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) in the reply filed on December 10, 2025 is acknowledged.
Claims 60-61, 63, 81 and 85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 10, 2025.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected compound species of Formula (I) conducted by the Examiner discover prior arts by Lyu et al. and Sun et al. that anticipates the claimed invention, wherein Lyu et al. teaches compound having the structure of:
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(Compound 112), Sun et al. teaches the compound having the structure of:
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(Compound 21); and Ji et al. teaches the compound having the structure of:
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. In light of this discovery, the search is expanded to the subject matter of the compound species of Formula (I) to include the compound 112 of Lyu et al., the compound 21 of Sun et al., and the compound 147 of Ji et al. in addition to the elected compound species of Formula (I), such that it does not encompass the full scope of the claim.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 10, 2025, wherein claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, 60-61, 63, 81, 85 and 89 are unchanged; and claims 4-7, 9-15, 17-25, 27, 29, 31-35, 37, 39-41, 43-46, 49-55, 57-59, 62, 64-80, 82-84, 86-88 and 90-102 are cancelled.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, 60-61, 63, 81, 85 and 89 are pending.
Claims 60-61, 63, 81 and 85 are withdrawn.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 are under examination in accordance with the elected species along with the expanded compound species sets forth in the Expansion of Election of Species Requirement section above.
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, 201. It is noted, however, that applicant 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.
In view of the foregoing, claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 under examination 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 9, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0031]: the chemical structure of the targeting group W is partially cropped and unreadable, e.g.,
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.
Paragraph [0032]: the chemical structures recite therein are partially cropped and unreadable, e.g.,
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and
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; and therefore, it is not clear what these are.
Table 1, cpd no. 17-18: the chemical structure of Ra is cropped and unreadable, e.g.,
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(cpd no. 17) and
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(cpd no. 18).
Appropriate correction is required.
Claim Interpretation
The limitation of “wherein the composition is suitable 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.
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 1, 16, 26, 28, 30, 36, 38, 42, 48, 56 and 89 are 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.
Instant claim 1 recites “[a] compound of Formula (I), or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:
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where: W is a targeting group that binds specifically to KRAS-G12D protein”. The specification only discloses compound species of Formula (I) with targeting group W having the structure of Formula (Ia)
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. The specification also does not disclose any compound species of Formula (I) with targeting group W having the structure of Formula (IIb)
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; and does not disclose any other species of targeting group W that binds specifically to KRAS-G12D protein as broadly encompassed by the instant claims.
While applicant is in possession of Formula (Ia) at targeting group W, applicant is not in possession of the entire scope of targeting group that binds specifically to KRAS-G12D protein.
Regarding the requirement for adequate written description of chemical entities, Applicant's attention is directed to the MPEP §2163. In particular, Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plain for obtaining the claimed chemical invention." Eli Lilly, 119 F.3d at 1566. The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office ("PTO") Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.I "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5,2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter alia, "functional characteristics when coupled with a known or disclosed correlation between function and structure ..." Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)). Moreover, although Eli Lilly and Enzo were decided within the factual context of DNA sequences, this does not preclude extending the reasoning of those cases to chemical structures in general. Univ. of Rochester v G.D. Searle & Co., 249 Supp. 2d 216, 225 (W.D.N.Y. 2003).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the present case, Applicant only discloses compounds of formula (I) having Formula (Ia) as the targeting group W that binds specifically to KRAS-G12D protein. Applicant has failed to provide any examples for compounds of formula (I) having Formula (Ib) as the KRAS-G12 targeting proteins. No other KRAS-G12D targeting groups are described in the specification. Therefore, the disclosure does not appear to describe a sufficient number of representative species of KRAS-G12 targeting proteins. While applicant is in possession of compound species of Formula (I) with targeting group W having the structure of Formula (Ia), it is not apparent that Applicant was in possession of each and every targeting group that binds specifically to KRAS-G12D protein based on the limited disclosure provided.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 8, 16, 28, 38 and 42 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.
Regarding claim 1, the recitation of “Z3 and Z4 are independently hydrogen (H)” renders the claim indefinite. To the extent that “Z3 and Z4 are independently hydrogen (H)” in the structure of
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at Ring A, Z3 and Z4 cannot independently be a hydrogen. For instance, Z3 cannot be a hydrogen substituted on the phenyl of phenyl-fused ring because the carbon atom in the phenyl ring cannot bear 2 hydrogens. The lack of clarify renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
Regarding claim 3,
the recitation of “and/or” in the phrase of “wherein the substituted carbon is…; wherein the halogen substituted methyl is; and/or wherein the benzo-fused ring is…” 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) the substituted carbon is… or (the halogen substituted methyl is … and the benzo-fused ring is…); (ii) the substituted carbon is …or (the halogen substituted methyl is …) or (the benzo-fused ring is…); or (iii) (the substituted carbon is … and the halogen substituted methyl is…) or (the benzo-fused ring is…).
