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) with the addition of compound 28c
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as the elected compound species in the reply filed on 06/15/2026 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Claims 2-5, 9-14, 22, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.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 application is a continuation of U.S. Patent Application No. 18/168,055, filed February 13, 2023; which is a continuation of U.S. Patent Application No. 16/622,816, filed December 13, 2019, now U.S. Patent No. 11,661,426; which is a U.S. National Stage Application of International Patent Application No. PCT/US2018/037503, filed June 14, 2018; which claims the benefit of priority to U.S. Provisional Patent Application serial number 62/520,150, filed June 15, 2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/29/2024 has been considered by the examiner.
Status of Claims
Claims 1-26 are pending. Claims 27-30 are canceled. Claims 2-5, 9-14, 22, and 25 are withdrawn. Claims 1, 6-8, 15-21, 23-24, and 26 are examined in accordance to the elected species.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
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, 6-8, 15-21, 23, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for the preparation and evaluation of the compounds recited in claim 24, does not reasonably enable a person of ordinary skill in the art to make and use the full scope of the compounds encompassed by formula (I) and (II), commensurate with the breadth of the claims, without undue experimentation.
The specification enables the preparation and biological evaluation of numerous exemplified compounds. However, the claims encompass an extraordinarily broad genus defined by multiple structurally distinct fused bicyclic scaffold classes together with expansive Markush definition for numerous independently variable substituents. Consequently, the claims encompass a vast number of compounds extending far beyond the exemplified embodiment of claim 24.
The issue presented is not whether a person of ordinary skill in the art could prepare additional compounds within the claimed genus. Rather, the issue is whether the specification enables a person of ordinary skill in the art to identify and use, throughout the full scope of the claimed genus, compounds possessing the claimed biological activity without undue experimentation.
Applying the factors set forth in in re Wands, 858, F.2d 731 (Fed. Cir. 1988), the claimed invention is not enabled.
(A) Breadth of the claims
Claims 1 and 26 encompass multiple distinct bicyclic scaffold classes together with numerous independently variable substituents definitions. The resulting genus encompasses an extremely large number of structurally distinct compounds, substantially exceeding the number of compounds actually prepared and evaluated.
(B) Nature of the invention and predictability of the art
The invention resides in medicinal chemistry directed toward kinase inhibitors. Although persons of ordinary skill in the art possesses the knowledge necessary to synthesize structurally related analogs, the art demonstrates that biological activity within such compound families cannot reliably predicted solely on structural similarity. The medicinal chemistry literature consistently demonstrates that optimization of kinase inhibitors requires iterative synthesis and biological evaluation of numerous analogs to establish structure-activity relationships. Hunt et al. (J. Med. Chem. 2004, 47, 4054-4059) describe systematic preparation and evaluation of numerous pyrrolotriazine analogs to identify potent kinase inhibitors, illustrating that biological activity depends upon empirical optimization rather than single structural prediction. (See Abstract, Scheme 1 and page 4055.) Hunt et al. also reports that appendage of a methyl group to either the 5-or 6-position of the pyrrolotriazine provided analogues 10 and 11, respectively, which showed inhibitory potency similar to the unsubstitutedcompound9.The7-methylanalogue12 was substantially poorer as an inhibitor of EGFR, suggesting that this RTK makes close contacts with the pyrrolo[1,2,4]triazine nucleus in the region around the 7-position.Keepinginmindtheslightlydifferentvectors produced by the7-pyrrolotriazineand8-quinazoline substituents, these data are consistent with the observation that 8-substituents in the quinazoline-based EGFR inhibitors do not generally lead to improved biochemical potency. (See left column of page 4056.) Hunt et al. conclude that A search for novel kinase inhibitor templates identified the pyrrolo[1,2,4]triazine nucleus as one which effectively mimics the well-known quinazoline kinase inhibitor template. Attachment of C4-substituents which were known from quinazoline-based compounds to confer inhibitory activity against the kinase activity of EGFR or VEGFR-2 provided potent pyrrolotriazine based inhibitors of these receptor tyrosine kinases. Initial structure-activity studies identified positions 5 and 6 as ones which tolerated substitution, while substitution at the 7-position led to substantial loss of inhibitory activity. (See Conclusion Section.)
Likewise, Singh et al. (Med Chem Res. 2021 Nov 13;31(1):1–25) explains that development of pyrrolotriazine kinase inhibitors has required continual SAR optimization over many years and that different substitution patterns influence biological activity in different ways depending upon the biological target. (See Abstract, Title, Table 1, and page 18.)
