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 67
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in the reply filed on 06/17/2026 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Claims 8-9, 12-13, 19-21, 26-27, and 31-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the elected species. In light of this discovery, the search is expanded to compounds
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and
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. However, the election of species has not been expanded to the full scope of the claim.
Priority
This application is a United States National Phase Patent Application of International Patent Application Number PCT/US2022/045876, filed on October 6, 2022, which claims the benefit of priority to 63/252,739, filed October 6, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/02/2024 and 02/26/2025 has been considered by the examiner.
Status of claims
Claims 1, 2, 6, 8-9, 12-14, 16-17, 19, 21, 26-32 are pending. Claims 3-5, 7, 10-11, 15, 18, 22-25, and 33 are canceled. Claims 8-9, 12-13, 19-21, 26-27, and 31-32 are withdrawn. Claims 1, 2, 6, 14, 16-17, 28-29, and 30 are examined in accordance to the elected species for prior art purposes.
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, 2, 6, 14, 16-17, 28, and 30 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.
Possession of a claimed chemical genus is not established merely by describing a desired result or by reciting a broad generic formula. Rather, the specification must disclose either (1) a representative number of species falling with the scope of the claimed genus or (2) structural features common to the members of the genus such that one of ordinary skill in the art can reasonably conclude that the inventor possessed the entire genus. Id; see also MPEP 2163.
Although the present specification provides numerous synthesized compounds and working examples, the examples are concentrated within a relatively narrow subset of the extraordinary broad chemical genus now recited in claim 1 and 28. The disclosure therefore does not reasonably convey possession of the full scope of the presently claimed genera.
A. Variable A
The claims define variable A as: “6- to 10-membered monocyclic or bicyclic aryl; and 5- to 10-membered monocyclic or bicyclic heteroaryl.” Accordingly, A encompasses numerous structurally distinct subclasses, including monocyclic aryls, bicyclic aryls, monocyclic heteroaryls, bicyclic heteroaryls, and ring systems containing five through ten atoms. However, the working examples of Formula (I) are concentrated primarily in a comparatively small number of monocyclic aromatic and heteroaromatic ring systems, including phenyl, pyridyl, thienyl, furanyl, and thiazolyl groups. While these species provide support for those particular ring systems, the specification does not identify representative species employing the claimed bicyclic aryl, or bicyclic heteroaryl subclasses, nor does it identify structural feature demonstrating that the disclosed monocyclic ring systems are representative of the substantially broader bicyclic subclasses encompassed by the claims. Thus, the specification does not reasonably convey possession of the entire genus of A presently recited.
B. Variable R3
The claims further define R3 as including:
C3-C8 monocyclic or bicyclic cycloalkyl;
C3-C6 cycloalkenyl;
3- to 8- membered monocyclic or bicyclic heterocycle;
6- to 10-membered monocyclic or bicyclic aryl; and
5- to 10-membered monocyclic or bicyclic heteroaryl; and
B-C.
This definition encompasses numerous structurally distinct chemical subclasses, including
saturated carbocycles, unsaturated carbocycles, aromatic carbocycles, aromatic heterocycles, saturated heterocycles, bicyclic carbocycles, bicyclic heterocycles, and linked B-C substituent systems. The specification, however, primarily exemplifies substituted phenyl groups together with a limited number of five- and six-membered ring monocyclic heterocyclic substituents. Although, several B-C embodiments are disclosed, the specification does not provide representative species corresponding to the claimed bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, or bicyclic heterocycle subclasses, nor does it describe common structural characteristics demonstrating that the disclosed monocyclic species are representative of these undisclosed structural subclasses. Consequently, the specification fails to reasonably convey possession of the full breadth of the claimed R3 genus.
C. Variable R4
Formula II defines R4 as OR5 or NR6R7. These alternatives represent two chemically distinct classes of substituents in which the atom directly attached to the Formula (I) core differ (oxygen versus nitrogen). The working examples associated with Formula (II) are concentrated in compounds employing amino-containing substituents corresponding to the Nr6R7 branch. The Examiner has not identified representative working examples employing the alternative OR5 branch. Moreover, the specification does not identify structural features establishing that the disclosed amino-containing substituents are representative of the entire genus encompassed both oxygen-linked and nitrogen-linked classes. Accordingly, the written description does not reasonably demonstrate possession of the full scope R4 presently recited.
