Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. Claims 63-82 are pending.
Priority
2. This application is a 371 of PCT/CN2022/073906 01/26/2022; Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119 (a)-(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to FOREIGN APPLICATIONS: PCTCN2021076144 02/09/2021, PCTCN2021091050 04/29/2021, PCTCN2021117189 09/08/2021, PCTCN2021119368 09/18/2021, PCTCN2021124714 10/19/2021, PCTCN2021128807 11/04/2021, PCTCN2021129056 11/05/2021. is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 (a)-(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application, as follows:
PCTCN2021076144 fails to provide support for the instant claims at least because the rings size of A, B, C in claim 1 on page 80 does not exceed 12 members while claim 1 is 20.
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The generic language is different and the rings in the various optional statements is also 20 members. A large number of species in claim 80 do not appear in the ‘144 application.
PCTCN2021091050 has the same issue as the ‘144 PCTCN2021076144 as it also fails to provide support for the instant claims at least because the rings size of A, B, C in claim 1 on page 80 does not exceed 12 members while claim 1 is 20. The generic language is different and the rings in the various optional statements is also 20 members. A large number of species in claim 80 do not appear in the ‘050 application.
PCTCN2021117189 does not support the as filed claimed genus and is drawn to compounds only with D ring as shown on page 111/1:
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None of the species in claim 80 appear in the ‘189 application.
PCT CN2021119368 does not support the as filed claimed genus and is drawn to compounds only with D ring as shown on page 162:
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None of the species in claim 80 appear in the ‘368 application.
PCTCN2021124714 fails to provide support for the instant claims at least because the rings size of A, B, C in claim 1 on page 94 does not exceed 12 members while claim 1 is 20.
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The generic language is different and the rings in the various optional statements is also 20 members. A large number of species in claim 80 do not appear in the ‘714 application.
PCTCN2021128807 fails to provide support for the instant claims at least because the rings size of A, B, C in claim 1 on page 116 does not exceed 12 members while claim 1 is 20.
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The generic language is different and the rings in the various optional statements is also 20 members. A large number of species in claim 80 do not appear in the ‘807application.
PCTCN2021129056 fails to provide support for the instant claims at least because the rings size of A, B, C in claim 1 on page 116 does not exceed 12 members while claim 1 is 20.
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The generic language is different and the rings in the various optional statements is also 20 members. A large number of species in claim 80 do not appear in the ‘056 application. The date afforded the instant claims is the date of the filing of the PCT/CN2022/07390 01/26/2022.
Response to Restriction Election
3. Applicant’s election of group I and the species compound 45,
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in the reply filed on December 29, 2025 is acknowledged. According to applicants’ representative claims 63-81 read on the elected species. As best as can be determined this is a compound where X5 is N, C is a piperazine(6 membered heterocyclic), X1 is C, X2 is N, A is pyrrole (5-membered heteroaryl or heterocyclic), X3 is C, X4 is C, B is pyridine, (6-membered heteroaryl or heterocyclic) Z1/Z2/Z3 is methyl and -CF3, Y3is C=O, m 3 is 0, one of m3 or m4 is 1 and the other is 0, where R9/R10 or R11/R12 are H, Y2 is O, R5/R6 are H, R7/R8 are H, one of m2 or m1 is 1, the other is 0, one of R1/R2/R3/R4 is methyl the other H, Y1 is O, R13 is CF3, R15 is H, R14 is H. The election was made with traverse and the examiner finds the arguments unpersuasive. According to the arguments, all claims have a common structural feature and activity. Although the chemical compounds of the Formula I share a common structure of some carbon atoms and a pyridazine, the common structure is not a significant structural element because it represents only a small portion of the compound structures and does not constitute a structurally distinctive portion in view of the radical permutations of A, B, C, Y1, Y2 and Y3. Further, the compounds of these groups do not belong to a recognized class of chemical compounds. The structures are not equivalent and not a recognized class of chemical compounds where each member could be substituted for one another with the same intended result. There is no expectation that the corresponding technical feature results in a common activity (or property), therefore the claims lack a special technical feature. With regard to search burden, search burden or lack thereof is not a grounds for traversal of an application filed under 35 U.S.C. 371, it is only the presence of a special technical feature.
