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 .
Priority
Applicant’s claim for the benefit a prior-filed application under 35 U.S.C. 119(e) is acknowledged. The instant application, filed 11/08/2024, claims the benefit of U.S. Provisional Patent Application No. 63/548,135, filed on 11/10/2023.
Information Disclosure Statement
The Information Disclosure Statement received on 06/04/2026 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered. Page 26 c3-12
Status of Claims
Claims 1-95 were originally presented on 11/08/2024. Applicant’s preliminary amendments to the claims received on 05/20/2025 are acknowledged and entered. Claims 3, 5-6, 8-12, 15-17, 21-22, 27-29, 33-35, 39-40, 42-43, 46-48, 50-61, 63-64, 67-68, 72, 74, and 84-95 are cancelled.
Accordingly, claims 1, 2, 4, 7, 13, 14, 18-20, 23-26, 30-32, 36-38, 41, 44, 45, 49, 62, 65, 66, 69, 70, 71, 73, and 75-83 are pending and under consideration.
Claim Rejections - 35 USC § 112 (b)
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 19 and 20 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.
Claims 19 and 20 recite the compound of claim 1 wherein the variable X2 is CR2 or N. One of ordinary skill in the art would not reasonably understand the metes and the bounds of the claimed invention because the variable X2 is not defined in the parent claim 1.
Accordingly, claims 19 and 20 are rejected as indefinite.
Claim Rejections - 35 USC § 112(a)
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.
Non-compliance with the written description requirement
Claim 1, 2, 4, 7, 13, 14, 18-20, 23-26, 30-32, 36-38, 41, 44, 45, 49, 62, 65, 66, 69, 70, 71, 73, and 75-77, and 79-83 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(s) 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.
Applicant claims to have discovered compounds of Formula (I), where the X variables may be N or CR. R permits extensive substitution. Cy can be any 5 – 10 membered heterocyclic ring also extensively substituted. Applicant alleges that all of these compounds may be used for treating MRGPRX2 dependent conditions including contact dermatitis, cancer, HIV infections, end-stage renal failure, pseudorabies, and so on. See Formula (I) from claim 1,
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, and an embodiment:
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.
The claimed invention permits the following options for the X variables.
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Applicant reports zero data regarding compounds of Formula (I) wherein X5 or X6 is N. See Applicant’s exemplified embodiments of its claims, the Example 1-18 compounds:
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Applicant’s Example 1-18 compounds.
Applicant provided preliminary in vitro characterization of these compounds in Specification at 82, Table A. While the Specification also discusses examples of in vivo use of these compounds, e.g., a pharmacokinetics (“PK”) experiment on page 85, such examples are prophetic, with no data disclosed.
Compliance with the written description requirement for genus claims requires disclosing a representative number of species that describe the entire genus. See MPEP 2163, subsection 3(a)(ii).
Applicant discloses zero species wherein:
X5 or X6 is N.
Zero species for explicit embodiments of the claimed invention is not a representative number of species that describe the entire genus. See also, instant claims 38 and 45, requiring this specific configuration.
Therefore, Applicant failed to draft claims that comply with the written description requirement.
Further, Applicant discloses zero species wherein:
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and, the variable n is anything other than 0 (all exemplified cyclohexane diamine linkers are fully saturated, see above Examples)
The disclosure of zero species for “n is an integer from [1] to 8” that are explicit embodiments of the claimed invention is not the disclosure of a representative number of species that describe the entire genus. See also, instant claim 73, requiring this specific configuration.
Further, Applicant claims extensive substitution about the R and Cy variables. See claim 1 options for the R variables:
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Options available for the R variables.
However, upon review of the disclosed species, the only exemplified R variable options are H, CH3, CF3, and Br.
The disclosure of zero species for the extensive R variable substitutions that are explicit embodiments of the claimed invention is not the disclosure of a representative number of species that describe the entire genus.
