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 with traverse of Group I, drawn to a compound of formula (I) and compositions thereof, and the following species:
Compound 30 having the structure of:
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as the elected species of compound of formula (I),
in the reply filed on August 19, 2026 is acknowledged.
The traversal is on the ground(s) that the Examiner fails to demonstrate the groups of inventions are independent or distinct and does not create a serious burden as they would have an overlapping search.
This is not found persuasive because applicant appears to mischaracterize the basis for restriction practice under PCT Rule 13. While restriction practice in regular U.S. application requires independent or distinct inventions and a serious search burden, the restriction requirement for PCT international phase application uses the “unity of invention” standard to evaluate whether the common technical feature shared between the group of inventions is not a special technical feature in view of the prior arts; and therefore, applicant’s arguments with respect to the restriction requirement appears to be irrelevant to the unity of invention requirement. Given that applicant did not particularly point out the supposed errors with respect to the unity of invention and the prior art(s) set forth in the restriction requirement under the PCT Rule, the requirement is still deemed proper and is therefore made FINAL.
Please note applicant states the elected species of compound represented by formula (I) reads on claims 1-6 and 12-19; However, the Examiner identified claim 13 as being drawn to a species non-elected, because said claim depends on claim 11 drawn to non-elected subject matter.
Claims 7-11, 13, 16-18 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on August 19, 2026.
Priority
The instant application 18/725,087 filed on June 27, 2024 is a 371 of PCT/CN2022/140618 filed on December 21, 2022, which claims priority to, and the benefits of Foreign Application No.
CN202111606278.X filed on December 27, 2021; Foreign Application No. CN202210170157.3 filed on February 24, 2022; Foreign Application No. CN202211104699.7 filed on September 9, 2022; and Foreign Application No. CN202211391154.9 filed on November 11, 2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Please note the certified copies of Foreign Application No. CN202111606278.X and Foreign Application No. CN202211391154.9 do not appear to contain any disclosure pertinent to the subject matter of the instant application, these certified copies only contain 2 pages.
Receipt is acknowledged of a certified copy of foreign application CN202111606278.X, CN202210170157.3 and CN202211391154.9, however the present application does not properly claim priority to the submitted foreign applications. It is respectfully noted that none of these foreign applications disclosed the elected species of compound represented by general formula (I), i.e., compound 30; and said species appear to be disclosed only in Foreign Application No. CN202211104699.7 filed on September 9, 2022. However, since these foreign applications are written in foreign language, a certified English translation of the foreign application must be submitted in reply to this action.
If this copy is being filed to obtain priority to the foreign filing date under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a), applicant must also file a claim for such priority as required by 35 U.S.C. 119(b) or 365(b), and 37 CFR 1.55. If the application was filed before September 16, 2012, the priority claim must be made in either the oath or declaration or in an application data sheet; if the application was filed on or after September 16, 2012, the claim for foreign priority must be presented in an application data sheet.
If the application being examined is an original application filed under 35 U.S.C. 111(a) (other than a design application), the claim for priority must be presented during the pendency of the application, and within the later of four months from the actual filing date of the application or sixteen months from the filing date of the prior foreign application. See 37 CFR 1.55(d)(1). If the application being examined is a national stage application under 35 U.S.C. 371, the claim for priority must be made within the time limit set forth in the PCT and Regulations under the PCT. See 37 CFR 1.55(d)(2). Any claim for priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) not presented within the time period set forth in 37 CFR 1.55 is considered to have been waived. If a claim for foreign priority is presented after the time period set forth in 37 CFR 1.55, the claim may be accepted if the claim properly identifies the prior foreign application and is accompanied by a grantable petition under 37 CFR 1.55(e) to accept an unintentionally delayed claim for priority and the applicable petition fee under 37 CFR 1.17(m)(1) or (m)(2).
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.
In view of the foregoing, the instant claims are not entitled to the benefit of the foreign applications written in foreign language, and will receive an effective filing date of December 21, 2022, which is the filing date of 371 of PCT/CN2022/140618.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/27/2024, 8/27/2025, 2/11/2026, and 8/26/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Please note that foreign references without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Status of Claims
Claims 1-20 are pending.
Claims 7-11, 13, 16-18 and 20 are withdrawn.
Claims 1-6, 12, 14-15 and 19 are under examination in accordance with the elected species.