Rejections Under the Judicially Created Doctrine of Improper Markush Grouping
4. Claims 63-79, 81 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. 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: The only non-variable atoms in Formula I is pyridazin-one. This structure is insubstantial to the disclosure of the compounds in the specification. According to the specification the compounds are inhibitors of PARP7. The specification discloses number of compounds however these compounds are homogenous. All compounds have a C ring as piperazine, B ring as pyridine or pyrimidine and A as a limited group of saturated rings and pyrrole. The linker is already known and the substituents on the pyridazinone are already optimized. The claims are drawn to nearly any ring for A, B and C up to 20 members as well as various additional rings on pages 2-13 outside of A, B, and C where the various groups form an even greater and larger number of fused rings. Taken to its logical conclusion, the CAB construct with various rings from embraces millions of distinct rings up to 50 fused rings or so. Assuming some of these could be prepared there is no expectation that such diverse compounds would have the same or similar properties. It is well known that molecular structure is correlated with physical properties and in particular in heterocyclic chemistry the change from one ring to another often results in dramatic changes in properties. Pozharskii et. al. Heterocycles in Life and Society Wiley, 1997, pgs. 1-6: "It is rumored that the Russian scientist Beketov once compared heterocyclic molecules to jewelry rings studded with precious stones. Several carbon atoms thus make up the setting of the molecular ring, while the role of the jewel is played by an atom of another element, a heteroatom. In general, it is the heteroatom which imparts to a heterocycle its distinctive and sometimes striking properties..." The SAR for these compounds is known. Qiu “PARP7:an Emerging Therapeutic Target-Insights into Biological Functions and Advances in Small-Molecule Inhibitor Development” J. Med. Chem. 2025, 68, 19846−19870 explains:
The interaction mode of RBN 2397 with PARP7 can be concluded as three primary regions: (1) the pyridazinone-binding NAD + subpocket; (2) the pyrimidine moiety-binding adenosine pocket; (3) the alkoxyethane flexible linker situated in the D-loop region. In addition, a distinct PAR/MAR pocket exists beside the NAD+ pocket. (Figure 6B). The pyridazinone core of PARP7 inhibitors engages in important specific interactions with the NAD+ subpocket, thereby affecting the catalytic activity and enzyme kinetics of PARP7. The flexibility of the D-loop region facilitates the binding of PARP7 inhibitors with different linkers. Furthermore, the structure of the adenosine receptor pocket dictates the ability of the PAR polymer to interact with the ADPr unit, thereby impacting its capacity to extend the PAR chain or produce branched modifications. Interaction analysis revealed that Gly565 and Ser604 form significant hydrogen bond interactions with the pyridazinone core of RBN-2397, while Phe607 and His564 establish π−π interactions; Tyr596 forms a hydrogen bond interaction with the carbonyl group of the linker, while Asp580 establishes a hydrogen bond interaction with the nitrogen atom of the pyrimidine ring (Figure 6C).
Regarding the linker and substituents on the terminal right hand side ring B, the importance is discussed on page 19853,
In order to more comprehensively elucidate the SAR of the novel core compound, we further investigated the length of the linker chain and found that extending the linker chain is not conducive to the interaction between the compound and the protein. In the subsequent exploration of side-chain substituents, we observed that the activity of compounds with other alkyl and halogen substitutions decreased. Additionally, after a series of attempts with substituents on the pyrimidine ring, we concluded that electron-withdrawing groups seem to be more favorable for maintaining activity, while the removal of substituents essentially led to a loss of activity (Figure 8D).
Qiu discusses the approach of the instant claims on page 19858, “In 2022, Kargbo et al. from Jacobio Pharmaceuticals Co.,Ltd. reported a series of compounds featuring a tricyclic rigid
structure through an annulation strategy in patent WO2022170974A9. This approach involved modifying the piperazine and pyrimidine rings within the adenosine subpocket, based on the structure of RBN-2397.” All that is disclosed in the specification is this approach where some A ring changes described in A (g) figure of Qiu:
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The compounds share the same basic core as compounds in Zhang “Exploring the structural-activity relationship of hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine derivatives as potent and orally-bioavailable PARP7 inhibitors.” European Journal of Medicinal Chemistry, 2023, 261, 115836., who made the same type of conformationally constrained cyclic analogs. Zhang looked at the same fused compounds of the instant claims, and substituents on the terminal B ring in Table 2 on page 4 and discusses the importance of these groups:
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With the potent tricyclic hexahydropyrazino[1,2-d]pyrido[3,2-b] [1,4]oxazine core-structure in hand, we next turned to probe the SAR of the group conjugated to the fused rings. Substitution of trifluoromethyl (1) to other electron-withdrawing groups including cyano (7), chlorine (8), and fluorine (9) reduced the inhibitory potency to NCIH1373 cells (Table 2). However, replacing trifluoromethyl with chlorine seemed acceptable for PARP7 binding, as the proliferation inhibition of 8 (IC50 = 106 nM) on NCI-H1373 cells was close to that of 1. Different from 8, the substitution of fluorine (9) significantly reduced the potency (IC50 = 694 nM), possibly caused by the insufficient pocket occupancy of fluorine. Noteworthy, the conjugation of electron-donating methyl (10) to the tricyclic rings was extremely disadvantageous for efficacious PARP7 inhibition (IC50 = 954 nM).