D. Claimed genus versus Representative Species
Although the specification contains numerous individual compounds, those compounds occupy only a relatively limited region in the multidimensional chemical space encompassed by the claims. The presently claimed genus results from combining multiple independently broad Markush variables, each of which encompasses numerous structurally distinct subclasses. The disclosure does not provide representative species spanning these structurally distinct subclasses, nor does it identify common structural characteristics sufficient to establish possession of the entire claimed genus.
As explained in Ariad, written description requires more than a mere wish or plan to obtain the claimed invention. Likewise, disclosure of a limited number of species does not necessarily establish possession of an expansive chemical genus containing numerous structurally distinct subclasses absent representative species or common identifying characteristics demonstrating possession of the entire scope. Here, the specification principally exemplifies:
monocyclic aromatic A groups;
monocyclic heteroaromatic A groups;
substituted phenyl and monocyclic heterocyclic R3 substituents; and
amino-containing Formula (II) substituents.
By contrast, the claims additionally encompass:
bicyclic aryl A groups;
bicyclic heteroaryl A groups;
bicyclic aryl R3 groups;
bicyclic heteroaryl R3 groups;
bicyclic cycloalkyl R3 groups;
bicyclic heterocyclic R3 groups; and
oxygen-linked Formula (II) substituents corresponding to the OR5 branch. The
specification neither exemplifies representative members of those claimed structural subclasses nor identifies structural features demonstrating that the disclosed compounds are representative of these undisclosed portions of the claimed genus. Accordingly, one of ordinary skill in the art would not reasonably conclude from the specification that Applicants were in possession of the entire scope of the genera presently recited in the claims.
Therefore, 1, 2, 6, 14, 16-17, 28, and 30 fail to satisfy the written description requirement under 325 U.S.C. 112(a).
Claim 1, 2, 6, 14, 16-17, 28-29, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using the preparation and use of certain species of compounds of claim 29, does not reasonably provide enablement for the full scope of the claimed genera and the full scope of the compounds of claim 29 without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims
Although claims 1 and 28 are directed to structural compounds and do not expressly recite ULK1 inhibitory activity as claim limitation, the specification identifies ULK1 inhibition as the disclosed substantial and specific utility of the claimed compounds. Accordingly, the enablement inquiry under 35 U.S.C. 112(a) encompasses whether the specification teaches one of ordinary skill in the art how to use the full scope of the claimed compounds as ULK1 inhibitors without undue experimentation. The Office is not relying upon Morozova as establishing nonenablement by itself. Rather, Morozova is relied upon as evidenced that even within the same claimed 7-azaindole scaffold, relatively modest structural modification can result in significant or complete loss of ULK1 inhibitory activity. This evidence is relevant to the predictability of the art, the amount of guidance provided by the specification, and the quantity of experimentation required under the factors set for in in re Wands. The Office therefore concludes that the specification does not enable a person of ordinary skill in the art to identify, without undue experimentation, which compounds encompassed by the full scope of claims 1 and 28 possess the disclosed ULK1 inhibitory utility.
The subject matter considered enabled includes, at minimum, certain specifically prepared and biologically evaluated compounds disclosed in Table 1-5and structurally proximate analogs for which the disclosed synthetic methods and structure-activity information provide a reasonably basis for predicting the asserted ULK1 inhibitory utility. The rejection is directed to the substantially broader unexplored portions of the claimed genera resulting from the numerous independently variable and combinable alternatives recited for R1, R2, R3, R4, R5, R6, R7, B, C, X, Y, Rx, Ry, and Rz.
I. Legal Standard
The enablement requirement of 35 U.S.C. 112(a) requires the specification to teach a person of ordinary skill in the art how to make and use the claimed invention without undue experimentation. In in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Whether experimentation is undue from the evidence as a whole, including:
1. the breadth of the claims;
2. the nature of the invention;
3. the state of the prior art;
4. the level of ordinary skill;
5. the predictability or unpredictability of the art;
6. the amount or direction or guidance provided;
7. the existence of working examples; and
8. the quantity of experimentation required.