Specification
The disclosure is objected to because of the following informalities:
The chemical structures and the text within the reaction scheme in Example 1 to Example 51 appear to be blurry and unreadable.
Appropriate correction is required.
Claim Objections
Claims 1-2 and 6 are objected to because of the following informalities:
Regarding claim 1, the term” selected” implies choosing from multiple options; However, the phrase of “which compound is selected from a compound as represented by general formula (I)” appears to lack clear sentence structure because there is only one choice that can be selected. The “compound” recites therein also lacks proper article and that is grammatically incorrect. Thus, the phrase should read –wherein the compound is a compound represented by general formula (I)--. Regarding claim 2, the comma recites in the phrase of “wherein,” should be deleted, because it appears to be grammatically incorrect.
Regarding claim 6, the claim repeatedly recites “wherein R1 is selected from” more than once, and that appears to be unnecessary repetition. The list of alternateives should be group together under a single selection phrase, so it is clear that any one of them can be selected.
Appropriate correction is required.
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 1-6, 12, 14-15 and 19 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 instant claims encompassed a genus of compounds or stereoisomers, deuterated forms, solvates, prodrugs, metabolite, pharmaceutically acceptable salts or co-crystals thereof, which compound is selected from a compound as represented by general formula (I)
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. Although the specification expressly set forth general formula (I) and provides definition for the variables thereof, the disclosure does not reasonably convey to one of ordinary skill in the art that the inventor had possession, as of the filling date, of the full structural genus presently encompassed by the claims.
The rejection is not based merely upon the numerical size of the genus, nor upon a requirement that Applicant expressly exemplify every species encompassed by general formula (I). Indeed, the specification describes specific compounds of general formula (I) in Table E-1 and Table E-2, and exemplified the preparation of Compound 1-52 in the working examples, and those examples are evidenced that Applicant possessed the specifically disclosed compounds and structural families represented thereby. Rather, the deficiency is that the claimed genus encompassed substantial qualitative structural variation resulting from the independent selection and combination of, inter alia, Ring A, R1, R2, and R3, whereas the disclosed species do not reasonably represent the structural diversity encompassed by those alternatives and their combinations.
Ring A and R2
Claim 1 defines Ring A independently as, inter alia, 5-membered heteroaromatic ring, 9- to 10 membered fused heteroaromatic ring, C8-10 fused carbocycle, the recited diazine, pyridine, benzene, and dihydroindolizinone ring systems, each optionally substituted in addition to the positive recited R2. Said claim 1 further defines R2 substituted on the Ring A moiety to be C1-6 alkyl, a C6-10 aromatic ring group, a 5- to 10-membered heteroaromatic ring group, C3-10 carbocyclyl, and 5- to 10 membered heterocyclyl.
Thus, general formula (I) does not merely encompass closely related homologous substitutions. Ring A and R2 may independently comprise chemically and structurally different classes of rings, including aromatic carbocycles, saturated carbocycles, heteroaromatic systems, and nonaromatic heterocyclic systems. The specification provides definition and examples of the meanings of “carbocycle” and “heteroaryl,” but such generic definitions identify the universe encompassed by the terminology, they do not themselves demonstrate possession of compounds represented by general formula (I) spanning the full range of independently selectable Ring A and R2 combinations.
Claims 2-5 narrow Ring A and R2 to enumerate ring systems. Nevertheless, substantial structural breadth remains because Ring A and R2 continue to be independently selectable from multiple chemically distinct ring systems, and the remaining R1 and R3 variables are not correspondingly limited to the exemplified combination.
R1
Claim 1 defines R1 to be -CHR1aR1b or -NR1aR1b, wherein R1a and R1b are independently selected from a different list of alternate variables, each optionally substituted. Claim 1 permits R1a to be C1-6 alkyl optionally substituted with 0 to 4 substituents selected from, inter alia, amino, carboxylic acid, the amine functional groups, C3-6 cycloalkyl; and permits R1b to be C4-10 carbocyclyl or 5- to 10-membered heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N, each optionally substituted with, inter alia, oxo, carboxylic acid, the amine functional groups, and the open-chain or closed chain structures that can also be optionally substituted. The alternate substituents in the group of R1b moiety can materially change the architecture of the claimed compounds, for instance, one or more oxo group(s) can be introduce into the ring system(s) that change the chemical class of a simple cycloalkane to cyclic ketone.