Further, Applicant discloses zero species wherein Cy is a “5-10 membered heterocycloalkyl”. Moreover, Applicant discloses only 5 species where Cy is substituted with RCy, and in each case, the substitution is methyl. However, see Applicant’s claimed options for the Cy variable and its substitutions:
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…
Options for the Cy variable and its substitutions.
The disclosure of zero species for the extensive RCy variable substitutions that are explicit embodiments of the claimed invention is not the disclosure of a representative number of species that describe the entire genus. The disclosure of zero species for the Cy is a “5-10 membered heterocycloalkyl” species that are explicit embodiments of the claimed invention is not the disclosure of a representative number of species that describe the entire genus.
Accordingly, claims 1, 2, 4, 7, 13, 14, 18-20, 23-26, 30-32, 36-38, 41, 44, 45, 49, 62, 65, 66, 69, 70, 71, 73, and 75-77, 79-83 are rejected for failing to comply with the written description requirement.
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4, 7, 13, 18, 23, 24, 25, 31, 32, 36, 37, 41, 44, 49, 62, 65, 66, 69, 70, 71, 75-76 and 79-83 Anticipated by WO’946
Claim(s) 1, 2, 4, 7, 13, 18, 23, 24, 25, 31, 32, 36, 37, 41, 44, 49, 62, 65, 66, 69, 70, 71, 75-76 and 79-83 is/are rejected under 35 U.S.C. (a)(2) as being anticipated by WO’946.1
A machine translation of WO’946 was obtained using WIPO PatentScope, referenced herein as the “WO’946 Translation”. The printout of the translation occasionally splits across pages (e.g., chemical structures), so at times the following rejection will reference WO’946 page numbers directly. Other times, the translation fails to capture certain text like subscript or embedded figures. In those cases, a screenshot of the WO’946 text was processed through Google Translate and is provided below when necessary. When reading the WO’946 Translation, certain subscripts/superscripts get pushed to the end of the paragraphs, as explained below.
Applicant claims to have discovered compounds of Formula (I), where the X variables may be N or CR. R permits extensive substitution. Cy can be any 5 – 10 membered heterocyclic ring also extensively substituted. Applicant alleges that all of these compounds may be used for treating MRGPRX2 dependent conditions including contact dermatitis, cancer, HIV infections, end-stage renal failure, pseudorabies, and so on. See Formula (I) from claim 1,
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, and an embodiment:
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WO’946 Translation teaches methods of treating an MRGPRX2 dependent condition in a patient comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 1, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis.
See WO’946 Translation at 97/98, claim 15, and the following compounds recited in claim 13 (shown below from WO’946 at 110-113):
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See also WO’946 Translation at 93/98, claim 12, teaching the method wherein the compound also includes the following compound of instant claim 1:
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.
The methods of WO’946 also teach the “stereoisomer[s]” of the above compounds, which includes their enantiomers and diastereomers. See WO’946 Translation at 24, paragraphs [0213]-[0214]. See also, WO’946 Translation at 23 and 24, paragraphs [0198] and [0205], explaining that the “use” of the compounds/compositions is for “a method for … treating MRGPX2-related diseases…”.
As shown below, Applicant’s instant Example 5 compound is a bioisostere of one of the compounds recited in claim 13 of WO’946 that is designated compound 11 of WO’946:
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Applicant’s claimed invention
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WO’946 at 111, claim 13, bottom right
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Designation as compound 11 of WO’946, see WO’946 Translation at 43/98.
Compound 11 of WO’946 is a compound of instant claims 1, 2, 4, 13, 18, 23, 24, 25, 31, 36, 37, 41, 44, 49, 62, 66 (Cy = imidazo[1,5-a]pyrazinyl), 69, 70, 71, and 75. Claim 15 of WO’946 teaches its administration in the form of a pharmaceutical composition with a carrier or excipient (see WO’946 Translation at 24/98, paragraph [0211]) for treating contact dermatitis.
Accordingly, claims 1, 2, 4, 13, 18, 23, 24, 25, 31, 36, 37, 41, 44, 49, 62, 66, 69, 70, 71, 75, and 79-83 are anticipated by WO’946. Compound 11 of WO’946 also anticipates the indefinite instant claims 19 and 20 because the compound still reads on claims 19 and 20, being a compound of claim 1.
