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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof: W-L-T; a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof and a pharmaceutically acceptable excipient, carrier or diluent; and a kit comprising the compound or the pharmaceutically acceptable salt or ester thereof, and instructions for use thereof, optionally further comprising at least one additional therapeutic agent; and compound 2a, 1-(6-(1-(7-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4, 3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-5-fluoro-1-methyl-1 H-indazol-3-yl)dihydropyrimidine-2,4(1 H,3H)-dione, having the structure of:
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as the elected compound species of Formula (I) are maintained.
Claims 60-61, 63, 81 and 85 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on June 23, 2026, wherein claims 1, 3, 8, 16, 28, 47 and 56 are amended; claims 2, 4-7, 9-15, 17-25, 27, 29-46, 49-55, 57-59, 62, 64-80, 82-84, 86-88 and 90-102 are canceled; claims 26, 48, 60-61, 63, 81, 85 and 89 are unchanged; and claims 103-107 are newly added.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 8, 16, 26, 28, 47-48, 56, 60-61, 63, 81, 85, 89 and 103-107 are pending.
Claims 60-61, 63, 81 and 85 remain withdrawn.
Claims 1, 3, 8, 16, 26, 28, 47-48, 56, 89 and 103-107 are under examination in accordance with the elected species.
Priority
The instant application 18/466,473 filed on September 13, 2023 claims priority to, and the benefits of Foreign Application No. PCT/CA2023/050308 filed on March 9, 2022, Foreign Application No. CN202211110187.1 filed on September 13, 2022, Foreign Application No. CN202211107827.3 filed on September 13, 2022, Foreign Application No. CN202310218694.5 filed on March 9, 2023, and Foreign Application No. CN202310861549.9 filed on July 13, 2023.
Acknowledgment is made of applicant's claim for foreign priority based on applications filed in People’s Republic of China on September 13, 2022, March 9, 2023, and July 13, 2023; and an application filed in WIPO on March 9, 2022. It is noted, however, that applicant still has not filed a certified copy of the PCT/CA2023/050308, CN202211110187.1, CN202211107827.3, CN202310218694.5, and CN202310861549.9 application as required by 37 CFR 1.55. It is respectfully noted that a certified copy of foreign priority documents must be filed in the original language as it was filed in the foreign patent office, such copy was, again, not provided by the Applicant in response to the Non-Final Office Action mailed on March 4, 2026.
While applicant attempted to provide English translations of CN202211110187.1, CN202211107827.3, CN202310218694.5, and CN202310861549.9 application, these translations are not certified. Once an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) and it must be filed together with a statement that the translation of the certified copy is accurate.
In view of the foregoing, instant claims are not entitled to the benefit of the prior-filed applications noted above and will receive an effective filing date of September 13, 2023, which is the filing date of instant application.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Acknowledgment is made of applicant's claim for priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) based upon an application filed in China on March 9, 2022. The claim for priority cannot be based on said application because the subsequent nonprovisional or international application designating the United States was filed more than twelve months thereafter and no petition under 37 CFR 1.55 or request under PCT Rule 26bis.3 to restore the right of priority has been granted.
Applicant may wish to file a petition under 37 CFR 1.55(c) to restore the right of priority if the subsequent application was filed within two months from the expiration of the twelve-month period and the delay was unintentional. A petition to restore the right of priority must include: (1) the priority claim under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) in an application data sheet, identifying the foreign application to which priority is claimed, by specifying the application number, country (or intellectual property authority), day, month, and year of its filing (unless previously submitted); (2) the petition fee set forth in 37 CFR 1.17(m)(3); and (3) a statement that the delay in filing the subsequent application within the twelve-month period was unintentional. The petition to restore the right of priority must be filed in the subsequent application, or in the earliest nonprovisional application claiming benefit under 35 U.S.C. 120, 121, 365(c), or 386(c) to the subsequent application, if such subsequent application is not a nonprovisional application. The Director may require additional information where there is a question whether the delay was unintentional. The petition should be addressed to: Mail Stop Petition, Commissioner for Patents, P.O. Box 1450, Alexandria, Virginia 22313-1450.
Action Summary
Applicant's arguments filed on June 23, 2026 have been fully considered.
All rejections pertaining to claims 2, 30, 36, 38 and 42 are moot because the claims were cancelled in view of the claim amendments filed on June 23, 2026.
