DETAILED ACTION
Claims 1-6, 10, 16-17, 27-37, 40-42, 50-52, 54-58, 64, 75, 77, and 78, submitted 01 August 2023, are pending in the application. Claims 77 and 78 have been withdrawn. Claims 1-6, 10, 16-17, 27-37, 40-42, 50-52, 54-58, 64, 75, 77, and 78 are under examination in the instant Office 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 .
Election/Restrictions
Applicant’s election without traverse of Group I and the elected species,
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, in the reply filed on 22 January 2026 is acknowledged.
Claims 77 and 78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 22 January 2026.
Claims 1-6, 10, 16-17, 27-37, 40-42, 50-52, 54-58, 64, 75, 77, and 78 are allowable. Claims 77 and 78, previously withdrawn from consideration as a result of a restriction requirement, require all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between inventions I-III, as set forth in the Office action mailed on 23 October 2025, is hereby withdrawn and claims 77 and 78 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Specification
The lengthy 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 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 77 and 78 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 inhibition of KRAS G12D protein with some compounds of the instantly claimed invention, does not reasonably provide enablement for the inhibition of KRAS G12D proteins for the entire genus as claimed in claim 77 nor does the specification reasonably provide enablement for the treatment of all cancers as claimed in claim 78. 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.
Breadth of the Claims
Claim 77 recites “A method of inhibiting KRAS G12D protein in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1…”. Claim 77 identifies the compound being used by the mechanistic function and additionally is drawn to independent claim 1. As such, claim 77 claims the whole genus of the instantly claimed invention instead of individual compounds in the inhibition of KRAS G12D protein.
Claim 78 recites “A method of treating cancer in a subject in need thereof…”. Claim 78 is not drawn to any cancer in particular and thus can be interpreted to encompass all cancers. Claim 78 is also drawn to independent claim 1 and as such claims the whole genus of the instantly claimed compound instead of individual compounds in the treatment of cancer.
Nature of the Invention
The nature of the invention is within the pharmaceutical art with regards to the inhibition of KRAS G12D protein and the treatment of cancer comprising administering a therapeutically effective amount of a compound of formula (I).
State of the Prior Art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc.
v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
The prior art at the time of the filing of the instantly claimed invention teaches a compound, with a similar structure to that of the compounds taught by the Applicant, which is used in the inhibition of KRAS G12D proteins. Li et al. ("Inhibition of GTPase KRASG12D: a review of patent literature." Expert Opinion on Therapeutic Patents 34.8 (2024): 701-721.) teaches the compound MRTX1133,
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(pg. 703, Figure 1, Right Compound), which is capable of inhibiting KRAS G12D (pg. 702, Section 2.1.1. Pyridopyrimidine, Right Col., 1st-2nd paragraph) and also teaches that KRAS G12D mutation is the most frequent mutation and occurs in 33.8% of pancreatic cancer, 12% of rectum adenocarcinoma, and 10.3% of colon adenocarcinoma (pg. 702, Section “1.3. Breakthrough of inhibitor of targeting KRAS mutational proteins”, Left Col., 2nd paragraph).
Additionally, it is known that not all cancers can be treated with a single compound. Vodithala et al. ("Detection of KRAS mutations in triple-negative breast cancers by polymerase chain reaction." Journal of Datta Meghe Institute of Medical Sciences University 19.1 (2024): 71-76.) states, “Their study indicated that KRAS mutations in TNBCs are uncommon if not absent as the possibility that a minimum number of cells before the detection limit of the assay (1% of tumor cells) harbor mutation of KRAS” (pg. 74, Section “Discussion”, Left Col., 1st paragraph). Therefore, it can be understood that a cancer which does not exhibit the KRAS G12D mutation would not be an ideal candidate to be treated by a KRAS G12D protein inhibitor.
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known
the relevant art at the relevant time. Factors that may be considered in determining the
level of ordinary skill in the art may include: (A) “type of problems encountered in the
art;” (B) “prior art solutions to those problems;” (C) “rapidity with which innovations are
made;” (D) “sophistication of the technology; and” I “educational level of active workers
in the field. In a given case, every factor may not be present, and one or more factors
may predominate.” In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir.
