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 .
DETAILED ACTION
The preliminary amendment filed 10/03/2025, cancelled claims 1-51, and added claims 52-74.
Claims 52-74 are pending and examined on the merits herein.
Priority
This application claims the following priority:
PNG
media_image1.png
159
673
media_image1.png
Greyscale
Specification
The disclosure is objected to because of the following informalities:
-The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See, for example, pgs. 28-30 of the specification.
-The specification is blurry and many of the depicted compounds are illegible. As such, the specification should be replaced with a clear copy.
Appropriate correction is required.
Claim Objections
Claims 52 and 73-74 are objected to because of the following informalities:
-In claim 52, to clarify the Markush group members in the definition of R1, “C1-6 alkyl and C3-6 cycloalkyl which are optionally substituted with 1, 2 or 3 independently selected R50 group; or a 3-10 membered heterocycloalkyl having 1-3 ring atoms,” should be replaced with - - C1-6 alkyl optionally substituted with 1, 2 or 3 independently selected R50 group; C3-6 cycloalkyl optionally substituted with 1, 2 or 3 independently selected R50 group; or a 3-10 membered heterocycloalkyl having 1-3 ring atoms- -.
-In claims 73-74, the majority of the compounds are blurry. These compounds should be replaced with clear structures.
Appropriate correction is required.
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 52-70 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.
-In claim 52, in the definition of R1, the phrase “which optionally comprises a –(C=O)- group or -S(=O)2- group in the ring,” renders the claim indefinite because it is not clear if the heterocycloalkyl ring comprises a substituent group of –(C=O)- group or -S(=O)2-, or if a carbon atom or a sulfur atom in the heterocycloalkyl group contain a =O or (=O)2 group, respectively.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 71 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 71 depends from claim 52, wherein claim 52 defines R50 as
PNG
media_image2.png
78
614
media_image2.png
Greyscale
. Thus, the recitation of “methylsulfonyl” as R50, in claim 71 is outside the scope of the definition of R50 in claim 52. As such, claim 71 fails to further limit the subject matter of claim 52.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
35 USC § 112(a)-Scope of Enablement
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 52-74 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 MRGPRX2 by administering to a subject in need thereof, a compound of instant Formula (I), does not reasonably provide enablement for a method of treating an inflammatory disorder by administering, to a subject in need thereof, a compound of instant Formula (I). 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.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed toward a method of treating any inflammatory disorder by administering a therapeutically effective amount of any compound of instant Formula (I) and a pharmaceutically acceptable excipient, wherein the compound of Formula (I) is:
PNG
media_image3.png
619
453
media_image3.png
Greyscale
PNG
media_image4.png
734
638
media_image4.png
Greyscale
.
As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a scientist with a Ph.D. or a clinician.
State of the Prior Art
Ogasawara (Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells, published June 2019, PTO-892) teaches that MRGPRX2 antagonists inhibit the de novo synthesis of SP-induced prostaglandin D2 in human cord blood-derived MCs(hCMCs), and that they also inhibit p42/44 mitogen-activated protein kinase signal in hCMCs activated by substant P (SP). Ogasawara teaches that its study strongly suggests that MRGPRX2 antagonists may be a promising drug to prevent the IgE-independent allergic reactions and thus, MRGPRX2 antagonist development may lead to a promising therapeutic medication for the IgE-independent allergic reactions (abstract). The two MRGPRX2 antagonists tested are:
PNG
media_image5.png
235
110
media_image5.png
Greyscale
(pg. 1072, Fig. 2).
Thus, the prior art teaches MRGPRX2 antagonists as possible, future treatments of diseases, but that more testing is required.
WO 2014/040243 (PTO-892) teaches compounds structurally similar to, but distinct from instant Formula (I).
PNG
media_image6.png
77
241
media_image6.png
Greyscale
(pg. 30) differs from instant Formula I in that it does not teach R1 or R60. These compounds are taught as VEGRF-2 kinase inhibitors for the treatment of VEGFR-2 mediated diseases, such as cancer (abstract).