Acknowledgement is made of the receipt and entry of the amendment to the specification filed on June 23, 2026. Applicant’s amendment to the claims overcomes each and every objection previously sets forth in the Non-Final Office Action mailed on March 24, 2026 unless otherwise noted.
Claims 1, 16, 26, 28, 30, 36, 38, 42, 48, 56 and 89 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 are withdrawn in view of the claim amendments.
Claims 1, 3, 16, 28, 38 and 42 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 are withdrawn in view of the claim amendments.
Claim 8 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 are maintained, but revisited and modified in view of the claim amendments.
Claims 28, 36 and 47 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 are withdrawn in view of the claim amendments.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives are maintained, but revisited and modified in view of the claim amendments. Applicant’s arguments, see page 19, filed on June 23, 2026, with respect to the rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 48, 56 and 89 under 35 U.S.C. 102(a)(1) as being anticipated by Lyu et al. (CN 115785199 A) have been fully considered and are persuasive. The rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 48, 56 and 89 has been withdrawn.
Claims 1-3, 8, 16, 26, 28, 30, 36, 42, 48, 56, and 89 rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sun et al. (WO 2024/152247 A1) are withdrawn in view of the claim amendments. Specifically, the scope of L of Formula (I) has been amended.
Claims 1-3, 8, 16, 26, 30, 36, 38, 42, 48, 56, and 89 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ji et al. (WO 2023/215906 A1) are withdrawn in view of the claim amendments. Specifically, the scope of L of Formula (I) has been amended.
Applicant’s arguments, see page 20, filed on June 23, 2026, with respect to the rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56 and 89 rejected under 35 U.S.C. 103 as being unpatentable over Lyu et al. (CN 115785199 A), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) have been fully considered and are persuasive. The rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56 and 89 has been withdrawn.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 48, 56, and 89 rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (WO 2023/215906 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are withdrawn in view of the claim amendments. Specifically, the scope of L of Formula (I) has been amended.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8, 10, 32-33 and 36 of copending Application No. 18/119,592 (reference application) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are maintained, but revisited and modified in view of the claim amendments.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7-11, 15-17, 20-24 and 36-37 of copending Application No. 18/533,634 (reference application) in view of Wang et al. (WO-2021041671-A1) are maintained, but revisited and modified in view of the claim amendments.
Claim Interpretation
The limitation of “wherein the composition is formulated for injection” in claim 56 is reasonably
construed to be an intended use of the pharmaceutical composition instantly claimed; and therefore, if the prior art meets the structural limitation of the product, it is capable of performing the intended use. See MPEP 2111.02.
Specification
The amendment filed on June 23, 2026 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows:
Paragraph [0032] of the specification has been amended to replace several structures, e.g.,
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, recites in the embodiments of the left end fragment of “KRAS-G12D targeting groups of Formulae (Ia) and (Ib)” with the new structure formulae shown below:
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; While some of these newly added structures are exemplified in the working example, for example, compound no. 1:
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contains the
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; the originally filed disclosure only support the particular compound species to have one of these structures, and that does not support the full scope of Formulae (Ia) and (Ib) can contains one of these newly added moieties. Therefore, adding additional structures to the left end fragment of KRAS-G12D targeting groups of Formulae (Ia) and (Ib) introduce new matter.
Page 26, Compound 18 of the specification newly added Rb having the structure of:
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, and that particular Rb is not supported by the originally filed disclosure.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Objections
Claim 1 is objected to because of the following informalities (newly applied as necessitated by amendments):
Regarding claim 1, the L1 structure “
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” is recited twice, and one of them should be deleted.
Appropriate correction is required.
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.
Claim 8 remain rejected and Claim 3 is 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 (partially newly applied as necessitated by amendments).