In order to advance prosecution, the Examiner is examining the claim in light of the elected compound species, such that only one out of the three limitations need to be meet.
Regarding claim 8,
the structure of the targeting group W is cropped and unreadable shown below (see shaded):
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.
the recitation of “and/or” in the phrase of “wherein W has the structure of Formula (Ia); 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.
the recitation of “X is a substituted carbon selected from the group consisting of CH” renders the claim indefinite, because the term “unsubstituted” construed in view of paragraph [00158] of the specification refers to a compound or part thereof has no substituent except the undetermined chemical saturation of hydrogen atom; whereas the term “substituted” construed in view of paragraph [00156] of the specification refers to a parent compound or part thereof has at least one substituent group. 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 further substituted with another hydrogen atom, thus, said carbon atom has a total of two hydrogen atoms. To that extent, said substituted carbon violates the octet rule. 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.
In order to advance prosecution, the Examiner is examining the claim in light of the elected compound species such that the
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of Formula (Ia) has the elected structure:
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.
Regarding claim 16,
the recitation of “or” and “and/or” in the phrase shown below (see shaded):
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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)
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; (ii)
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; or (iii)
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. In addition, the recitation of “Y1 is N; Y3 is N” also renders the claim indefinite, because it is not clear if Applicant is intending to claim that (Y1 is N or Y3 is N); or (Y1 is N and Y3 is N). Thus, the claim is considered indefinite because it does not clearly set forth the metes and bounds of the patent protection desired.
The term "preferably" and the term “optionally” also renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, example and preference may lead to confusion over the intended scope of a claim. In addition, the limitation followed after the term “optionally” is a narrower statement of the limitation, thus, it is not clear if the narrower language is merely exemplary of the remainder of the claim, and therefore not required.
In order to advance prosecution, the Examiner is examining the claim to the extent that the claim is drawn to the very first interpretation (i) sets forth above, and each limitation separated by a semicolon has a coordinating conjunction “or”.
Regarding claim 28, the limitation of "the connecting point" lacks antecedent basis, it is not clear what it is referring to. The recitation of “where the connecting point is any position of the phenyl ring capable of substitution” also lacks clarity, because there is no connection point drawn on the phenyl ring presents in the claimed E3-ligase binding group T. For example, the E3-ligase binding group T having the structure of:
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only has a connecting point drawn on the nitrogen of the piperidine ring, and that is not a phenyl; and therefore, it is not clear what “phenyl ring” is being referred to therein, especially there is more than one phenyl rings present in the claimed compound, such as ring A and Formula (Ia).
Regarding claim 38, the term “optionally” in the phrase of “wherein n is an integer from 0 to 20, optionally an integer form 0 to 5, optionally 1 or 2” renders the claim indefinite, because it is unclear whether the limitation(s) following said term are part of the claimed invention. The limitation of “an integer form 0 to 5” and “1 or 2” are narrower statements of the broader range “an integer from 0 to 20”. These limitations followed after the term “optionally” are considered indefinite because it is not clear if these narrower language is merely exemplary of the remainder of the claim, and it may lead to confusion over the intended scope.
Regarding claim 42,
the term “optionally” in the phrase of “p is an integer from 0 to 20, optionally from 0 to 10” and the phrase of “q is an integer from 0 to 10, optionally from 0 to 5” renders the claim indefinite, because it is unclear whether the limitation(s) following said term are part of the claimed invention. The limitation of that follows after the term “optionally” is a narrower statement of the broader range proceeding said term. The limitation followed after the term “optionally” are considered indefinite because it is not clear if this narrower language is merely exemplary of the remainder of the claim, and it may lead to confusion over the intended scope.
the chemical structure of L2 and L3 together includes more than one occurrence of p, q and m, for instance,
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and
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. When these structures are joined together with the limitation of “p is an integer from 0 to 20…m is an integer from 0 to 5…q is an integer from 0 to 10”, it is not clear if each p, q and m has to be the same integer, or each p, q and m can be different but falls within the claimed ranges. It is also unclear if applicant is intending to claim only one out of these p, q and m has to be in the claimed range. The lack of clarify renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
In order to advance prosecution, the Examiner is examining the claim to the extent that each p and m can be different but falls within the claimed ranges.
