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 of group I in the reply filed on 08/21/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of Compound of Example 73
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in the reply filed on 08/21/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 12, 13, and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.
Priority
This patent application is a National Stage Entry of International Application No. PCT/CN2023/073579, filed January 28, 2023, which claims the benefit of International and International Application No. PCT/CN2022/140318, filed December 20, 2022 and Application No. PCT/CN2022/074739, filed January 28, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/31/2024 and 01/06/2026 has been considered by the examiner.
Status of Claims
Claims 1, 3, 5, 12-13, 23-24, 26, 31, 34, 37, 42, 52, 55, 61-63, and 85 are pending. Claims 2, 4, 6-11, 14-22, 25-28, 30, 32-33, 35-36, 38-41, 43-51, 53-54, 56-60, and 64-84 are canceled.
Claims 12, 13, and 63 are withdrawn. Claims 1, 3, 5, 23-24, 29, 31, 34, 37, 42, 52, 55, 61-62, and 85 are examined to the extent they read on the elected species.
Claim Rejections - 35 USC § 112
Claims 1, 3, 5, 23-24, 29,31, 34, 37, 42, 52, 55, are 61-62 are rejected on the 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). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the alternative chemical compounds encompassed by Formula I or claim 1, including the alternative Ring A, Ring B, linker L, and X/Y-containing fused heterocyclic scaffold classes and the alternative specifically depicted compounds recited in claim 61 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The alternatives are not all members of the same recognized physical or chemical class or the same art-recognized class and, when consi8dered as complete compounds, do not share a single substantial structural feature shown to be responsible for their asserted common ENPP1-related use. Claim 1 permits heterocycloalkyl, aryl, and heteroaryl; Ring B independently among cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; L among a bond, -NH-, and -O-; and the X/Y-containing fused heterocyclic portion among materially different fused-ring architectures depending upon X, Y, and whether the X-Y bond is single or double. Claim 61 likewise recites material different central fused heterocyclic nuclei. Although recurring sulfonamide-containing aryl/heteroaryl portions are present in certain species, the disclosure does not establish that such fragments constitute one substantial structural feature common to the compounds as wholes and essential to the asserted ENPP1-related use.
Claims 1, 3, 5, 23-24, 31, 34, 37, 42, 52, 55, and 61-62 are rejected on the basis they contain, or depend from a claim containing an improper Markush grouping. 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) and MPEP §2117.
Claim 1 encompasses material different structural classes at multiple major regions of Formula I. Ring A and Ring B each independently encompass cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; L may be a bond, -NH-, or -O-; and the X/Y definitions permit materially different fused heterocyclic architectures. The alternatives therefore are not merely peripheral substitutions around one invariant nucleus.
Claim 61 further illustrates the problem because its specifically depicted alternatives traverse different fused heterocyclic core families, including differences in number, identity, and arrangement of heteroatoms, and the presence or absence of a carbonyl within the fused five- membered ring.
Although the compounds may share an asserted ENPP1-related utility and certain recurring fragments, the record does not establish that the complete compounds are members of one recognized chemical or art-recognized class or that a single substantial structural feature common throughout the grouping responsible for the common use. Accordingly, the grouping is improper.
Claims 3, 5, 23-24, 31, 34, 37, 42, 52, and 55 narrow individual variables but retain the material different alternatives throughout the remaining Formula I variables. Claim 62 incorporates a compound of claim 1. Claim 61 independently recites the structurally diverse depicted species. Claim 85 is not included because it is limited to the single elected compound.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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, 3, 5, 23-24, 29,31, 34, 37, 42, 52, 55, are 62 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.
The specification, while convey possession of numerous specifically disclosed and exemplified compounds, does not reasonably convey possession of the full scope of the structural genera presently claimed.
For a chemical genus, written description may be established by a representative number of species reflecting the structural variation within the genus or by identifying structural characteristics common to the genus such that the skilled artisan can visualize or recognize its members. See MPEP § 2163.
The specification demonstrates possession of numerous specific compounds, including elected Example 73. The deficiency is the disparity between the breadth of Formula I and the structural breadth actually demonstrated. Claim 1 independently varies Ring A among cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Ring B among those same broad classes; L among a bond, -NH-, and -O-; and X/Y region among materially different fused heterocyclic scaffold classes depending on X, Y, and the X-Y bond. Those alternatives are further combined with extensive R1-R6 and associated substituent definitions.
Thus, claim 1 is not merely peripheral substitution about on invariant core. It encompasses materially different central fused heterocyclic scaffolds together with independently variable Ring A, Ring B, linker, and substituent classes. The specifically disclosed compounds do not provide representative species distributed throughout this full multidimensional structural genus, nor does the specification identify a structural feature common throughout the complete scope.