Regarding claim 3, the recitation of “the substituted carbon is CH” renders the claim indefinite, because the term “unsubstituted” construed in light of the definition provides in paragraph [00158] of the specification, is taken to mean a compound or part thereof has no substituent except the undetermined chemical saturation of hydrogen atom; and the term “substituted" construed in view of paragraph [00156] of the specification refers to a parent compound or part thereof has at least one substituents. In other words, the chemical saturation of a carbon atom with hydrogen is considered as part of the parent structure rather than a substituent according to the definition sets forth in the specification; and therefore, the claim recites the term “substituted carbon” include “CH” is not consistent with the definition sets forth in the specification, and the “CH” recites therein is considered to be broader than the limitation of “substituted carbon”. In addition, it is also not clear if applicant is intending to claim that the unsubstituted carbon is substituted a hydrogen atom, thus, said carbon atom has a total of two hydrogen atoms. In view of foregoing, the lack of clarity renders the claim indefinite, because one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 8,
the recitation of “and/or” in the phrase of “wherein X is N; R1 is -OH; and/or R2 and R3…form a substituted benzo-fused ring” renders the claim uncertain, because it is not clear whether these limitations can be selected individually, in combination, or all of them must be present together. The claim language can be interpreted in various ways, for instance, it is unclear if Applicant is intending to claim (i) X is N or (R1 is -OH and R2 and R3 form a substituted benzo-fused ring); (ii) X is N or (R1 is -OH) or (R2 and R3 form a substituted benzo-fused ring); or (iii) (X is N and R1 is -OH) or (R2 and R3 form a substituted benzo-fused ring). Thus, the claim is considered indefinite because it does not clearly set forth the metes and bounds of the patent protection desired.
Response to Arguments
Applicant's arguments filed on June 23, 2026 with respect to the rejection of claim 8 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 have been fully considered but they are not persuasive.
In Summary, Applicant argues the term “and/or” has been deleted from the claim language; and therefore, it overcomes the rejection of record.
In response, Applicant’s arguments are not found persuasive, because the term “and/or” has not been deleted; therefore, the rejection of record has been maintained for the same reasons of record and for the reasons set forth herein.
Claims 1, 3, 8, 16, 26, 28, 47-48, 56, and 89 remain rejected and claims 103 is rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives (partially newly applied as necessitated by amendments). See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) The species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
Instant claim 1 broadly recites a compound of Formula (I), or pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof. The Markush grouping of the compounds of Formula (I) with the combination of these different W, L, and T moieties are improper, because the alternative embraced by the Markush grouping do not share a substantial structure feature, and the alternated compound species do not share a common use that flows from the substantial structure feature.
For instance, the Markush grouping of compounds of Formula (I) contains vast variety of W, L and T moieties that do not share a substantial structure feature and are not known to belong to the same art-recognized class, for example,
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and
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at L2 of L are structurally distinct and are not known to belong to the same art recognized class. Additionally, the Markush grouping of compounds of Formula (I) includes a variety of E3 ligase binding group T having formulae (IIIa) or Formula (IIIb), and they also do not share a substantial structure feature in common, and a common use that flows from the substantial structure feature. In this case, the E3 ligase binding group T only shares the formylacetamide (see shaded
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) in common, and that does not constitute a significant portion of the compound as a whole. According to Hartmann et al. (US4,839,370), 3-(4-aminophenyl)-3-cyclohexyl-piperidine-2,6-dione is a compound of general formula I:
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that is useful for inhibiting estrogen biosynthesis (see e.g., Example 1; abstract). Even though the compound species of general formula I taught by Hartmann et al. also shares formylacetamide in common, said compound is taught to inhibit estrogen biosynthesis rather than recruiting E3 ligase, promoting ubiquitination and degrading KRAS-G12D target protein. Therefore, it is not apparent that this formylacetamide alone (
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) at the E3-ligase binding group T contributes to the substantial structure feature essential for the compound to give the desired properties of recruiting E3 ligase, promoting ubiquitination and degrading KRAS-G12D target protein.
Furthermore, the Markush grouping of the compounds of Formula (I) includes a variety of targeting groups that bind specifically to KRAS-G12D protein having Formula (Ia)
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; and Instant claim 47 recites vast variety of compound species, including compound having the structure of:
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. It is noted that the compound species alternatives encompassed by formula (I), and the compound species recited in claim 47 do not share a substantial structure feature and a common use that flows from the substantial structural feature. These compound species only share the structure of:
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or
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in common, and that does not constitute a significant portion of the compound as a whole. According to Wang et al. (WO 2021/041671 A1), the compounds of Formula (I)
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, including
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(see e.g., p. 846, last row), bind to KRAS G12D and that inhibits the activity of KRAS G12D (see e.g., [0007];[0180]; Table 2); However, even though the compounds of Wang et al. share the same structure feature of:
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, the compounds of Wang et al. only bind to KRAS G12D and does not recruit E3 ligase, promoting ubiquitination and degradation. Therefore, it is not apparent that this common structure alone (“
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”) contributes to the substantial structure feature essential for the compound to give the desired properties of recruiting an E3 ligase, promoting ubiquitination and subsequent degradation of KRAS-G12D.