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.
Claims 28, 36 and 47 are 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.
Regarding claim 28, several chemical structures recite therein is not a E-3 ligase binding group T having Formula (IIIa) or Formula (IIIb) sets forth in claim 1, which it depends upon. For instance,
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and
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recites in the claim has a linker in between
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and phenyl ring; However, such linker (-CH2- or NH) is not recited in Formula (IIIa) or Formula (IIIb).
Regarding claim 36, the recitation of “the compound of claim 30, wherein L1 is oxygen, nitrogen…” in line 1 fails to further limit the L1 sets forth in claim 30, which it depends upon. The recitation of L1 in claim 30 does not include a single heteroatom. In order to advance prosecution, the Examiner is examining claim 30 in light of the elected compound species such that L1 can be an oxygen.
Regarding claim 47, several compound species recite therein is not a compound of Formula (I) instantly claimed. For instance, compound having the structure of “
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…
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…
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…
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” fails to further limit the compound of Formula (I) sets forth in claim 1. It is noted that claim 1 requires the E-3 ligase binding group T to have the following structure:
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, wherein Y1 and Y2 are independently carbon or nitrogen. However, each of these compound does not have the structure of Formula (IIIa) nor Formula (IIIb) sets forth in claim 1.
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.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. 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 recites “[a] compound of Formula (I), or pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:
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”, such that W can be any targeting group that binds specifically to KRAS-G12D protein; T is an E3-ligase binding group having the structure of Formula (IIIa) or Formula (IIIb); and L can be absent or any bivalent linking group that connects W and T together via a covalent linkage. The Markush grouping of the compound species of Formula (I) is improper, because the alternatives 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. Specifically, each of these compound species of Formula (I) only shares the formylacetamide(see shaded
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) at the E3-ligase binding group T 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.
In addition, the Markush grouping of the compounds of Formula (I) include a variety of targeting groups that bind specifically to KRAS-G12D protein at W, including Formula (Ia)
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and Formula (Ib)
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. It is noted that these formulae only shares the structure of:
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in common. According to Harris et al. (WO 2006/050965), the compound of Example 10 having the structure of:
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is a histamine H4 receptor modulator. Even though the compound of Example 10 taught by Harris et al. contains the same common structure, it has histamine H4 receptor modulating effect rather than binding to KRAS-G12D protein.
Moreover, the Markush grouping of the compounds of Formula (I) include a variety of L moiety:
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, wherein L1, L2 and L3 can each be any bivalent alkyl group, any alkyloxyl group, any oxyalkyl group, any cyclic hydrocarbon group, any heterocyclic hydrocarbon group, any acylalkyl group, any alkylacyl group, any carbonylalkyl group, any alkylcarbonyl group, any amidoalkyl group, any alkylamide group, any aryl group, and any oligopeptide group; and they belong to different chemical classes. In addition, L1-L2 and L3 can be combined in various ways, such that does not share any structural similarities. For instance, L of Formula (I) includes structures, such as piperazine (
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), naphthalene (
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) and thiazole (
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), that belongs to different chemical class. Piperazine is a monocyclic heterocyclic compound consisting of two nitrogen atoms, and it is widely used to treat worm infections, such as roundworms and pinworms. Naphthalene is a polycyclic aromatic hydrocarbon consisting of a fused pair of benzene rings, and it is commonly used as an agricultural pesticide. Thiazole is a five-membered heterocyclic ring containing nitrogen and sulfur, and it is mainly used as dyes and fungicides. Therefore, each of these L structure do not share a substantial structure feature and a common use that flows from the substantial structure feature.
Instant claim 47 recites vast variety of compound species, including compound having the structure of:
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. It is noted that these compound species alternatives do not share a substantial structure feature and a common use that flows from the substantial structural feature. In the present case, these compound species only share the structure of:
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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).
Claim Rejections - 35 USC § 102
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 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 48, 56 and 89 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lyu et al. (CN 115785199 A).
Please note Lyu et al. is written in foreign language and machine translation has been provided, the specific portions cited in this instant office action will refer to the sections of the machine translation. Such translation should be interpretated as corresponding to the disclosure of the aforementioned CN 115785199 A. Lyu et al. is available as prior art under pre-AIPA 35 USC § 102(a)(1) as its publication date of March 14, 2023.