The following compound recited in claim 13 of WO’946 is designated compound 5 of WO’946:
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WO’946 at 111, claim 13 middle
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Designation as compound 5 of WO’946, see WO’946 Translation at 37/98.
Compound 5 of WO’946 is a compound of instant claims 7 and 76, among others.
The examiner notes in the instant claim 76, the cyclohexane diamine linker is drawn as follows:
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The examiner does not interpret the A-9 structure as requiring a particular chirality because the darkened lines are not wedges. To the extent that Applicant may amend or assert that the A-9 structure requires a particular chirality, WO’946 teaches the administration of the diastereomers of its compounds in the claims.
Accordingly, claims 7 and 76 are also anticipated by WO’946.
Moreover, WO’946 effectively teaches a structural activity relationship study (a “SAR” study, or just a “SAR”), about the Mas-related G protein coupled receptors (MRGPRs), with MRGPX2 exemplified. See WO’946 Translation at 2-3, Background section, discussing MRGPX2 antagonism and its applications in medicine. See WO’946 Translation at 77, Table 1 (disclosing results from an in vitro calcium flow assay for exemplified embodiments of the invention of WO’946, which is the same assay Applicant reports in the Instant Specification at 82, Table A, header MRGPRX2 FLIPR):
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WO’946 Translation at 77.
PatentScope does not always translate the text in images (see above Table 1). Below is the same above table ran through Google Translate:
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Table 1 of WO’946 Translation at 77 (processed through Google Translate).
See the corresponding compounds from the Specification of WO’946 Translation:
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The above compounds 1, 2, 4, 10, 11, 30, and 1A are all compounds of the instant claim 1. As shown within the SAR of WO’946, the 6-6 and 5-6 fused aromatic heterocycles attached to the top side of the cyclohexane diamine linker are bioisosteric. Further, the 1,3- and 1,4- cyclohexane diamine linkers are bioisosteric. Moreover, CH and N exchanges are bioisosteric. See, e.g., compounds 2 and 4, which show that the exchange of a CH unit for N results in compounds that affect the same pharmacological target in the same way and thereby have related properties.
One of skill in the art at the time of filing, reading WO’946, would recognize that such bioisosterism was discussed throughout its Specification and claims. For example, see WO’946 Translation at 92/98, claim 11, explaining that the 6-6 and 5-6 fused aromatic heterocycles attached to the top side of the cyclohexane diamine linker are bioisosteric, as well as CH and N exchanges, as well as exchanging the 1,3- and 1,4- cyclohexane diamine linkers:
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WO’946 Translation at 92/98, claim 11.
The above screenshot shows a common issue with PatentScope’s machine translation – that certain superscripts get pushed to the end of the paragraph in the order that they appear.
The final wherein clause in the above screenshot appears at the bottom of WO’946 at 106 and states:
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WO’946 at 17.
Therefore, the “1123” in the final wherein clause pertains in order to the “X, R, R, R” variables and means “X1, R1, R2, R3”.
X1 in the above claim 11 structures are N or CH. See WO’946 Translation at 81/98, claim 1:
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WO’946 Translation at 81/98, claim 1.
For the limited class of compounds taught in claim 11, the only available option for X1 was either N or CH. Each exemplified compound represented a preferred embodiment of the of the formulas of claim, for which there was a large unchanging structural nucleus. There would be no reason for including claim 11 of WO’946 but for expressly teaching the X1 = N bioisosteres of its exemplified compounds. Therefore, one of skill in the art at the time of filing, reading WO’946, would recognize that WO’946 taught the X1 = N bioisosteres of its exemplified compounds, like the X1 = N bioisostere of compound 11. Accordingly, one of skill in the art reading WO’946 would at once envisage the X1 = N bioisostere of compound 11, shown below on the right.
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Following the exact same analysis, one of skill in the art reading WO’946 would at once envisage the X1 = N bioisostere of the compound 5.
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Accordingly, claim 32 is also anticipated by WO’946.