Accordingly, the claim encompasses compounds having materially different connectivity between the carbonyl core to the unsubstituted or substituted alkyl group of R1a, and to the unsubstituted or substituted saturated or unsaturated ring systems of R1b. The disclosed compound species demonstrates possession of particular R1a (clustered around unsubstituted branched alkyl and alkyl substituted with cyclopropyl) in combination with particular R1b (clustered around oxo-substituted pyridine, piperidine and particular 9-10 membered heterocyclyl ring systems), but does not provide representative species spanning the full structural variation of R1 resulting from all claimed R1a and R1b alternatives in combination with the independently variables Ring A and R2 groups.
Deuterated forms, prodrugs, metabolites, and co-crystals thereof
Claims 1 encompasses vast variety of deuterated forms, prodrugs, metabolites, and co-crystals forms of the compound genus represented by general formula (I). The dependent claims and independent claims incorporating the limitation of claim 1 likewise encompass the vast variety of deuterated forms, prodrugs, metabolites, and co-crystals forms.
The specification repeatedly recites the deuterated forms, prodrugs, metabolites, and co-crystals are contemplates for use in the claimed invention; However, literal recitation of these forms in the disclosure does not, by itself, reasonably convey to one of ordinary skill in the art that Applicant was in possession of the full scope of the deuterated forms, prodrugs, metabolites, and co-crystals of the claimed compound genus.
The specification does not identify or characterize any particular species of deuterated forms, prodrugs, metabolites, and co-crystals of the compound encompassed by general formula (I), synthetic preparation, or representative examples thereof. The specification provides no guidance identifying the structural characteristics of these particular forms, for instance, identifying with coformer may be combined with the claimed compound genus in a particular ratio to form a co-crystal, which prodrug moieties may be added, which metabolites may be obtained, and which deuterated forms provide the desired chemical or physical properties, spanning across varying the combination of variables presented in the broad general formula (I).
The lack of written description is not merely based upon the lack of literal description of deuterated forms, prodrugs, metabolites, and co-crystals forms, nor based upon the lack of particular method for preparing deuterated forms, prodrugs, metabolites, and co-crystals forms alone. Rather, the lack of written description is also based upon the absence of disclosure reasonably demonstrating possession of the claimed compound genus of general formula (I), and the fact that it encompasses wide variety of deuterated forms, prodrugs, metabolites, and co-crystals of the compound represented by general formula (I) composed independently selected variables.
The disclosed compounds recite in Table E-1 and Table E-2
The Examiner acknowledges that the specification provides examples in Table E-1 and E-2, in which Compound 1-52 recite therein includes detailed synthetic preparation in the working examples. Those species demonstrate possession of those compounds and of structural subject matter reasonably represented thereby. However, the mere number of disclosed species does not resolve the written-description inquiry where the claimed genus contains substantial qualitative structural variation not adequately represented by these species. Here, the disclosed compounds occupy particular structural families involving selected R2 substituted Ring A systems (clustered around particular phenyl-substituted 5 to 6-membered aromatic ring systems, and phenyl-substituted 9 to 10-membered fused ring systems) in combination with selected R1 group composed of particular R1a and R1b (R1a clustered around unsubstituted branched alkyl and alkyl substituted with cyclopropyl; and R1b clustered around oxo-substituted pyridine, piperidine and particular 9-10 membered heterocyclyl ring systems). The specification does not identify a structural principle demonstrating that the disclosed species are representative of the full genus generated by independently selecting the substantial broader Ring A, R1-R2 and terminal ester functional group R3.
Claims 2-6 narrow selected variables but do not restrict the remaining general formula (I) variables sufficiently to cure the above deficiency.
Claim 12 restricts the compound to general formula (I-f) or (I-g), and that restricts certain Ring A, R1-R3 alternatives. Nevertheless, said claim encompass deuterated forms, prodrugs, metabolites and co-crystals along with structural variation in the remaining independently variable groups. Accordingly, the disclosed examples do not provide representative species reasonably commensurate with the full breadth remaining in these claims.
Claim 14 expressly limits the claimed compounds to compounds in Table E-1 and E-2 of the specification, which as specifically disclosed and structurally identified in the specification; However, said claim encompasses vast variety of deuterated forms, prodrugs, metabolites, and co-crystals thereof , and the specification does not reasonably convey to one of ordinary skill in the art that applicant was in possession of the full scope of the deuterated forms, prodrugs, metabolites, and co-crystals at the time of filing.