Lyu et al. teaches a compound 112 having the structure of:
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is an exemplary compound of the general formula: W-L-T (see e.g., p. 68, “Example 85”; Table 1). Lyu et al. further teaches the W-L-T structure, W is the targeting group of KRAS-G12D protein; T is the ligand group of E3 ubiquitin ligase; L is a divalent linking group that chemically links the targeting group (W) to the ligand group (T); wherein the ligand of the E3 ubiquitin ligase is selected from the group consisting of compounds capable of binding to, inter alia, CRBN (Cereblon) (see e.g., claims 1 and 8). Lyu et al. further teaches a drug composition comprising the compound, or pharmaceutically acceptable salts, esters, hydrates, solvent complexes, or stereoisomers; and optionally at least one pharmaceutically acceptable excipient or carrier or diluent; wherein the composition is suitable for injection administration (see e.g., claims 11 and 14). Lyu et al. further teaches a kit comprising the compounds or any of the compositions that may be prepared for the treatment, inhibition, or prevention of KRAS-G12D mutation-related diseases (see e.g., p. 25, line14; p. 31, last 4 lines).
In the present case, the compound 112 of Lyu et al. is a compound of Formula (I) instantly claimed:
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, wherein W is
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(i.e.,
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where X is nitrogen; R1 is hydroxyl; R2 and R3, together with the phenyl-ring structure to which they are attached, form an substituted benzo-fused ring [i.e., naphthyl ring system substituted with -F and C2 alkynyl); L is
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(i.e., L1 is
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, L2 is
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, L3 is
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, wherein p is 0; or L1 is oxygen; L2 is
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, wherein p is 1; and L3 is
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); T is
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(i.e.,
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, wherein Y3 is carbon; A is
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, Z3 is absent; Z4 is -CH3; Y2 is carbon; Y1 is N). Therefore, the drug composition taught by Lyu et al., which comprising said compound and a pharmaceutically acceptable excipient, carrier or diluent anticipates the claimed invention; and said drug composition with the same structural limitation would necessary be suitable 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, optionally further comprising at least one additional therapeutic agent” in claim 89, the “instructions for use” is not given patentable weight because the content of the printed matter does not distinguish the claimed product from the prior art. According to MPEP 2112.01, “[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, Lyu et al. clearly teaches a kit comprising said compound, and that anticipates the claimed invention.
Therefore, the claimed invention is being anticipated by Lyu et al.
Claims 1-3, 8, 16, 26, 28, 30, 36, 42, 48, 56, and 89 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sun et al. (WO 2024/152247 A1).
Sun et al. is available as prior art under pre-AIPA 35 USC § 102 (a)(2) as its filing date of January 18, 2023.
Sun et al. teaches a compound 21 having the structure of:
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is an exemplary compound of Formula (IA) that cause degradation of K-ras G12D via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by K-ras G12D (see e.g., p. 40, comp #21; p. 1, line 5-9). Sun et al. further teaches a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient (see e.g., claim 2).
In the present case, the compound 21 of Sun et al. is a compound of Formula (I) instantly claimed
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, where W is
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(i.e.,
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, where X is nitrogen; R1 is hydroxyl; R2 and R3, together with the phenyl-ring structure to which they are attached, form an substituted benzo-fused ring [i.e., naphthyl ring system substituted with -F and C2 alkynyl); L is
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(i.e., L1-L2-L3, wherein L1 is oxyalkyl, L2 is heterocyclic hydrocarbon group, L3 is alkylcarbonyl group; or L1 is
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[i.e., oxyalkyl substituted with
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], L2 is
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, right p is 0 and left p is 1, L3 is
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, p is 0); T is
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(i.e.,
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, wherein Y3 is N; A is
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, Z3 is absent; Z4 is -CH3; Y2 is carbon; Y1 is N). Therefore, the pharmaceutical composition taught by Sun et al. which comprising said compound and a pharmaceutically acceptable excipient anticipates the claimed invention; and said pharmaceutical composition with the same structural limitation would necessary be suitable 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, optionally further comprising at least one additional therapeutic agent” in claim 89, the “instructions for use” is not given patentable weight because the content of the printed matter does not distinguish the claimed product from the prior art. According to MPEP 2112.01, “[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, Sun et al. clearly teaches compound 21, which is a compound and that anticipates the claimed invention.
Therefore, the claimed invention is being anticipated by Sun et al.
Claims 1-3, 8, 16, 26, 30, 36, 38, 42, 48, 56, and 89 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ji et al. (WO 2023/215906 A1).
Ji et al. is available as prior art under pre-AIPA 35 USC § 102(a)(1) as its publication date of May 5, 2023.