The issue is not that every theoretical species must be synthesized or expressly described. Rather, the disclosed species must adequately reflect the structural variation within the genus or the disclosure must be otherwise provide identifying characteristics establishing possession across the genus.
Claims 3, 5, 23-24, 29,31, 34, 37, 42, 52, and 55 narrow individual variables but retain substantial unsupported breadth through the remaining Formula I variables. Claim 62 incorporates a compound of claim 1 and therefore likewise incorporates that breadth.
Claims 61 and 85 are not included in this written-description rejection on the present record because the specifically depicted structure, to the extent expressly disclosed in the specification demonstrate possession of those species.
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.
Claims 1, 3, 5, 23-24, 29, 31, 34, 37, 42, 52, 55, 61-62, and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Hao et al. (WO2021/061803 A1) in view of Hawley et al. (WO2022/212488 A1), Doganc et al. (ChemistrySelect 2021, 6, 1519–1525), and Gao et al. (European Journal of Medicinal Chemistry 178 (2019) 177e194).
Hao et al. teaches compounds that inhibit ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) and their use in treating ENPP1-related disorders. Hao explains ENPP1 hydrolyzes 2’3-cGAM and that inhibit of ENPP1 prevents cGAM hydrolysis, thereby enhancing cGAM/STING-mediated signaling and stimulating an antitumor immune response. See pp. 1-3, ¶¶[0004]-0006]. Of particular relevance, Hao expressly discloses compound 89
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(6-((7-methoxy-2,4-dimethyl-1H-imidazo[4,5,c][1,8]naphthyridine-1-yl)methyl)pyridine-3-sulfonamide). See Table 1 and also ¶[0231].
Compound 89 provides a particular close starting compound because it contains a single ENPP1-directed molecule:
(i) a methoxy group on the six-membered portion of the fused heterocyclic system;
(ii) methyl substitution of the imidazole-containing fused system;
(iii) an N-linked methylene group;
(iv) a pyridinyl ring connected through that methylene group; and
(v) a pyridine-3-sulfonamide (-SO2NH2) functionality. These features correspond closely to the substitution arrangement of the elected compound of Example 73.
Fluorine modification taught by Hao
Hao compound 89 itself does not contain the fluoro substituent present on the pyridine-sulfonamide ring of elected Example 73. However, Hao expressly teaches fluorine as a substituent on the corresponding aryl/heteroaryl portion of ENPP1 inhibitor genus of formula A, including Formula (II).
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wherein A denotes aryl or heteroaryl that can be substituted with halogen. See ¶[0035]. Hao defines “halo” or “halogen” to include fluoro, bromide, chlorine, and iodine. See ¶[0021]. Hao further teaches aryl and heteroaryl embodiments, including phenyl and pyridinyl groups, which may be substituted with halogen, and expressly identifies F as the halogen. See ¶¶[0046]-[0047].
Hao’s exemplified compounds additionally demonstrate that fluorination of a sulfonamide-bearing aromatic ring was actually practiced within the disclosed compound series. For example, Hao compounds 61 and 62 contain fluoro-substituted sulfonamide-bearing aromatic groups. See Table 1, p. 49. Hao’s compounds 70 and 71 likewise contain fluoro-substituted sulfonamide-bearing aromatic groups. See Table 1, p. 51. Thus, Hao does not merely generically identify fluorine among a large number of unrelated substituents. Hao both expressly identifies F as a contemplated halo substituent and exemplifies fluorinated sulfonamide-bearing aromatic analogues within the disclosed compound series.
Accordingly, one of ordinary skill in the art seeking additional ENPP1-inhibitory analogues of compound 89 would have reason to introduce fluorine onto the sulfonamide-bearing pyridinyl ring of compound 89, in accordance with Hao’s express teaching of halo/F-substituted aryl and heteroaryl embodiments and its exemplification of fluorinated sulfonamide-bearing analogues. Such modification represents selection and application of a substituent expressly taught by Hao within the same ENPP1-inhibitor genus.
One of ordinary skill would have had a reasonable expectation that the resulting fluorinated analogue would remain suitable for evaluation as an ENPP1 inhibitor because Hao itself teaches the fluorinated alternatives within its ENPP1-directed compound genus and actually exemplifies fluorinated sulfonamide-bearing analogues.