Claims 15 and 19 incorporate the compounds, deuterated forms, prodrugs, metabolites and co-crystals of claim 1 directly or through dependency, and their additional pharmaceutically acceptable carrier or amount range limitations do not cure the lack of written description for the underlying structural genus.
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 2-6, 12, 14-15 and 19 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 claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
Regarding claim 1, the claim lacks clear grammatical and sentence structure, and that makes it difficult to reasonably determine the intended meaning of the structural limitations with sufficient certainty. Particularly, the following issues have been identified:
Claim 1 repeatedly uses the terms “and” and “or” together or uses one of them more than once within the same sentence, and that renders the metes and bounds of the structural limitations unascertainable. For example, the phrase “ring A is substituted with one substituent selected from C2-6 alkenyl or C2-6 alkynyl and optionally substituted with 1 to 3 Ra5” can be interpreted such that (a) ring A is substituted with one C2-6 alkenyl or (C2-6 alkynyl and optionally substituted with 1 to 3 Ra5), such that the optional substituents is only applicable to the proceeding C2-6 alkynyl; or (b) ring A is substituted with C2-6 alkenyl or C2-6 alkynyl, and the recited alkenyl or alkynyl can both be optionally substituted with 1 to 3 Ra5. Therefore, it is not clear which interpretations apply;
Claim 1 repeatedly recites "or ring A is selected from...” followed by different substitution requirements, and the grammatical boundaries between the alternatives are not sufficiently clear. For examples, the claim recited “ring A is selected from
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or a C8-10 fused carbocycle, and the ring A is optionally substituted with 0 to 4 Ra5; or ring A is selected from
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, and the ring A is substituted with one substituent selected from C2-6 alkenyl or C2-6 alkynyl and optionally substituted with 1 to 3 Ra5; Ra5 is selected from halogen….”. In this instance, It is not clear which particular ring A is being referred to as “the ring A”, for example, is applicant referring to (a) just the singular ring A proceeding said phrase (e.g., referring to just the “C8-10 fused carbocycle” as the ring A that can be optionally substituted with 0 to 4 Ra5), or (b) referring to all the Ring A presents in the claims (e.g., referring to
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and C8-10 fused carbocycle collectively as the Ring A). In addition, it is also not clear if the structural limitation of “Ra5” recited along with
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at Ring A is (a) only applicable to this particular Ring A instance; or (b) is attempting to apply the Ra5 limitations all Ring A alternatives present in the claim. If the structural limitations recited in each instance are applicable to all Ring A alternatives, then it is not clear which structural limitations recited in the claim should be coupled with a particular ring A instance rather them all of them together;
Claim 1 recites numerous situational or conditional limitations, for example, the use of the term “when” in the phrase of “when ring A is selected from
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…one of the following conditions is met” refer that in this particular situation, the structural limitation of variables within general formula (I) is limited to those recited in the following. However, before the recitation of “when” noted above, the claim does not appear to be establishing that
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is one of the ring A alternatives encompassed by general formula (I) that can be selected, and that renders metes and bounds of the ring A indefinite because it is not clear whether the recited restructure is one of the required feature of the claim.
the recitation of “each Rb is independently selected from H” as part of the structural limitation of “R1b…the carbocyclyl or heterocyclyl is optionally substitued with 0 to 4 Rb” renders the claim indefinite, because the limitation does not clearly identify whether the Rb is intending to replace an implicit hydrogen atom present in the carbocyclyl or heterocyclyl group, or (ii) Rb being added in addition to the already implied valence state of the ring carbons. Therefore, one of ordinary
skill in the art would not reasonably be apprised of the metes and bounds of the claimed
structure with reasonable uncertainty;
The claim repeatedly recited “optionally substituted with 0 to 4” R groups, e.g., Rb, and that renders the claim indefinite, because a substituted group appears to include an unsubstituted group; and therefore, it is not clear if the “substituted” group referred at each instance throughout the claim, e.g., “halogen-substituted C1-6 alkyl” is supposed to include unsubstituted group, e.g., “C1-6 alkyl”, or exclude unsubstituted group. Therefore, one of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the substituted group with reasonable uncertainty.
In view of the foregoing, the examples provided above demonstrate, at a minimum, the issues identified and should not be construed as encompassing each and every issue in its entirety. Same logics are applicable to dependent claims 2-6 and 12. Applicant is required to carefully check the entire claims for any and all of the issues noted above. Claims 2-6, 12, 14-15 and 19 are also rejected based on their dependency on a rejected base claim.