All of the compounds, have a very specific structure absent from the instant claims. 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 § 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.
5. Claims 64-69, 73-74 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. The term "in some embodiments" appear 16 times in the claim 64. The phrase ”X5 is selected from N or CH; in some embodiments, X5 is selected from N; X2 is selected from N or CH; in some embodiments, X5 is selected from N;” If X5 and X2 are given two choices of N and CH then explaining that “in some embodiments” they are chosen from one of the selection casts doubt on what the intention is, to speak of a preferred embodiment or a narrowed embodiment within the same claim. It is improper to speak of preferred embodiments within a claim since this is the purpose of a dependent claim. In other cases the ambiguity is numerical, for example with respect to the m9 variable, “m7 is selected from 0, 1, 2, 3, 4, 5, or 6; in some embodiments, m7 is selected from 1, 2 or 3; in some embodiments m7 is selected from 1 or 2; in some embodiments, m7 is selected from 2;” “m9 is selected from 0, 1, 2, 3, 4, 5, or 6; in some embodiments, m9 is selected from 0, 1, 2 or 3; in some embodiments, m9 is selected from 0, 1 or 2;” The variable m8 has the same or similar construction. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. The variable Y4 has three subgenera as does Y5 and Y6. Claim 73 and 74 use a similar construction to describe chirality.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
6. Claim(s) 63-81 is/are rejected under 35 U.S.C. 102(a)(2)as being anticipated by Gu WO 2022166749 A1 [English equivalent is US 2024/0166664 A1]. Gu on page 27-40 US ‘664 starting at paragraph [0337] teaches anticipatory species. 58 of the compounds appear in CN 2021107681969 filed July 7, 2021, while another 25 species are disclosed in CN 2021101515579 filed February 3, 2021. These two documents support the date(s) of the 102(a)(2) rejection. These compounds include but are not limited to compounds shown below with the same left hand portion of the elected species, i.e. Y3 is C=O, m 3 is 0, one of m3 or m4 is 1 and the other is 0, where R9/R10 or R11/R12 are H, Y2 is O, R5/R6 are H, R7/R8 are H, one of m2 or m1 is 1, the other is 0, one of R1/R2/R3/R4 is methyl the other H, Y1 is O, R13 is CF3, R15 is H, R14 is H:
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The compounds complete the right hand portion in various ways through the generic language of disparate claims1, including in claim 63 where X1 is C, X2 is N, X5 is N, C is piperazine (the elected species), A is a morpholine, oxazepane, diazepane, piperazine, piperidine (a 6 or 7 membered heterocycle), X3 is C, X4 is C, B is pyridine, (6-membered heteroaryl or heterocyclic) Z1/Z2/Z3 is halogen (Cl, F), -CF3. At least compounds 2 and 24 appears in the list of rings in claim 70. The specific ring with the -CF3 appears in claim 72 on page 22, which is also subsumed by the last substructure on page 39 of claim 74 and the first one on page 40. A number of these compounds are also in claim 80 including but not limited to 5-(2S)-1-(2-hydroxy-3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-dipyrazino[2,3-b:1',2'-d][1,4|oxazepin-9-yl)propoxy)propan-2-yl)amino)4-(trifluoromethyl)pyiidazin-3(2H)-one, which is compound 2 above.
Conclusion
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 Claim 63 uses the A, B, C ring language to describe the tricycle, however claim 64 introduces new variables and some new substructure presumably subsumed by the language of claim 62. The new variables, X6, X7, X8, X9, Y4, Y5, Y6, and new subscript repeating groups with m variables. Some of the member are “absent”, and a number of proviso and “some embodiment” language create the same ring in a number of ways. For example compound 2 creates the morpholine where the m7 is 2, m 8 is 1, Y6 is O, m9 is 0, Y4 is CH2, however where all the ring members Y4-Y6 are methylene any number could form the last compound shown above where a piperidine is formed, i.e. Y6 is methylene, Y4 is absent, m9 is 1, or Y4 is CH2 and m9 is 0.