WO 2007/086584 (IDS of 10/03/2025) teaches compounds structurally similar to, but distinct from instant Formula (I). Compounds Nos. 356, 370, 375-377, 379, 383, and 387 (pgs. 134-137) differ from instant Formula (I) in that they do not teach R1 as an alkyl substituted with R50. These compounds are taught as inhibiting both FabI and FabK, fatty acid synthases, for the treatment of antibacterial infections, such as Streptococcus pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis (abstract).
Thus, the prior art does not teach the instantly claimed compounds. While the prior art teaches structurally similar compounds, these compounds are taught as effecting chemical pathways distinct from that taught by the instant specification and claims, and are taught in methods of treatment distinct from the instantly claimed method of treatment.
Predictability in the Art
Weiler (published 2019, PTO-892) teaches that further research is needed in studying MRGPRX2 and its variants, activators, and inhibitors as they relate to human anaphylaxis. Rodent experimental research and in vitro studies of human mast cell and mast cell lines is the first step, but it is not sufficient for generalization until further evidence becomes available (last paragraph).
Weiler additionally teaches that it is hypothesized that the mechanisms involved in patients’ life-threatening reactions are mediated via direct activation of the Mas-related G protein-coupled receptor (MRGPR) MRGPRX2 and that it is of critical importance to understand the mechanisms of non-IgE-mediated acute life-threatening reactions. Such understanding will further researchers’ abilities to prevent those reactions and identify MRGPRX2 antagonists that could result in new therapeutic strategies. Weiler teaches that it is clear that further clinical and epidemiologic studies are needed to evaluate drug allergy profiles in patients with mastocytosis (2nd and 3rd paragraphs).
It is noted that Weiler is published approximately four months prior to the instantly claimed invention.
Thus, in view of the prior art, which does not teach the instantly claimed compounds or structurally similar compounds for the treatment of an inflammatory disorder, and Weiler, which teaches that it is hypothesized that MRGPRX2 is involved in patient allergic reactions and that further tests are needed, the art of treating diseases with of MRGPRX2 antagonists is unpredictable.
Working Examples
Beginning on pg. 94 of the instant Specification, synthetic examples of compounds of instant Formula (I), i.e., compounds E132-E215, are provided.
Beginning on pg. 133 of the instant Specification, the IC50 values for the instant compounds were tested as MrgprX2 antagonists.
PNG
media_image7.png
268
598
media_image7.png
Greyscale
The IC50 molar concentration values for these compounds vary from 5.1-9.2.
Direction and Guidance
In view of what is known in the art, the unpredictability of the art, and the lack of working examples that shows methods of treating any single inflammatory disorder, the instant specification does not provide sufficient guidance or direction to use the invention as instantly claimed.
Quantity of Experimentation
The amount of experimentation required to determine which inflammatory disorders are treated by which compounds of instant Formula (I) would be astronomical. This amount of experimentation amounts to invention and not development; it is an undue amount of experimentation.
Thus, while being enabling for a method of inhibiting MRGPRX2 receptors by administering a compound of instant Formula (I), the instant specification does not reasonably provide enablement for a method of treating an inflammatory disorder by administering a compound of instant Formula (I).
Prior Art
The closest prior art is WO 2007/086584 (IDS of 10/03/2025), which teaches compounds structurally similar to, but distinct from instant Formula (I):
PNG
media_image8.png
77
274
media_image8.png
Greyscale
PNG
media_image9.png
112
320
media_image9.png
Greyscale
PNG
media_image10.png
303
360
media_image10.png
Greyscale
PNG
media_image11.png
90
282
media_image11.png
Greyscale
PNG
media_image12.png
99
281
media_image12.png
Greyscale
PNG
media_image13.png
102
290
media_image13.png
Greyscale
.
(compounds Nos. 356, 370, 375-377, 379, 383, and 387;pgs. 134-137). The reference teaches these compounds as inhibiting both FabI and FabK, fatty acid synthases, for the treatment of antibacterial infections, such as Streptococcus pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis (abstract).
The reference does not teach the instant R1 position of the compounds as a C1 alkyl substituted with a chemical group defined by instant R50, and does not further teach that R1 can be a C3-6 cycloalkyl or a 3-10 membered heterocycloalkyl. Additionally, the reference does not teach these compounds for the treatment of inflammatory disorders or as antagonists of MRGPRX2.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LAUREN WELLS/Examiner, Art Unit 1622