Regarding claim 14, the claim directs to one of the two tables, i.e., “Table E-1 or E-2”, which are not present in the claim. According to MPEP 2173.05(s), “[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)”. Therefore, the metes and bounds of claim 14 is unclear and that renders the claim indefinite.
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.
Claim 12 is 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 12, the recitation of general formula (I-g) fails to further limit the general formula (I) set forth in claim 1. Particularly, instant claim 12 recites the general formula (I-g) ”
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, wherein p2 is selected from 0, 1, or 2”, in which the Ring A of its formula is
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. In contrast, claim 1 recites Ring A is selected from “
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”; selected from “
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and the ring A is substituted with one substituent”; or selected from “
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”. In other words, the general formula (I) does not establish that the benzene has the corresponding Rak group at Ring A in combination with any 0-2 Ra5 added to any available position(s) of said benzene.
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 1-6, 12-15 and 19 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 claim 1 is improper because the alternatives encompassed by general formula (I) do not constitute a recognized physical or chemical class and do not share a substantial structure feature that has been shown to be essential to their asserted common utility. Although the specification generally attributes a4[Symbol font/0x62]7 integrin inhibiting utility to the claimed compounds, the existence of an asserted common utility alone is insufficient where the members do not share a substantial structural feature essential to that utility.
Although the claimed compounds may contain the recited secondary amide and ester moiety circled as follows:
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, the specification does not establish that this moiety constitutes a substantial structural feature responsible for the asserted common α4[Symbol font/0x62]7 integrin inhibiting utility throughout the claimed genus. Rather, the instant general formula (I) permits substantial and independent structural variation at R1, Ring A, R2, R3, including materially different carboxylic, carbocyclyl, heterocycly, fused and spiro ring systems, and terminal functional moieties.
Moreover, the biological data are limited to selected compounds and selected α4β7 or α4β1 intergin, and do not establish that the structurally diverse alternatives encompassed by general formula (I) possess the asserted common utility by virtue of a shared substantial structural feature. Accordingly, the members encompassed by the Markush grouping have not been to share the requisite structural relationship necessary to support their inclusion in a single Markush group.
Likewise, claim 14 is additionally included in this rejection. Although claim 14 limits the claimed subject matter to the specifically enumerated compounds shown in Table E-1 or E-2 of the specification, the limitation to expressly disclosed species does not, by itself, establish proper Markush grouping. The enumerated compounds encompass substantially different molecular architecture, including materially different ring systems, substitution patterns, and terminal functional domains, and the biological data are limited to particular combination of R1, Ring A, R2 and R3 group, and does not establish that these structurally diverse species possess the asserted common utility by virtue of the shared secondary amide and ester moiety.
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.
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 1-6, 12, 14-15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Bursavich et al. (WO 2021/076890 A1; cited in the IDS filed on June 27, 2024), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176), Shehata et al. (Sci Rep, 2016. Vol. 6: 36681) and Biediger et al. (US 2003/0199692 A1; cited in the IDS filed on February 11, 2026), as evidenced by CAS Registry Number 434899-71-5 (Entered STN Registry on June 28, 2002).
Bursavich et al. teaches a compound having the structure of:
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(referred to herein as “Compound 1”) is an exemplary compound of Formula (I) (see e.g., Figure 4, p. 745, left column, last row; p. 4, line 1-3); and measures its α4β7 inhibition potency with a IC50 value of A (< 5 nM) obtained using the FP assay of Example 5 (see e.g., p. 629, line 11-16). Bursavich et al. further teaches the compounds are useful for the treatment of α4β7 integrin-mediated conditions, such as inflammatory bowel disease (see e.g., p. 3, 2nd paragraph). Bursavich et al. further teaches the drug substance pharmaceutical composition can comprise the active pharmaceutical ingredient (API) (i.e., a compound of Formula (I) or pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and/or excipients (see e.g., p. 58, line 1-9). Bursavich et al. further teaches the pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound of Formula (I) per unit dose (see e.g., p. 67, last paragraph). Bursavich et al. further teaches the compounds of Formula (I):
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, wherein R3a and R3b are independently selected from the group consisting of, inter alia, H, -CN, halide, CF3 and provided that R3a and R3b are not both H; R3c is selected from, inter alia, H, substituted or unsubstituted (C1-C5)-alkyl; R3d is selected from the group consisting of, inter alia, H and halide (see e.g., p. 2-3). Bursavich et al. further teaches the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention; all such isomers, as well as mixtures thereof, are intended to be included in this invention (see e.g., p. 8, line 1-8). Bursavich et al. further teaches the term “halide” means fluoro, chloro, bromo, iodo, and the like (see e.g., p. 11, 4th paragraph).