Regarding claim 65, reciting that Cy is unsubstituted heteroaryl, see WO’946 Translation at 90-91, claim 10. Claim 11, which provides the above Formulas Ic-3 and Ic-4, depends on claim 10. Claim 10 at 91 states, “Preferably, ring D is…”:
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While the general formulas recited in WO’946 may seem to describe an immense number of compounds, every Ic-3 and Ic-4 compound with preferrable D rings could be drawn by hand. The compounds include those wherein Cy is unsubstituted heteroaryl,
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Accordingly, one of skill in the art at the time of filing, reading WO’946, would at once envisage compound 30 of WO’946
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, which is recited in WO’946 at 113, claim 13 (middle right, designated compound 30 in WO’946 Translation at 63/98), wherein Cy was a preferred unsubstituted heteroaryl
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Accordingly, claim 65 is anticipated by WO’946.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 7, 13, 14, 18-20, 23-26, 30-32, 36-38, 41, 44, 45, 49, 62, 65, 66, 69, 70, 71, 73, and 75-83 Obvious over WO’946 in view of Patani 1996
Claim(s) 1, 2, 4, 7, 13, 14, 18-20, 23-26, 30-32, 36-38, 41, 44, 45, 49, 62, 65, 66, 69, 70, 71, 73, and 75-83 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’946 in view of Patani 1996.2
The preceding discussion of WO’946 and rejections of claim(s) 1, 2, 4, 7, 13, 18, 23, 24, 25, 31, 32, 36, 37, 41, 44, 49, 62, 65, 66, 69, 70, 71, 75-76 and 79-83 under 35 U.S.C. (a)(2) as being anticipated by WO’946 are incorporated herein.
As discussed in the preceding rejection, one of skill in the art, reading WO’946, would recognize it discussed bioisosterism through its Specification and claims.
As discussed, one of skill in the art at the time of filing, reading WO’946, would at once envisage compound 30 of WO’946
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, which is recited in WO’946 at 113, claim 13 (middle right, designated compound 30 in WO’946 Translation at 63/98), wherein Cy was a preferred unsubstituted heteroaryl
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.
Compared to WO’946 compound 30, the unsubstituted variant was just another example of a bioisostere of the compounds exemplified throughout WO’946, depicting a H for F bioisosteric exchange:
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One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering the H-bioisostere of WO’946 compound 30 in a method of treating an MRGPRX2 dependent condition, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis, because
the H-bioisostere of WO’946 compound 30 was indeed a compound expressly taught by the claims of WO’946 and therefore was useful in its methods, and
Patani 1996 teaches that there was a reasonable expectation that the bioisostere would affect the same pharmacological targets as the WO’946 compound 30 and thereby have related properties.
Patani 1996
The exchange of fluorine and hydrogen represents a classical bioisosteric exchange of F with H “according to Grimm”. See Patani 1996 at 3148, right column, Table 2, discussed below.
Patani 1996 has been cited thousands of times by numerous authors for its review of “Bioisosterism: A Rational Approach in Drug Design”. See Patani 1996 at Title. On the first page, it explains that “Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents.” Patani 1996 at 3147. The approach was considered “intuitive”, id., and had its roots back to 1919, id. at 3148. Bioisosteres are “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. Id. “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Id.
“Bioisosteres have been classified as either classical or nonclassical.” Id. One such group of classical bioisosteres were those “according to Grimm”, see Patani 1996 at 3148, Table 2 and surrounding text (third column shows the H and F exchange, and other equivalents OH, NH2, and CH3; second column shows the bioisosteric exchanges of N with CH employed in the aromatic rings of WO’946):
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Patani 1996 at 3148, Table 2.
See also, Patani 1996 at 3149:
Similarities in certain physicochemical properties have enabled investigators to successfully exploit several monovalent bioisosteres. These can be divided into the following groups: (1) fluorine vs hydrogen replacements; (2) amino−hydroxyl interchanges; (3) thiol−hydroxyl interchanges; (4) fluorine, hydroxyl, amino, and methyl group interchanges (Grimm's Hydride Displacement Law); (5) chloro, bromo, thiol, and hydroxyl group interchanges (Erlenmeyer's Broadened Classification of Grimm's Displacement Law).