Ji et al. teaches compound no. 147 having the structure of:
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is an example compound of structure formula A: [KRAS G12Di]-L'-[Degron], wherein KRAS G12Di is a KRAS G12D binding moiety; L’ is a covalent bond or a bivalent, saturated or saturated, straight or branch C1-50 hydrocarbon chain, wherein 0-10 methylene units of L' are independently replaced by X; degron is a cereblon binding moiety (see e.g., p. 259, Compound No. 147; claim 1). Ji further teaches in some aspect, degron is
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(see e.g.,
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)(see e.g., [00179]). Ji et al. further teaches a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (see e.g., claim 42). Ji et al. further teaches a kit comprises a therapeutically effective amount of the compound to treat a disease, disorder or condition described herein, and a therapeutically effective amount of the one or more additional therapeutic agents to treat the disease, disorder or condition; and in some aspects, the kit further comprises written instructions for administering the compound of the disclosure and/or the additional agent(s) to a subject to treat a disease, disorder or condition (see e.g., [00210]).
The compound no. 147 taught by Ji et al. is a compound of Formula (I) instantly claimed, W is
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, L is
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(i.e., L1 is
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; L2 is
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, p is 0; L3 is
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, p is 4); and T is
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(i.e.,
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, wherein Y3 is N; A is
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, Z1 is absent; Y2 is N; Y1 is N); Therefore, the pharmaceutical composition taught by Ji et al. which comprising said compound and a pharmaceutically acceptable excipient anticipates the claimed invention; and said pharmaceutical composition with the same structural limitation would necessary be suitable 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, optionally further comprising at least one additional therapeutic agent” in claim 89, Ji et al. clearly teaches a kit comprising said compound and written instructions; and that anticipated the claimed kit.
Therefore, the claimed invention is being anticipated by Ji et al.
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, 30, 36, 38, 42, 47-48, 56 and 89 are 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).
Please note Lyu et al. is written in foreign language and machine translation has been provided, the specific portions cited in this instant office action will refer to the sections of the machine translation. Such translation should be interpretated as corresponding to the disclosure of the aforementioned CN 115785199 A. Lyu et al. is available as prior art under pre-AIPA 35 USC § 102(a)(1) as its publication date of March 14, 2023.
The teachings of Lyu et al. are sets forth above and applied as before.
Lyu et al. does not teach the elected compound species of Formula (I) 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).
In the present case, the difference between the compound 112 of Lyu et al. and the elected compound species of Formula (I) instantly claimed is that the prior art compound has
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rather than
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at T of Formula I 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 112 of Lyu et al., and then modify said compound 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 to arrive at an analogous. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 112 of Lyu et al., 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 for treating KRAS-G12D-related diseases.
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, optionally further comprising at least one additional therapeutic agent” in claim 89, 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 112 of Lyu et al. 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.
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.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 48, 56, and 89 are 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).
Ji et al. is available as prior art under pre-AIPA 35 USC § 102(a)(1) as its publication date of May 5, 2023.
The teachings of Ji et al. are sets forth above and applied as before.
Ji et al. does not teach the E3-ligase binding group T in claim 28.
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).
In the present case, the difference between the compound 147 of Ji et al. and the claimed compound recites in claim 28 is that the prior art compound has
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rather than
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at the E3-ligase binding group T. 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 147 of Ji et al., and then modify said compound by substituting one nitrogen in the piperazine ring with a carbon atom to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches trivalent substitution of -CH= with -N= is commonly used in modern drug design based on Grimm’s Hydride Displacement Law to arrive at an analogous with similar activity. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 147 of Ji. et al., which substitutes the trivalent nitrogen in the piperazine with a carbon atom based on the Grimm’s Hydride Displacement Law would have successfully arrive at a compound that is similarly useful for treating KRAS-G12D-related diseases.
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.
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, 30, 36, 38, 42, 47-48, 56, and 89 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).
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). 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., claim 33, 36).
The claims of the reference application does 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).
In the present case, the compound 101 of the reference application noted above is a compound of Formula (I)
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, W is
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; L is
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; T is
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; and that anticipates the claimed invention.
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 suitable 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, 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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537
548
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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.
Claims 1-3, 8, 16, 26, 28, 30, 36, 38, 42, 47-48, 56, and 89 are 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).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application is 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 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).
In the present case, the compound 203 of the reference application noted above is a compound of Formula (I)
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, W is
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; L is
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; T is
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; and that anticipates the claimed invention.
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 203 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. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 203 of the reference application is a compound of Formula (I), thus, said compound 203 a pharmaceutically acceptable excipient, carrier or diluent can successfully arrive at a pharmaceutical composition, and would necessary be suitable 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 203 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 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.
Regarding the limitation of the elected compound species in claim 47, the difference 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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569
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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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628