Bursavich et al. does not teach the elected species of compound of formula (I).
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 shown below:
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(see e.g., p. 3148-3149). 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).
Shehata et al. identified 12 GPR139 agonists containing previously untested aromatic bioisosteres (see e.g., abstract); and further teaches benzyl bioisosteres
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includes, inter alia, 2,3-dihydro-1H-indene having the structure of:
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, and said 2,3-dihydro-1H-indene has polar surface area and solubility values comparable to the parent moieties (see e.g., p. 10, 1st paragraph; Table 5; p. 10, line 1-8).
Biediger et al. teaches compounds with ability to inhibit binding of α4β1 in Table 1-4, in which it includes (3S)-3-(2,3-dihydro-1H-inden-5-yl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid that has an IC50 of 63 nM in Table 4 (see e.g., p. 35, Table 4); and Compound 14, (3S)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)-3-(4-fluorophenyl)propanoic acid, having the structure of:
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that has an IC50 of 150 nM in Table 1 (see e.g., [0196]; Table 1). Please note (3S)-3-(2,3-dihydro-1H-inden-5-yl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid of Biediger et al. has a chemical structure of:
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, as evidenced by CAS Registry Number 434899-71-5. Biediger et al. further teaches the compounds are inhibitors of a α4β1 binding, and useful for treating disease, including inflammatory bowel disease (see e.g., [0009]; [0178]); and may be described by Formula III:
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(see e.g., [0037]), presently preferred compound of Formula III has R4 as aryl (see e.g., [0048]); and the term “aryl” as used therein refers to, inter alia, phenyl or indenyl (see e.g., [0105]). Biediger et al. further teaches the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day (see e.g., [0153]).
In the present case, the difference between the compound 1 of Bursavich et al. and the claimed elected compound is shown below (see shaded):
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353
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.
Bursavich et al. does not teach the elected species of compound of formula (I). Although Bursavich teaches that R3a and R3b are independently selected from, inter alia, hydrogen and halide, Bursavich further teaches that R3a and R3b are not both hydrogen. Accordingly, Brusavich does not itself expressly disclosed the particular R3a/R3b hydrogen pattern of the elected compound 30.
Patani et al. is relied upon as evidence that, at the relevant time, replacement of fluorine by hydrogen was a recognized bioisosteric modification employed by medicinal chemists in the rational modification of biologically active lead compound. Patani et al. teaches that bioisosterism is an approach used in medicinal chemistry for rational modification of lead compounds into safer and more clinically effective agents (p. 3147), and identifies fluorine/hydrogen substitution as commonly employed monovalent isosteric replacement based on similar steric parameters of fluorine and hydrogen (p. 3149).
It would have been prima facie obvious ton one of ordinary skill in the art at the time the invention was filed, to select compound 1 of Bursavich et al., an expressly exemplified and potent α4β7 integrin inhibitor, as a lead compound and to prepare structurally related analogs thereof by (1) replacing the indicated fluorine substituent(s) with hydrogen and replacing the indicated CF3 substituent with hydrogen, and (2) replacing the indicated phenyl moiety with the corresponding 2,3-dihydro-1H-indene moiety, thereby arriving at the elected Compound 30.
For the F/H portion:
With respect to the fluorine-to-hydrogen modification, Bursavich et al. establishes that hydrogen and halogen are tolerated alternatives at the relevant positions within its α4β7 inhibitor scaffold, although Bursavich excludes the particular embodiment in which R3a and R3b are simultaneously hydrogen. Patani et al. establishes that fluorine-to-hydrogen replacement was a conventional bioisosteric modification available to medicinal chemists for rational modification to biologically active lead compounds. Thus, starting from the expressly exemplified Compound 1 of Bursavich, one of ordinary skill seeking additional structurally related α4β7 inhibitors would have had reason to investigate the known fluorine-hydrogen bioisosteric modification taught by Patani, rather than being limited to the particular substitution pattern encompassed by Bursavich’s Formula I.