Pharmaceutical Composition
Hao further teaches pharmaceutical compositions comprising its disclosed ENPP1 inhibitors together with one or more pharmaceutically acceptable carriers, including excipients and administration of such compositions in therapeutically acceptable amounts for ENPP1-related disorders. See claims 24-25 and 35; see also ¶0025] and ¶¶[0085]-[0091]. Accordingly, the pharmaceutical composition and pharmaceutically acceptable excipient limitations recited in instant claim 62 are included in the teaching of Hao as the primary reference and need not to be supplied by a separate reference.
Differences remaining after Hoa
Beginning with compound 89 and applying Hao’s express fluorine teaching, the resulting fluorinated analogue contains the elected pyridine-sulfonamide substitution, including the fluoro substituent.
Hao nevertheless, does not expressly disclosed the elected compound of Example 73 because the resulting Hao analogue still differs into two principal respects relevant to the present rejection:
(1) compound 89 contains the imidazo[4,5,c][1,8]naphthyridine scaffold rather than the elected imidazopyridine scaffold;
(2) compound 89 lacks the phenyl group directly attached to the six-membered portion of the elected fused bicyclic scaffold.
Hao’s Compound 89 Elected Compound
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Hawley and Doganc are relied upon for the scaffold modification, and Gao is relied upon for the phenyl substitution.
Hawley and Doganc-Modification to the imidazopyridine scaffold
Hawley independently teaches bicyclic heteraryl compounds as ENPP1 inhibitors, thereby establishing that alternative fused bicyclic heteroaryl scaffolds were known for precisely the same ENPP1-directed purpose disclosed by Hao. See p.2, ¶¶[0004]-[0008].
Hawley provides compounds of
Formula I Formula IA Formula IB
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and
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having fused nitrogen-containing bicyclic heteroaryl systems, wherein: dashed line is a bond between x and y or y and z; b, d, and e are CH; or one or two of b, d, and e are N and remaining of b, d, and e are CH; one of x and z is NH, O, or S and the other of x and z is CH or N; and y is CH or N; provided that, at least one of y and the x or z that is CH or N, is CH. See Abstract; pp. 5-6, ¶[0011], and pp. 7-8, ¶[0012]. Hawley therefore establishes that, in the ENPP1 inhibitor art itself, a person of ordinary skill was not limited to the Hao’s imidazo[4,5,c][1,8]naphthyridine system but had reason to investigate alternative fused bicyclic nitrogen-containing heteroaryl scaffolds while pursuing the same ENPP1 inhibitory objective.
Doganc provides additional teaching concerning the particular imidazo[4,5,b]pyridine derivative as medicinally active small-molecule scaffolds. See p. 1519, Abstract and introduction, left and right cols. Doganc further teaches construction and subsequent derivatization of the imidazo[4,5,b]pyridine fused nucleus. See p. 15820, left col. §2. “Results and Discussion,” and Scheme 1, p. 1520. Doganc additionally demo9nstrtes N-substitution and medicinal-chemistry elaboration of that scaffold. See Scheme 1-3, pp. 1520-1521.
It would therefore been obvious to one of ordinary skill seeking additional ENPP1 inhibitors based upon Ha compound 89, including the fluorinated expressly suggested by Hao, to replace Hao’s tricyclic fused heterocyclic system with the alternative imidazopyridine fused scaffold taught in the ENPP1 inhibitor art by Hawley, particularly in view of Doganc’s teaching that the imidazo[4,5,b]pyridine nucleus was a known and synthetically accessible medicinal-chemistry scaffold capable of further substitution.
The reason for investigating the alternative scaffold is supplied principally by Hawley, because Hawley teaches the alternative fused bicyclic heteroaryl architecture for the same ENPP1 target as Hao, Doganc provides additional structural synthetic support for employing the particular imidazo[4,5,b]pyridine scaffold.
One of ordinary skill would have had a reasonably expectation of successfully preparing the scaffold-modified analogue because Hawley and Doganc demonstrate the synthetic accessibility and medicinal-chemistry derivatization of the relevant fused heterocyclic systems.
The proposed modification does not require relocating the phosphonate-containing substitution of Hawley onto the elected compound. Rather, Hao compound 89 remains the starting compound and supplies the pyridine-sulfonamide-containing side chain, while Hawley and Doganc are relied upon for their teaching of the alternative fused heterocyclic scaffold.
Gao et al-Phenyl substitution of the imidazopyridine scaffold
The fluorinated Hao compound as modified in view of Hawley and Doganc still lacks the phenyl group directly attached to the corresponding carbon of the six-membered portion of the elected fused bicyclic system. Gao supplies this remaining structural limitation.