Each of these findings demonstrates that not all members recited in the Markush grouping belong to the same recognized chemical class and these members do not share a common use. In addition, the alternated compound species fail to share a substantial structural feature that is essential for recruiting an E3 ligase to the KRAS-G12D protein, promoting its ubiquitination and subsequent degradation.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Response to Arguments
Applicant's arguments filed on June 23, 2026 with respect to the rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 on the judicially-created basis that it contains an improper Markush grouping of alternatives have been fully considered but they are not persuasive.
In Summary, applicant argues claim 1 has been amended to limit the structure of W and L, and that overcomes the rejection of record. Each of these findings demonstrates that the claim amendments changes the scope of the claims.
In response, applicant’s arguments are not found persuasive. Even though the claim amendments now narrow the scope of Formula (I)
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recites in claim 1, the Markush grouping of these compound species of Formula (I) recites therein and the Markush grouping of the compound species recites in claim 47, which includes compounds that are not encompassed by instant Formula (I), still do not share any substantial structural feature in common, i.e. a significant structural element is shared by all of the alternatives or all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
Again, the grouping is improper if either (1) the members of the Markush grouping do not share a “single structural similarity” or (2) the members do not share a common use. Applicant’s assertion that each of these Markush grouping of compounds species shares a substantial structural feature and a common use that flows from the substantial structure feature appear to be mere arguments without objective evidence. Applicant does not provide any sound technical and scientific reasonings to support the structurally distinct compounds, e.g.,
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,
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are, in fact, sharing a substantial structural in common. The compound species only share the structure feature of:
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in common, and that clearly does not constitute a significant portion of the compound as a whole. In other words, the structure they have in common does not occupy a large portion of their structures. Same analysis is applicable to the compound of instant Formula (I)
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, drawn to a broad genus of compounds composed of structurally distinct species of W, L, and T, the only thing they have in common is
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. Again, these structures clearly do not occupy a large portion of their structures as well.
According to Wang et al. (WO 2021/041671 A1), the exemplary compound
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(see e.g., p. 846, last row) embraced by Formula (I)
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is known to inhibit the activity of KRAS G12D by binding to KRAS G12D (see e.g., [0007];[0180]; Table 2). Even though the compounds of Wang et al. also share the structure feature of
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in common, the compounds of Wang et al. only bind to KRAS G12D and does not recruit E3 ligase, promoting ubiquitination and degradation. Applicant fails to provide any objective evidence demonstrating that this structure feature alone constitutes a substantial structure essential for the compound to give the properties of recruiting an E3 ligase, promoting ubiquitination and subsequent degradation of KRAS-G12D.
In view of the foregoing, applicant’s assertion that the Markush grouping of compound species shares a substantial structure feature and a common use that flows from the substantial structure feature does not have any factual support. If applicant contends the structure feature of:
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or
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alone can recruit an E3 ligase, promote ubiquitination and subsequent degradation of KRAS-G12D, such evidence is respectfully requested.
Therefore, the rejection has been maintained but revisited and modified in view of the claim amendments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 3, 8, 16, 26, 28, 47-48, 56, 89 and 103-107 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (WO 2023/138524 A1), in view of Cheng et al. (WO 2022/235945 A1) and Takwale et al. (European journal of medicinal chemistry, 2020. Vol. 208: 112769) (newly applied as necessitated by amendments).
Wu et al. is available as prior art under 35 USC § 102(a)(2) as effectively filling date of January 24, 2022. Because Wu et al. is written in Chinese and a machine translation of the WIPO patent application has been provided, the specific portions cited in this instant office action will refer to the sections of the machine translated copy. Such translated copy should be interpreted as corresponding to the disclosure of the aforementioned WO publication.