(2) Phenyl to 2,3-dihydro-1H-indene:
With respect to replacement of the phenyl moiety with 2,3-dihydro-1H-indene, Shehata e al. identifies the latter as a known bioiosteric replacement for the corresponding aromatic moiety, while Biediger et al. provides more specific evidence in the integrin-inhibitor art that compounds incorporating the indene/indenyl moiety retain integrin inhibitory activity. Thus, the teachings of Shebata and Biediger would have provided one of ordinary skill with reason to make this additional structural modification to Bursawich’s lead compound while seeing additionally integrin-inhibitory analogs.
One of ordinary skill in the art would have a reasonable expectation of success in obtaining a compound that retains the α4β7 inhibiting effect, because one would have reasonably expected that by modifying the Compound 1 of Bursavich et al. in accordance with its formula (I), and employing the known bioisosteric replacement techniques, including monovalent substitution of fluorine with hydrogen and benzyl to dihydro-1H-indene, would successfully provide the corresponding analog while retaining the biological activity associated with Bursavich’s α4β7 integrin inhibiting scaffold, thereby arrive at the elected compound 30 with a reasonable expectation of success.
Please note the elected species, i.e., compound 30, is a compound represented by instant general formula (I)
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, wherein R1 is
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(reading on
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, wherein R1a is isobutyl; b is 2; each Rb is independently selected from C1-4 alkyl substituted with 3 substituents selected from halogen or N(C1-4 alkyl)2); A is
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(reading on C8-10 fused carbocycle); R3 is H; R2 is
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(reading on a benzene ring substituted with 3 R2a, each R2a is selected from halogen or C1 alkyl).
Regarding the limitation of “1-1500 mg of the compound” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to incorporate the modified Compound 1 of Bursavich et al. set forth above at a daily dose range of about 0.0001 to about 1000 mg/kg/day with a pharmaceutically acceptable carrier to arrive at the claimed pharmaceutical composition. One would have been motivated to do so, because Bursavich et al. teaches the compound of formula (I) is an α4β7 integrin inhibitor useful for treating inflammatory bowel disease, and said compound is an active pharmaceutical ingredient that can be combine with one or more pharmaceutically acceptable carriers to arrive at a pharmaceutical composition; and Biediger et al. teaches structurally related compounds that are drawn to the class of integrin inhibitor, and teaches said integrin inhibitor can be administered at a total daily dose of about 0.0001 to about 1000 mg/kg/day to a human or lower animal for treating inflammatory bowel disease. Accordingly, one of ordinary skill in the art seeking to arrive at a pharmaceutical composition useful for treating inflammatory bowel disease would have had a reason to select the total daily dose of integrin inhibitor taught by Biediger et al. for incorporation as the therapeutically effective amount of the modified compound 1, thereby arriving at the claimed pharmaceutical composition with a reasonable expectation of success. According to MPEP 2144.05, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. For example, a subject that weights 60 kg would give a totally daily dose of 0.006 mg to 60000 mg, and that renders obvious the claimed limitation.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
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 1-6, 12, 14-15 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19/110,248 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of reference application are drawn to a compound of general formula (I)
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or stereoisomer, mesomere/racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, encompassing compounds recite in Table E-1, and said table includes compound having the structure of:
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(referred to herein as Compound 30)(see e.g., row 30, left column); and compound having the structure of:
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(referred to herein as Compound 39)(see e.g., row 39, left column). The claims of reference application further teach the R1 of its general formula (I) is selected from, inter alia,
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or
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.The claims of the reference application are also drawn to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises 1-1500 mg of the compound.
In this case, the difference between the compound 30 of reference application and the claimed elected compound species is shown below (see shaded):
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303
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.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select Compound 30 of the reference application, and then modify said compound by replacing the ethyl substituent of the di-substituted N-terminal group with methyl. One would have been motivated to do so, because the reference application expressly teaches R1 of its general formula (I) may be
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or
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. Accordingly, the reference application itself would have suggested methyl in place of ethyl added to the N-terminal group while retaining its biological activity. One would have a reasonable expectation of success to arrive at the claimed invention, because the claims of reference application demonstrate that methyl substituted on the N-terminal group, including Compound 39, is tolerated, and one would have expected that replacing the ethyl with methyl could likely be successful in arriving other analogs of general formula (I).
According to MPEP 2144.09, “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).”
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