(C) Guidance presented in the specification
Although the specification provides numerous working examples and biological data, it does not disclose any predictive principle, pharmacophore model, quantitative SAR, or other guidance permitting a skill artisan to determine, throughout the full claimed genus, which compounds will possess activity and which will not. Indeed, the specification’s own biological data demonstrate substantial variation in potency among structurally related compounds, indicating that activity is not uniform across the breadth of the claimed genus.
(D) Quantity of experimentation
In the absence of predictive guidance, a skilled artisan seeking to practice the full scope of the claims would be required to:
Synthesize numerous candidate compounds spanning the claimed scaffold classes;
Characterize each compound;
Evaluate each compound using the disclosed biological assay;
Compare biological activity;
Identify active compounds; and
Continue iterative optimization where activity is insufficient. Such experimentation
constitutes a research program rather than routine verification.
This conclusion is further supported by the medicinal chemistry literature (Mochulskaya et al., Chemistry 2023, 5, 2657–2676), which reports that closely related analogs of 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines frequently exhibit markedly different biological activities and that additional SAR studies remain necessary because no clear predictive correlation exists for many substitution patterns. (See Section 3.5 and page 2671.)
(E) Working examples
While the specification contains numerous working examples, the examples represent only selected members of the extraordinarily broad claimed genus. The disclosure therefore enables certain exemplified compound but does not enable the full scope of the claimed invention commensurate with the breadth of the claims.
Conclusion
When the Wands factors are considered as a whole, the specification does not enable the full scope of the claimed invention. Although, a person of ordinary skill in the art would be capable of synthesizing additional analogs, neither the specification nor the knowledge in the art provides sufficient guidance to identify throughout the full breadth of the claimed genera, which compounds possess the biological evaluation described in the specification without extensive empirical synthesis and biological testing. Accordingly, practicing the full scope of the claims would require undue experimentation, and the claims therefore fail to comply with the scope of enablement of 35 U.S.C. 112(a).
Claims 1, 6-8, 15-21, 23-24 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 fused bicyclic core structure in the formulas (I) and (II), together with the associated R1-R1a substituents, J substituents 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 recited alternatives do not share a single structural similarity. In particular, the claimed alternatives encompass multiple distinct fused bicyclic heterocyclic core scaffold classes, including, for example, pyrrolopyrimidine, thienopyrimidine, furopyrimidine, quinazoline, pyridopyrimidine, pyrazolopyrimidine, and other fused aza-heterocyclic ring systems. These scaffold classes differ in:
the identity of the fused five-membered ring;
the number and position of heteroatoms within the bicyclic core;
the ring fusion pattern; and
the overall bicyclic ring connectivity.
Accordingly, the alternatives are not members of the same recognized physical or chemical
Class not do they share a single substantial structural feature from which the asserted common use flows as required under MPEP 2117. Although many of the alternatives contain peripheral substituents, such as substituents imidazole and substituted aryl moieties, and those peripheral substituents do not constitute the required single structural similarity because the claimed alternatives are not only defined by multiple, structurally distinct core scaffold classes as the major or substantial part of the compounds. For example, these two compounds below
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recited in claim 24 contain essentially identical peripheral substituents, including the substituted imidazole, substituted aryl group, and substituted pyrrolidine moieties. Nevertheless, the fused bicyclic ring system constitutes the dominant structural feature of each compound. Accordingly, the identify of the fused bicyclic core, rather than the common peripheral substituents, define the principal structural framework of the claimed compounds.
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.
Claims 1, 6-8, 15-21, 23-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Fink et al. (WO2008/021924 A1) in view of Mastalerz et al. (WO2008/005956 A2).
Fink teaches compounds of formula (I) and pharmaceutically acceptable salts thereof:
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wherein: R1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, -OCH2cycloalkyl, arylalkyl, -COOH Or -CONR12R13;
that inhibit tyrosine kinase activity of such as TrkA, TrkB, TrkC, Jak2, Jak3 and CK2, thereby making them useful as antiproliferative agents for the treatment of cancer and other diseases. (See Title, Abstract and claim 1.) Moreover, Fink teaches the term "cycloalkyl" refers to an optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantly. (See paragraph [0035].) Fink also teaches a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. (See claim 7.) Fink particular prefers compounds 77
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as one of the compounds of Formula (I), (See page 59.)