Wu et al. teaches a compound 108 having the structure of:
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is an exemplary compound of X-Y-Z structure with KRAS inhibitory and degradative activities (see e.g., [0044], Compound 108; [0001]); and the compound may contain all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts (see e.g., [0071]). Wu et al. further teaches the compound of X-Y-Z structure is proteolysis-targeting chimeras (PROTAC) with ability to degrade KRAS G12D (see e.g., [0003]-[0004]; [00779]). Wu et al. further teaches a pharmaceutical composition can be prepared by combing the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, in can be formulated into, inter alia, injections (see e.g., [0073]; [0076]). Wu et al. further teaches the compound having an X-Y-Z structure, wherein X is a KRAS protein-binding ligand compound represented by general formula (I)
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; Y is a connecting chain connecting X and Z; and Z is an E3 ligase binding ligand compound (see e.g., abstract; [0006]). Wu et al. further teaches in some embodiments, X in formula (I) is selected from the structure, inter alia,
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(see e.g., [0022]); Y in formula (I) is selected from, inter alia,
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,
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or
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, wherein n is 0 to 10 (see e.g., [0033]); Z is selected from structure, inter alia,
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(see e.g., [0036]).
Wu et al. does not teach the elected compound species.
Cheng et al. teaches DSM in compounds of formula (A) or a pharmaceutically acceptable salt thereof can be a suitable moiety that binds to an E3 ubiquitin ligase (e.g., the cereblon protein) (see e.g., p, 32, line 10-12); and DSM is a degradation signaling moiety represented by one of the following formulae attached to L, inter alia,
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(see e.g., p. 45, line 21 to p. 54, moiety (D91); p. 182, line 1-5). Cheng et al. further teaches the compounds of Formula (A): BTK-L-DSM or a pharmaceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety that is covalently attached to the linker L, L is a linker that covalently attaches BTK to DSM, and BTK is a Btk binding moiety represented by Formula (I) or Formula (II) that is covalently attached to the linker (see e.g., abstract). Cheng et al. further teaches L is represented by the following formula, including formula (L-2):
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, wherein Alk1 is, inter alia, a bond; Alk2, inter alia, is a bond; Z4 is, inter alia, 4- to 10-membered saturated monocyclic or bicyclic heterocyclyl;
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represents a bond to DSM;
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represents a bond to BTK (see e.g., p. p. 62, line10 to p. 63, line 10). Cheng et al. further teaches the term “heterocyclyl” refers to a saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system (e.g., fused, bridged or spiro ring systems) (see e.g., p. 11, line 8-9). Cheng et al. teaches a compound of Example 271 having the structure of:
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as an exemplary compound of Formula (A) capable of activating the selective ubiquitination of Btk proteins via the ubiquitin-proteasome pathways (UPP) and cause degradation of Btk proteins (see e.g., p. 473, line 1-5; abstract).
Takwale et al. teaches proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule composed of a binder for target protein binding, a binder for E3 ubiquitin ligase binding, and a linker for connecting two binders (see e.g., p. 1, right column, line 12-15), and the strategy is illustrated as follows:
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(see e.g., Fig. 3). Takwale et al. further teaches the potency of PROTAC is generally influenced by the use of the E3 ligase, linker, and warhead independently (see e.g., p. 2, right column, line 1-3). Takwale et al. further teaches piperidine-based linker of different lengths are selected because the cyclic linker decreases the flexibility of large chimeric molecules, providing better physio-chemical properties, including the number of single rotational bonds (see e.g., p. 4, left column, last paragraph), and the linkers includes
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(see e.g., Scheme 3).
The difference between the compound 108 of Wu et al. and the instantly elected compound 2a is shown below (see shaded):
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.
In particular, the compound 108 of Wu et al. contains an E3 ligase binding ligand moiety (also referred to therein as “Z”) having the structure of:
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, while the E3 ligase binding ligand moiety of claimed compound is
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; and the linker of compound 108 of Wu et al. is
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rather than
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instantly claimed. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by selecting compound 108 of Wu et al., and then modifying said compound by replacing the E3 ligase binding ligand moiety (also referred as “Z”) of its X-Y-Z structure with the Formula D91 of Cheng et al. as the E3 ligase binding ligand moiety, and then modifying the linker moiety of its X-Y-Z structure to 7-azaspiro[3.5]nonane.