Patani 1996 at 3149 (emphases added).
Patani 1996 at 3149-3154 provides examples of these exchanges. The section titled “1. Fluorine vs Hydrogen Replacements” on page 3149 explains the H - F exchange. See also, Patani 1996 at 3152, right column, which explains that CF3 is a common bioisostere of CH3 (“In this study the effect of the interchange of NH2, OH, as well as CF3 (a bioisostere for a methyl group based on the replacement of hydrogen with fluorine) on activity was assessed.”).
The discussion of the trifluoromethyl group appears on page 3152 under the umbrella of the section “4. Fluorine and Hydroxyl, Amino, or Methyl Groups as Replacements for Hydrogen (Grimm's Hydride Displacement Law)”, which explains that “This monovalent group of isosteres is a result of the direct adaptation of Grimm's Hydride Displacement Law.”
Accordingly, the exchange of H and F, and even OH, NH2, CH3, and CF3, results in bioisosteres, that by definition, affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.
Claims 1, 2, 4, 7, 13, 18, 23, 24, 25, 31, 32, 36, 37, 41, 44, 49, 62, 65, 66, 69, 70, 71, 75-76 and 79-83 were obvious
Therefore, while WO’946 did not exemplify the H-bioisostere of its compound 30 in its methods, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering it a method of treating an MRGPRX2 dependent condition, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis, because there was a reasonable expectation it would affect the same pharmacological targets as compound 30 in the same way and thereby have related properties.
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Following the same analysis, while WO’946 did not exemplify the X1 = N bioisostere of compound 11 in its methods, shown below on the right, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering it a method of treating an MRGPRX2 dependent condition, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis, because there was a reasonable expectation it would affect the same pharmacological targets as compound 11 in the same way and thereby have related properties. N and CH are bioisosteric “according to Grimm”. See Patani 1996 at 3148, Table 2, second column, and Patani 1996 at 3158, “E. Ring Equivalents” section.
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Following the same analysis, while WO’946 did not exemplify the X1 = N bioisostere of compound 5 in its methods, shown below on the right, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering it a method of treating an MRGPRX2 dependent condition, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis, because there was a reasonable expectation it would affect the same pharmacological targets as compound 5 in the same way and thereby have related properties.
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Accordingly, claims 1, 2, 4, 7, 13, 18, 23, 24, 25, 31, 32, 36, 37, 41, 44, 49, 62, 65, 66, 69, 70, 71, 75-76 and 79-83 were obvious at the time of filing.
Applicant’s example 5 compound was obvious
As discussed in the preceding rejection, Applicant’s instant Example 5 compound is a bioisostere of one of the compounds recited in claim 13 of WO’946, i.e., compound 11 of WO’946. As shown below, the only difference between the two compounds is the bioisosteric exchange of a hydrogen for a methyl group.
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Applicant’s claimed invention
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WO’946 at 111, claim 13, bottom right
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Designation as compound 11 of WO’946, see WO’946 Translation at 43/98.
WO’946 teaches and suggests the chemical structure of Applicant’s claimed invention.
Compound 11 of WO’946 is constructed using the general formula Ic-4 from claim 11,
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with a preferred D ring for compound 11 (
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), recited in claim 10 of WO’946. The substituted D ring for compound 11 is prepared by using the general formula Ic-4 from claim 11
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with a preferred D ring scaffold taught also in claim 10 of WO’946,
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. WO’946 claim 10 teaches that in this configuration,
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.
Accordingly, the chemical structure of Applicant’s claimed invention, the example 5 compound and hydrogen bioisostere of the WO’946 compound 11, was taught and suggested by WO’946.