1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1
USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co.,
713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of
ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art
with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
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 of
the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount
of guidance or direction” refers to that information in the application, as originally filed,
that teaches exactly how to make or use the invention. The more that is known in the
prior art about the nature of the invention, how to make, and how to use the invention,
and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the
invention and the art in unpredictable, the specification would need more detail as to
how to make and use the invention in order to be enabling. The scope of the required
enablement varies inversely with the degree of predictability involved, but even in
unpredictable art, a disclosure of every operable species is not required. A single
embodiment may provide broad enablement in cases involving predictable factors, such
as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ
122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA
1971). However, in applications directed to inventions in arts where the results are
unpredictable, the disclosure of a single species usually does not provide an adequate
basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA
1938). In cases involving unpredictable factors, such as most chemical reactions and
physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide
more objective evidence to support the enablement of the aforementioned claims to
contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor regarding the currently claimed method of inhibiting KRAS G12D in a subject in need thereof through administration of a compound of the entire genus of Formula (I) and the method of treating all cancers with a compound of the entire genus of Formula (I) as there is no prior art or evidence in the specification to suggest that the whole genus can achieve the instantly claimed methods.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of
the unpredictability of the art. Given the context and scope of the claims mentioned
above, the inventor failed to provide the necessary amount of direction for one skilled in
the art to adequately use the invention across all suggested utility in the broadly stated
disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
Applicant has provided guidance for certain aspects of the invention such as the synthesis of numerous compounds (Examples 1-208, pages 514-635), KRAS G12D biochemical assay (Example A, pages 635-636), 2D cell viability assay (Example B, page 636), and a 3D cell viability assay (Example C, page 636). Additionally, the Applicant provided the biological data for some compounds of the instant application found in Table 2 on pages 637-673).
Existence of Working Examples
The provided working examples focused on the synthesis of the compounds and cell culture data. It does not appear, however, to support the claim language of instant claim 77 wherein the whole genus of compounds inhibit KRAS G12D protein in a subject in need thereof as there is no working example to support in vivo application. It also does not appear to support the treatment of all cancer types in a subject in need thereof as there is no working example drawn to the treatment of cancer in the instant specification. One skilled in the art would be unable to adequately use the invention without unduly experimentation, which would require the practitioner to discover that which the Applicant has failed to disclose.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the
predictability of the art, and the direction provided by the inventor. For one skilled in the
art to practice the invention as disclosed, the applicant would be required, but not
limited to providing:
Experimentation to show dosage and frequency required in the treatment of KRAS G12D related cancers.
Experimentation to show functional in vivo application in a subject as defined by the instant application.
Experimentation to show inhibition of KRAS G12D protein of all compounds of the genus of instant claim 1.
Allowable Subject Matter
Claims 1-6, 10, 16-17, 27-37, 40-42, 50-52, 54-58, 64, 75, 77, and 78 are drawn to allowable subject matter.
The following is a statement of reasons for the indication of allowable subject matter: Claims 1-6, 10, 16-17, 27-37, 40-42, 50-52, 54-58, 64, 75, 77, and 78 are deemed novel and non-obvious over the prior art.
The closest prior art is Wang et al. (US 11,453,683 B1), which teaches a genus similar to the Applicants, shown below.
Formula (I) taught by Wang
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(Col. 2, Lines 1-15)
This reference neither teaches nor renders obvious the genus of the instant application, shown below, and further fails to teach the compounds of the instantly claimed invention. For example, this reference fails to teach the L1-3 moieties at an identical position, shown below, which would point to a similar compound as that of the Applicants.
Genus taught by Applicant
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Therefore, the prior art neither anticipates, nor reasonably makes obvious the claimed invention and thus, the claimed invention is deemed novel and unobvious over the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUSTIN CHRISTOPHER SANCHEZ whose telephone number is (703)756-5336. The examiner can normally be reached Monday -Friday (0730-1700).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622