Gao describes diary-substituted imidazo[4,5,c]pyridine-2-ones and imidazo[4,5,c]pyridines as medicinally active fused heterocycles. See p. 177, Abstract,; p. 178, right col.. §2.1. Of particular relevance, Gao prepares 1,6-diaryl-substituted imidazo[4,5,c]pyridines in which an aryl group is directly attached to the six-membered portion of the fused imidazopyridine nucleus. Gao prepares compounds 17a-I and 18 by Pd-catalyzed Suzuki coupling of the corresponding halo-substituted fused heterocyclic intermediates with phenyl boronic acids. See p. 179, left col., §2.3; Scheme 3. p. 180.
Gao specifically provides 6-aryl analogues including 6-(4-methoxyphenyl) compound 17a, 6-(3-fluoro-4-methoxyphenyl) compound 17b, and 6-(4-ethoxyphenyl) compound 17f, as well as additional substituted phenyl analogues. See pp. 189-190, §§4.22-4.30. Gao additionally teaches that the position of the aryl substitution substituent on the fused scaffold is significant. Gao reports that the tested 1,7- and 1,2-diaryl compounds were inactive, whereas most corresponding 1,6-diaryl compounds demonstrated activity. See p. 181, left col., §2.5. 2.5.
Thus, Gao does not merely establish that phenyl substitution somewhere on a heterocyclic molecule was generally known. Gao specifically teaches direct aryl substitution at the corresponding position of imidazopyridine fused system and provides an established synthetic route for making such compounds.
It would therefore have been obvious to one ordinary skill, when employing the imidazopyridine scaffold suggested by Hawley and Doganc in the fluorinated Hao compound 89 analogue, to further provide a phenyl substituent at the corresponding position of the six-membered portion of the fused imidazopyridine system, as taught by Gao, in order to obtain an additionally aryl-substituted analogue for evaluation as an ENPP1 inhibitor.
One of ordinary skill would have had a reasonable expectation of successfully preparing the phenyl-substituted compound because Gao expressly demonstrates preparation of the corresponding aryl-substituted imidazopyridine by conventional Pd-catalyzed Suzuki coupling.
Gao is relied upon for the structural and synthetic teaching of phenyl substitution, rather than for an expectation that Gao’s particular biological activity would transfer to the modified compound. The ENPP1-directed purpose and expectation arise principally from Hao and Hawley.
Overall Rationale to combine
Taken together, the cited references would have provided one of ordinary skill with reason to arrive at the elected compound through three specifically supported modifications of the closely related ENPP1 inhibitor Hao compound 89.
First-fluorine: Hao itself introducing F as a halo substituent on the aryl/heteroaryl portion of its generic compounds and actually exemplifies fluorinated sulfonamide-bearing aromatic analogues. Thus, Hao supplies both the starting pyridine-sulfonamide arrangement and the teaching of the elected fluoro substituent.
Second-Fused scaffold: Hawley teaches alternative fused bicyclic nitrogen-containing heteroaryl scaffolds for the same ENPP1 inhibitory purpose, while Doganc establishes the particular imidazo[4,5.b]pyridine nucleus as a known and synthetically accessible medicinal-chemistry scaffold.
Third-phenyl: Gao teaches direct phenyl/aryl substitution at the corresponding position of an imidazopyridine fused system and demonstrates preparation of such compounds by conversion Suzuki coupling.
Accordingly, the proposed rejection does not rely upon an unsupported assertion that the skilled artisan would arbitrarily reconstruct Hao compound 89. Each material difference between Hao compound 89 and elected Example 73 is affirmatively addressed b the cited teachings:
Hao compound 89 → starting ENPP1 inhibitor
Hao → addition of the elected F substituent
Hawley and Doganc → substitution of the fused scaffold with the imidazopyridine scaffold
Gao → addition of the phenyl group at the corresponding position of the fused scaffold.
The combined teachings would therefore have provided both a reason to make the modification and a reasonable expectation of successfully preparing the resulting compound for evaluation as an ENPP1 inhibitor.
Applicant’s elected Example 73, expressly recited in claim 85, without traverse. Claims 1, 3, 5, 23-24, 29, 31, 34, 37, 42, 52, 55, 61-62, and 85 read on the elected species and are presently examined to the extent that they encompass the elected species. Accordingly, for purpose of the present rejection, the structural limitation of these generic and intermediate claims are met by the elected compound rendered obvious by the combined teachings discussed above. Separate repetition of the same elected-species structural mapping for each dependent claim is unnecessary.
Conclusion
Claims 1, 3, 5, 23-24, 29, 31, 34, 37, 42, 52, 55, 61-62, and 85 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