While WO’946 did not exemplify the administration of the hydrogen bioisostere of the WO’946 compound 11 in its methods, the compound was indeed a compound of its formulas. Being a bioisostere of the WO’946 compound 11, there was a reasonable expectation it would affect the same pharmacological targets as compound 11 in the same way and thereby have related properties. CH3 and H are bioisosteric “according to Grimm”. See Patani 1996 at 3148, Table 2, third column, and Patani 1996 section “4. Fluorine and Hydroxyl, Amino, or Methyl Groups as Replacements for Hydrogen (Grimm's Hydride Displacement Law)”, as discussed previously. Therefore, the person of ordinary skill in the art at the time of filing had a reasonable expectation that the hydrogen bioisostere of the WO’946 compound 11 would be effective in a method of treating an MRGPRX2 dependent condition, wherein the MRGPRX2 dependent condition is an itch associated condition selected from the group consisting of contact dermatitis.
Secondary considerations may provide evidence of obviousness or non-obviousness. Applicant discloses an in vitro study in the Specification at 82, Table A. The MRGPRX2 FLIPR assay appears to be the exact same assay also used to characterize the compounds of WO’946. Given that the instant Example 5 compound and WO’946 compound 11 are bioisosteres, there was a reasonable expectation that both compounds would affect the same pharmacological targets in the same way. Applicant’s data simply confirms what was reasonably expected from WO’946. The WO’946 compound 11 showed an IC50 of 53.7 nM. Applicant’s Example 5 compound had an IC50 of “>0.1 nM but ≤100 nM”, which was exactly what was reasonably expected form WO’946. Accordingly, Applicant’s data show evidence of obviousness.
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Applicant’s data
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Data from same Assay in WO’946
Therefore, claim 78 was obvious at the time of filing.
Claims 14, 25, 30 and 77 were obvious
WO’946 Translation at 92/98, claim 11 teaches formula Ic:
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Claim 11 depends upon claim 9, which teaches multiple preferences for the variables of the compounds of WO’946.
WO’946 Translation at 87, claim 9, states
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The phenyl and imidazolyl options were shown in formulas Ic-1 to Ic-4 of claim 11.
The very next preferred ring A option is pyrazolyl.
It results in WO’946 expressly teaching the following structures:
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Preferences for the variables were taught in claim 9 as well through the exemplified embodiments of WO’946.
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For example, WO’946 claim 9 states for Ra and R1,
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While claim 9 teaches the option of adding methyl for the R2 and R3 variables,
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the exemplified embodiments utilized hydrogen throughout.
X1 could be CH or N based upon the exemplified compounds. Breaking the aromatic nature of the ring by utilizing a CH2 group for X1 was never exemplified throughout WO’946.
Further, preferences for the D variable were known, as discussed in claim 10 and the exemplified embodiments of the compounds.
The preferences for the Rc variable state “Preferably, each R c is independently F, Cl, Br, I, CH 3, CH 2 F, CHF 2 or CF 3;”, i.e., halo, methyl, or a fluorinated methyl group.
Moreover, preferences for the location of the Rc variable were known from the exemplified embodiments, e.g., WO’946 compounds 11 and 5:
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WO’946 teaches and suggests that administering bioisosteres of its exemplified embodiments would be effective in treating contact dermatitis. For example, working with the example of compound 5, the scaffold narrows down to
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, and the following two compounds,
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and
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. Both compounds were clearly taught and suggested by WO’946 and the person of ordinary skill in the art at the time of filing had a reasonable expectation that both compounds would be effective in treating contact dermatitis because they were bioisosteres of the WO’946 example 5 compound.
Accordingly, claims 14, 25, 30 and 77 were obvious at the time of filing.
The Example 18 compound was obvious
It was pointed out that several pages back when discussing the SAR of WO’946 that it teaches the 6-6 and 5-6 fused aromatic heterocycles attached to the top of the cyclohexane diamine linkers are bioisosteric. For example, the following WO’946 compound 17 was effective in treating contact dermatitis and had a stellar IC50 in the calcium flow assay.
