with respect to the structure of
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. Therefore, the metes and bounds of the claim is indefinite.
2) Further, claim 1 recites “
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is 5- to 9-membered saturated or partially saturated heterocyclic ring … containing one nitrogen atom as ring-constituting atom … wherein the heterocyclic ring may further have one nitrogen atom, one oxygen atom and/or one sulfur atom as ring-constituting atom”. The scope of the claim is unclear since the generic structure “
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” already indicates that the ring has a “nitrogen” as a ring-constituting atom. The recitation of “heterocyclic ring … containing one nitrogen atom as ring-constituting atom” appears to be redundant and the further recitation of “the heterocyclic ring may further have one nitrogen atom, one oxygen atom and/or one sulfur atom as ring-constituting atom” causes ambiguity regarding the scope of the claim. It is not clear as to how many heteroatoms can be present in the N-containing ring of the compound of formula [I] as in claim 1 at a given time. Can the ring have a second nitrogen atom or just one, in addition to other optional heteroatoms of oxygen and/or sulfur?
For the purpose of applying prior art, claim 1 has been interpreted as “
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is 5- to 9-membered saturated or partially saturated heterocyclic ring[[ an oxo thereof, containing one nitrogen atom as ring-constituting atom]], which may optionally have an oxo, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, hydroxy or methylidene as substituent, wherein the heterocyclic ring may further optionally have one additional nitrogen atom, one oxygen atom and/or one sulfur atom as ring-constituting atom”.
3) Further, claim 1 recites “R2 is C4-8 cycloalkyl optionally substituted by halogen or C1-6 alkyl … C3-8 cycloalkyl-C1-6alkyl …”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP 2173.05 (c). In the present instance, claim 1 recites the broad recitation C3-8 cycloalkyl-C1-6alkyl for the variable R2, and the claim also recites C4-8 cycloalkyl optionally substituted by C1-6 alkyl as an option for R2 (this essentially constitutes C4-8 cycloalkyl-C1-6 alkyl) which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For the purpose of applying prior art, claim 1 has been interpreted with the broader limitation of C3-8 cycloalkyl-C1-6alkyl as an option of R2, when the cycloalkyl is substituted with an alkyl.
4) Regarding claim 2, the claim recites “
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is piperidinyl, azepanyl, … oxazepanyl or oxo thereof”. It is not clear as to what the limitation “or an oxo thereof” refers to with respect to the structure of oxazepanyl . Therefore, the metes and bounds of the claim is indefinite.
For the purpose of applying prior art, claim 2 has been interpreted as “
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is oxazepanyl [[or]] optionally substituted with an oxo [[thereof]]”.
Claims 6, 22-26 and 32-33 are similarly rejected since they depend from claim 1 either directly or indirectly, and do not remedy the indefiniteness.
Claim Interpretation
In claim 1, wherein R2 is defined as, for instance, C3-8 cycloalkyl-C1-6 alkyl, the R2 variable is interpreted as being attached to the pyrazolo[1,5-a]pyrimidine core via either end, i.e., the cycloalkyl or alkyl end. This interpretation holds for other similar R2 substituents as well.
In claim 2, in the limitation “oxazepanyl or oxo thereof”, the oxo substituent (see claim interpretation in the 35 U.S.C. § 112(b) rejection above) is only applied to oxazepanyl and none of the preceding
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heterocycles.
Allowable Subject Matter
Except for the 35 U.S.C. § 112(a) and 35 U.S.C. § 112(b) rejection above, compounds of general formula [I] are free of prior art. Claims 3-5, 39 and 68 are objected to as being dependent from a rejected base claim.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art of record is Farmer et al. (WO 2015/048245 A1, 02 April 2015, hereinafter Farmer, in the IDS) and Anderson et al. (WO 2004/089471 A2, 21 October 2004, hereinafter Anderson, in the IDS).
Farmer teaches imidazopyridazines as inhibitors of PAR-2 signaling pathway (Title; Abstract). Farmer teaches compounds of formula (I), with variables as defined (Para. [0011]).
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Farmer teaches the exemplary compound, compound I-65 (Para .[0055]).
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Compound I-65 of Farmer substantially overlaps the scope of instant formula [I], wherein R1 is C1 haloalkyl (CF3),
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heterocycle is piperazinyl substituted with C1 alkyl (methyl); R3 is hydrogen. Compound I-65 of Farmer differs in the core structure being an imidazopyridazine versus the instantly claimed pyrazolo[1,5-a]pyrimidine core and the R2 being a substituted aryl versus the instantly claimed R2 groups.
Anderson teaches pyrazolo[1,5-a]pyrimidines having 11βHSD1 inhibitory activity (Abstract). Anderson teaches compounds of formula (I), with variables as defined (Pg. 9, Ln. 27 – Pg. 11, Ln. 20).
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Anderson teaches the exemplary compound of example 3 (Pg. 37, Ln. 17- Pg. 38, Ln. 7) and example 4-4 (Pg. 39, third example).
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The compounds of Anderson substantially overlap the scope of instant formula [I], wherein R1 is C1 haloalkyl (CF3),
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heterocycle is piperazinyl; R3 is hydrogen. The compounds of Anderson differ from the instant compounds in the R2 variable being an alkyl or aryl versus the instantly claimed R2 groups.
The novelty of the instant compounds of formula [I] lies in the R2 variable as defined in instant claim 1, that is not taught or suggested by the prior art. Therefore, the instant compounds are novel and non-obvious variants of the compounds taught in the prior art.
Conclusion
Claims 1-2, 6-16, 22-26 and 32-33 are rejected.
Claims 3-5, 39 and 68 are objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached 9:00-5:30pm EDT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PADMAJA S RAO/Examiner, Art Unit 1627
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