One would have been motivated to modify compound 108 of Wu et al. by replacing the corresponding E3 ligase binding ligand moiety (also referred to therein as “Z”) with another known E3 ligase binding ligand moiety and replacing one linker for another known linker thereby arriving at the elected compound 2a in order to obtain analogs with similar utilities. Wu et al. expressly teaches compound of X-Y-Z structure is a proteolysis targeting chimera (PROTAC) consists of three structure building blocks, wherein X is a KRAS protein-binding ligand compound; Y is a connecting chain connecting X and Z; and Z is an E3 ligase binding ligand compound; and identifies compound 108 is useful for inhibiting and degrading KRAS G12D. Cheng et al. expressly identifies formula (D91) is a moiety suitable for binding to an E3 ubiquitin ligase. Accordingly, one of ordinary skill in the art seeking to arrive at additional analogs of compound 108 of Wu et al. would have been motivated to substitute the E3 ligase binding ligand moiety of compound 108 with another known E3 ligase binding ligand moiety having Formula D91 taught by Cheng et al. in order to retain the disclosed E3 ligase binding utility. With respect to substituting the linker moiety, Wu et al. expressly teaches that the connecting chain Y of its X-Y-Z can be selected from a list of alternatives; Cheng et al. teaches the linker can include a 4- to 10-mebered spiro ring system that can be directly linked to the E3 ligase binding ligand moiety; and Takwale et al. teaches the use of linker can influence the potency of PROTAC, and piperidine-based linkers of different lengths, including 7-azaspiro [3.5]nonane, improves the physiochemical properties of chimeric molecules like PROTAC by decreasing the flexibility of large chimeric molecules, including the number of single rotational bonds. Accordingly, Wu et al. itself would have suggested the modification of the connecting chain moiety (also referred to therein as “Y”), and one of ordinary skill in the art seeking to arrive at additional analogs of compound 108 of Wu et al. would have been motivated to modify said connecting chain to 7-azaspiro[3.5]nonane as the linker connecting the KRAS protein-binding moiety and E3 ligase binding moiety in order to improve the physio-chemical properties of the compound.
One of ordinary skill in the art would have a reasonable expectation of success in obtaining a compound retaining the KRAS inhibitory and degradative activities, because substituting one E3 ligase binding ligand moiety for another, and substituting one linker for another is a recognized approach to provide structurally related proteolysis-targeting chimera having similar biological activity. In view of these teachings, one of ordinary skill in the art would have reasonably expected that selecting the known Formula D91 of Cheng et al. in place of the E3 ligase binding ligand moiety of compound 108, and selecting the known 7-azaspiro[3.5]nonane linker in place of the linker of compound 108 would provide the corresponding PROTAC while retaining the KRAS inhibitory activities associated with Wu’s KRAS protein-binding ligand scaffold, thereby arriving at the elected compound 2a with a reasonable expectation of success.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant’s arguments with respect to the rejection of claims under 35 U.S.C. 102(a)(1), 102(a)(2) and 103 set forth in the Non-Final Office Action mailed on March 24, 2026 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 8, 16, 26, 28, 47-48, 56, and 89 remain provisionally rejected and claims 103-107 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8, 10, 32-33 and 36 of copending Application No. 18/119,592 (reference application) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) (partially newly applied as necessitated by amendments).
The claims of the reference application are drawn to a compound having the structure of:
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(referred to herein as “Compound 101”)(see claim 32), which is a compound of Formula (I):
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, wherein W has a structure of Formula (Ia)
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, wherein N is nitrogen;
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is
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; L is
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; and T is an E3-ligase binding group:
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(see claim 1); reading on the compound of Formula (I) instantly claimed. The claims of reference application are further drawn to a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof of claim 1, and a pharmaceutically acceptable excipient, carrier or diluent; wherein the composition is suitable for injection (see e.g., claims 33 and 36).
The claims of the reference application do not teach the elected compound species recites in claim 47.
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for
the rational modification of lead compounds into safer and more clinically effective agents (see e.g.,
“introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar
biological activity, and have been classified as either classical or nonclassical, wherein the classical
bioisosteres are a series of replacements defined by Grimm’s Hydride Displacement Law and
Erlenmeyer’s definition of isosteres (see e.g., p. 3148-3149). Patani et al. further teaches trivalent substitution of -CH= with -N= is commonly used in modern drug design; and exemplified said replacement using the pilocarpine shown below:
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to arrive analogue that is equipotent with pilocarpine (see e.g., p. 3159, right column, “2. Trivalent Ring Equivalents” section; p. 3160, left column, 1st paragraph under Table 30). Patani et al. further teaches the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements as these atoms are known to have similar steric parameters (see e.g., p. 3149, left column, “1. Fluorine vs Hydrogen Replacements” section).