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WO’946 explained that the 6-6 and 5-6 fused aromatic heterocycles could be exchanged because they were bioisosteric. Further, WO’946 explained that the “5” portion could be pyrazolyl, as discussed immediately above. Exchanging the chlorophenyl “6” portion of the above structure with the pyrazolyl group taught and suggested by WO’946 results in the following compound:
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There was a reasonable expectation of success in administering the above compound for treating contact dermatitis because WO’946 taught and suggested its structure and explained that it was bioisosteric with compound 17. The compound was considered a non-classical bioisostere, see Patani 1996 at 3149 (explaining the difference between classical and non-classical bioisosteres). It complied with definition from Burger in Patani 1996 at 3148 (“Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”.). Therefore, the ordinary chemist had a reasonable expectation of success in preparing the above compound for use in treating contact dermatitis.
The above compound is Applicant’s Example 18 compound,
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, which was obvious at the time of filing.
Claims 38 and 45 were obvious
Claim 1 of WO’946 provides the following structure for the compounds of its invention.
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Claim 1 explains that the X2 and X3 could be either CH, or its bioisosteric equivalent, N. See WO’946 Translation at 81.
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WO’946 Translation therefore teaches and suggests the X2 = N and X3 = N bioisosteres of its exemplified compounds. For example, it teaches and suggests the following bioisosteres of its compound 11,
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,
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, and
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.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering the X2 = N and X3 = N bioisosteres of the WO’946 compound 11 because Patani 1996 teaches that there was a reasonable expectation they would affect the same pharmacological targets as compound 11 in the same way and thereby have related properties.
Accordingly, claims 38 and 45 were obvious at the time of filing.
Claim 73 was obvious
Instant claim 73 is not exactly clear because as explained in the written description section Applicant does not demonstrate possession of its subject matter. Further, the functional groups that Applicant claims may be attached to its cyclohexane diamine linkers are so broad that nearly every functional group in the existence of medicinal chemistry may be endlessly attached to its linkers. However, one of the options is deuterium, which WO’946 suggests.
See WO’946 Translation at 87, claim 9 stating that the B ring its formulas may be a C3-6 monocyclic cycloalkyl group.
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See WO’946 Translation at 27, explaining that this includes polyvalent variants thereof, expressly permitting substitution at the C3-6 monocyclic cycloalkyl group:
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Substitution means the hydrogens may be replaced with deuterium. See WO’946 Translation at 25,
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The above “a variant of hydrogen and hydrogen” did not translate well with PatentScope. The text here states:
[0222]
除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“一个或多个”取代中，多个指的是2个以上，例如2，3，4，5个等。
Passed through Google Translate, it explains:
[0222] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent—including deuterium and hydrogen variants—provided that the valence of the specific atom is normal and the resulting compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on an aromatic group. In the context of "one or more" substitutions, "multiple" refers to more than two—for example, 2, 3, 4, 5, etc.
Accordingly, WO’946 suggests deuterated variants of its cyclohexane diamine linkers. Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in incorporating a deuterium into the cyclohexane diamine linkers of the compounds of WO’946.
Therefore, claim 73 was obvious at the time of filing.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
US 6372743 B1
Teaches compounds of claim 1 and its bioisosteres.
US 7557110 B2
Teaches bioisosteres of compounds of claim 1.
US 7667036 B2
Teaches bioisosteres of compounds of claim 1.
US 7737126 B2
Teaches bioisosteres of compounds of claim 1.
US 20250206734 A1
Possibly a double patent but currently unclear due to the nature of the instant claims.
US 20250243208 A1
Possibly a double patent but currently unclear due to the nature of the instant claims.
US 20250270208 A1
Possibly a double patent but currently unclear due to the nature of the instant claims.
Conclusion
No claims allowed.
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/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 Zhang, Xuejun, et al., “COMPOUND ACTING AS MRGPRX2 ANTAGONIST, AND PREPARATION METHOD THEREFOR AND USE THEREOF”, International Publication No. WO 2025044946 A1, published 2025-03-06, priority to 2023-08-25, Applicant Wuhan Humanwell Innovative Drug Research and Development Center Limited Company, hereinafter “WO’946”.
2 Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176, hereinafter “Patani 1996”.
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