The only two differences between the compound of Fink and the elected compound claimed are depicted below:
Fink compound 77 Elected compound
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. Fink compound bears a methyl-substituted pyrazole ring and the claimed elected compound contains a cyclohexyl-substituted imidazole. However, Fink explains that at the R1 of the generic formula can be alkyl, including a methyl group and cycloalkyl, including a cyclohexyl moiety.
Mastalerz teaches compounds of formula I
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and pharmaceutically acceptable salts thereof, wherein Q1 is aryl, substituted aryl, heteroaryl or substituted heteroaryl, including pyrazole or imidazole that can inhibit tyrosine kinase activity, R4 can be cycloalkyl among other substituents, thereby making them useful as anticancer agents and for the treatment of Alzheimer's Disease. (See Title, Abstract, paragraph [0011], and claim 1). Mastalerz further teaches compounds of formula II
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as preferred compounds of formula I. (See paragraph [0012]. Mastalerz teaches cycloalkyl encompasses cyclohexyl. (See paragraph [0069].)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to select compound 77 as one of the preferred compounds of formula I of Fink and modify the 5-methyl-1H-pyrrazole substituent by replacing it with the cyclohexyl-substituted imidazole moiety taught by Mastalerz. Fink expressly teaches that R1 substituent of Formula (I) may be selected from alkyl groups, including methyl, as well as cycloalkyl groups, including cyclohexyl, while Mastalerz teaches that heteroaryl substituents, including substituted pyrazoles and substituted imidazole where the substituents can be cyclohexyl, are suitable kinase-binding moieties for compounds possessing the same pyrrolotriazine core. Thus, the references collectively teach that these heteroaryl substituents represent alternative members of the same class of kinase-binding substituents that may be incorporated into the common pyrrolotriazine scaffold.
One of ordinary skill in the art would have been motivated to make the proposed modification because both Fink and Mastalerz are directed to structurally related pyrrolotriazine kinase inhibitors and teach that biological activity may be optimized through modification of peripheral heteroaryl substituents while maintaining the same fused bicyclic core. Substituting one known kinase-binding heteroaryl substituent for another known kinase-binding heteroaryl substituent would have merely involved the predictable use of prior-art elements according to their established functions in order to obtain another member of the known class of kinase inhibitors.
One of ordinary skill in the art would also have a reasonable expectation of success in making the proposed modification because both references teach compounds having the same pyrrolotriazine core scaffold and the same intended biological utility as kinase inhibitors. Neither reference teaches that replacement of the disclosed heteroaryl substituent would render the compounds inoperative or unsuitable for kinase inhibition. Rather, both references teach that various heteroaryl substituents may be incorporated into the common scaffold to provide biologically active kinase inhibitors. Accordingly, one of ordinary skill in the art would have reasonably expected that replacing the methyl-substituted pyrazole of Fink with the cyclohexyl-substituted imidazole taught by Mastalerz would have predictably yielded another functional kinase inhibitor while retaining the advantages properties associated with pyrrolotriazine.
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, 6-8, 15-21, and 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15-18 of U.S. Patent No. 11,661,426 B2; and claims 1-28 pf U.S Patent 12,054,492 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of the U.S. patents recite a compound represented by the formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein, inter alia:
A is a fused aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring optionally substituted by one or more occurrences of R4.
W is C or N;
Ra is H or alkyl;
-R1-R1a represents an imidazole or thiozole substituent, wherein Ra is cycloalkyl;
J is selected from -OR2, -NR2R3, -C(O)O(alkyl), or -C(O)OH;
R2 and R3, taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R2a; and
R2a includes hydroxyalkyl.
The presently claimed compound falls within the scope of compound of Formulas (I) of the U.S. patents. Furthermore, the elected compound also falls within the preferred subgenus recited by the dependent claims of the U.S. patents.
Accordingly, the elected compound of the present application represents nothing more than the selection of specific species expressly encompassed by the patent claimed genus and preferred subgenus. One of ordinary skill in the art would have reasonably expected that selecting the present claimed compound from the expressly disclosed genus and preferred subgenus of the U.S. patents would have yielded another member possessing the same intended utility as the preferred compounds. The presently claimed compound therefore would have been an obvious variant of the compounds of the U.S. patents.
Conclusion
Claims 1, 6-8, 15-21, 23-24, and 26 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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