Regarding the limitation(s) in claims 48 and 56, It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to incorporate the compound 101 of the reference application with a pharmaceutically acceptable excipient, carrier or diluent to arrive at the claimed invention. One would have been motivated to do so, because the claims of the reference application teaches the compound of Formula (I) and a pharmaceutically acceptable excipient, carrier or diluent can arrive at a pharmaceutical composition suitable for injection. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 101 of the reference application is a compound of Formula (I), thus, said compound 101 a pharmaceutically acceptable excipient, carrier or diluent can successfully arrive at a pharmaceutical composition, and be formulated for injection.
Regarding the limitation of “[a] kit comprising the compound or the pharmaceutically acceptable salt or ester thereof of claim 1 and instructions for use thereof…” in claim 89, the claimed limitations is drawn to the content of the printed matter that describes the use of the compound in the kit. Since the claim is interpreted to be a product, the method step(s) or the instructions for use recites in the printed matter does not appear to further limit the structural component of the product. According to MPEP 2112.01, III, “[w]here the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”. In the present case, the compound 101 of the reference application meets the structural limitation of the kit, and that anticipates the claimed invention. In the alternatives, to the extent that the “instructions for use” is given patentable weight, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to incorporate the compound 101 of reference application with instructions for use to arrive at the claimed invention. One would have been motivated to do so, because a kit or a package is required by law for pharmaceutical preparations and applications, and the FDA Guideline for Industry gives specific instructions for packaging and distributing medication for intended use and instructions for customers. One would have a reasonable expectation of success, because one of ordinary skill in the art would have recognized the need for providing the instructions for the caregiver as those are mandated by federal law to include such instructions; and that renders obvious the limitations instantly claimed.
Regarding the limitation of the elected compound species in claim 47, and newly added claims 104-107, the difference between the compound 101 of the reference application and the elected compound species of Formula (I) instantly claimed is that the reference application teaches
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rather than
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shown below:
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.
It would have been prima facie obvious to one ordinary skill in the art at the time the application was filed to select the compound 101 of reference application, and then modify said compound 101 by substituting the hydrogen of 1-methyl-1H-indazole with a fluorine, and then substituting the trivalent carbon in the 3-substitued-2,6-piperidinedione with a nitrogen atom based on the Grimm’s Hydride Displacement Law taught by Patani et al. to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches hydrogen and fluorine are monovalent isosteres that can result in analogues with similar biological activity; and trivalent substitution of -CH= with -N= is commonly used in modern drug design based on Grimm’s Hydride Displacement Law. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 101 of reference application, which substitutes the hydrogen of 1-methyl-1H-indazole with a fluorine, and the trivalent carbon in the 3-substitued-2,6-piperidinedione with a nitrogen atom based on the Grimm’s Hydride Displacement Law would have successfully arrive at a compound that is similarly useful.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed on June 23, 2026 with respect to the provisional rejection of claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8, 10, 32-33 and 36 of copending Application No. 18/119,592 (reference application) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) have been fully considered but they are not persuasive.
In the present case, applicant amends the scope of compound of Formula (I); deletes claims 2, 30, 36, 38 and 42; and newly added claims 103-107. Each of these findings demonstrate that the claim amendments change the scope of the claims.
In Summary, Applicant requests the double patenting rejections be held in abeyance until one of the applications has been allowed.
In response, since Applicant did not put forth any arguments specifically against this obviousness-type double patenting rejection, the rejection is maintained but revisited and modified in view of the claim amendments.
Claims 1, 3, 8, 16, 26, 28, 47-48, 56, and 89 remain provisionally rejected and claims 103-107 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7-11, 15-17, 20-24 and 36-37 of copending Application No. 18/533,634 (reference application) in view of Wang et al. (WO-2021041671-A1) (partially newly applied as necessitated by amendments).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application are drawn to a compound 203 having the structure of:
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shown in Table 3 is a bifunctional compound of Formula (A) useful for treating KRAS-G12D-associated disease (see claims 1, 23, and 37). The claims of the reference application further teaches the bifunctional compound of Formula (A)
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, wherein K is a targeting group that binds specifically to a KRAS protein and has the structure of Formula (I):
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, W is N; R1, R2 and the W linked to them form a heterocycloalkyl or one of the following groups:
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, Y1 is, inter alia, C or N; R3 is independently, inter alia, alkyl; any two non-adjacent R3 groups together with the ring to which they are connected from a bridge ring (see claim 1). The claims further teaches the E3-ligase binding group T binds to a ligand which is, inter alia, cereblon (CRBN). The claims further teaches a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient, carrier or diluent (see claim 24).
The reference application does not teach the targeting group W having the structure of Formula (Ia):
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as claimed in claim 1. The reference application also does not teach the elected compound species of Formula (I) in claim 47.
Wang et al. teaches compounds of Formula (I)
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, including
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(see e.g., p. 846, last row), bind to KRAS G12D and inhibits the activity of KRAS G12D (see e.g., [0007];[0180]; Table 2).
The differences between the compound 203 of the reference application and the elected compound species of Formula (I) instantly claimed is that the reference application teaches
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rather than
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as the
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shown below:
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.
It would have been prima facie obvious to one ordinary skill in the art at the time the application was filed to select the compound 203 of reference application, and then modify said compound 203 by substituting the heterocycloalky having the structure of:
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with
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as the
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as taught by Wang et al. to arrive at the claimed invention. One would have been motivated to do so, because the reference application teaches R1, R2 and the W linked to them (see shaded
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) can form a heterocycloalkyl or
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, wherein Y1 is N; R3 is independently alkyl; any two non-adjacent R3 groups together with the ring to which they are connected from a bridge ring; and Wang et al. teaches compound of formula (I)
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, including
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can bind to KRAS G12D and inhibits the activity of KRAS G12D.
One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 203 of reference application, which substitutes
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with
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taught by Wang et al. as the
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would have successfully arrive at a targeting group K that binds specifically to a KRAS protein, and said modified compound would be useful for treating KRAS-G12D-associated disease.
Regarding the limitation(s) in claims 48 and 56, and newly added claims 106-107, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to incorporate the modified compound 203 of the reference application set forth above with a pharmaceutically acceptable excipient, carrier or diluent to arrive at the claimed invention. One would have been motivated to do so, because the claims of the reference application teaches the compound of Formula (I) and a pharmaceutically acceptable excipient, carrier or diluent can arrive at a pharmaceutical composition. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 203 set forth above which has very close structural similarities with compound 203 of reference application can successfully arrive at a pharmaceutical composition with a pharmaceutically acceptable excipient, carrier or diluent, and that meets the structural limitation of “the composition is formulated for injection”.
Regarding the limitation of “[a] kit comprising the compound or the pharmaceutically acceptable salt or ester thereof of claim 1 and instructions for use thereof…” in claim 89, the claimed limitations is drawn to the content of the printed matter that describes the use of the compound in the kit. Since the claim is interpreted to be a product, the method step(s) or the instructions for use recites in the printed matter does not appear to further limit the structural component of the product. According to MPEP 2112.01, III, “[w]here the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”. In the present case, the modified compound 203 of the reference application set forth above meets the structural limitation of the kit. In the alternatives, to the extent that the “instructions for use” is given patentable weight, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to incorporate the modified compound 203 of reference application with instructions for use to arrive at the claimed invention. One would have been motivated to do so, because a kit or a package is required by law for pharmaceutical preparations and applications, and the FDA Guideline for Industry gives specific instructions for packaging and distributing medication for intended use and instructions for customers. One would have a reasonable expectation of success, because one of ordinary skill in the art would have recognized the need for providing the instructions for the caregiver as those are mandated by federal law to include such instructions; and that renders obvious the limitations instantly claimed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed on June 23, 2026 with respect to the provisional rejection of Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7-11, 15-17, 20-24 and 36-37 of copending Application No. 18/533,634 (reference application) in view of Wang et al. (WO-2021041671-A1) have been fully considered but they are not persuasive.
In the present case, applicant amends the scope of compound of Formula (I); deletes claims 2, 30, 36, 38 and 42; and newly added claims 103-107. Each of these findings demonstrate that the claim amendments change the scope of the claims.
In Summary, Applicant requests the double patenting rejections be held in abeyance until one of the applications has been allowed.
In response, since Applicant did not put forth any arguments specifically against this obviousness-type double patenting rejection, the rejection is maintained but revisited and modified in view of the claim amendments.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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