No single factor is dispositive, and the factors must be weighed together. MPEP 2164.01(a).
The specification need not describe every embodiment within the claim. Nevertheless, the disclosure must be enabled the full scope of the claimed invention. The more extensive the claimed genus and the less predictable the art, the more guidance and representative disclosure may be required. MPEP 2164.08.
Consistent with Amgen Inc. V. Sanofi, 598 U.S. 594 (2023), a specification does not enable an entire genus merely by providing instructions that amount to a research assignment to make and screen candidates until additional operative members are found. The Wands factors remain the USPTO framework for applying that full scope enablement requirement. MPEP 2164.01(a).
The existence of some inoperative embodiments does not necessarily render a claim non-enabled. The relevant is whether the specification and the knowledge in the art permit the skilled artisan to distinguish operative from inoperative embodiments with no more than reasonable experimentation. Claims encompassing significant number of inoperative embodiments may be non-enabled when the specification does not identify the operative embodiments and extensive experimentation would be required to determined which embodiments work. MPEP 2164.08 (b).
Here, the specification identifies ULK1 inhibition and resulting modulation of autophagy-related processes as the disclosed utility of the claimed compounds. The issue is therefore not whether the chemical structures can necessarily be drawn or whether every individual compound would be synthetically inaccessible. The issue is whether a skilled artisan, using the disclosure and the knowledge existing in the art, could make and use the full claimed genus for the disclosed ULK1 inhibitory purpose without conducting an undue structure-activity discovery.
II. Detailed analysis under Wands factors
Factor 1: Breadth of the claims
This factor weighs strongly against enablement. Claim 1 encompasses a compound of Formula (I) or Formula (II), together with pharmaceutically acceptable salts, solvates, prodrugs, and derivatives thereof. Within those formulas, the claim permits multiple independently selected structural variables.
Formula I
Formula I permits variables in at least:
A, 6- and 10-membered moncyclic or bicyclic aryl and 5- to 10-membered monocyclic or bicyclic heteroaryl;
R1, selected from numerous alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl alternatives, each optionally substituted;
R2, selected from hydrogen and similar broad carbon-chain and ring-containing alternatives, each optionally substituted;
R1 and R2 optionally being joined to form a monocyclic or bicyclic heterocycle or heteroaryl;
R3, encompassing monocyclic or bicyclic cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, or the separate B-C construct;
The broad substituent genus X, whose members may themselves contain Rx, Ry, Rz, and additionally option Y substituents.
Formula II
Formula II permits:
The broad R3 alternatives discussed above;
R4 = OR5 or NR6R7, where R5, R6, and R7 independently encompass numerous alkyl, haloalkyl, unsaturated, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or R6 and R7 may be joined to form additional monocyclic or bicyclic heterocyclic or heteroaryl systems.
Claim 28 adds Formula Ia and Formula IIA alternatives, including additional variables R3a,
Ca, and R4a, while retaining the broad X and Y definitions.
The breadth does not arise merely from a long list of individual disclosed compounds. Rather, the claims permit independent selection and combination of multiple broad Markush variables. The resulting genus includes and exceptionally large number of compounds occupying substantial different steric, electronic, conformational, aromatic, hydrogen-bonding, ionization, lipophilicity, permeability, and solubility profiles. The disclosed examples do not proportionately sample that multidimensional scope. The examples instead cluster around particular monocyclic heterocyclic R3 groups, and particular amino-containing R4 groups. The specification’s Tables 1-5 contain many individual compounds, but the numerical quantity of examples does not by itself establish that those examples are representative of every materially different combination encompassed by the claims. The disclosed Formula I and Formula II examples illustrate this concentration. Accordingly, the claims are far broader than the region of chemical space actually prepared and characterized.
Factor 2: Nature of the invention
This factor weighs against enablement of the full scope. The invention concerns small-
Molecule kinase inhibitors intended to interact with the ULK1 binding pocket and product the disclosed ULK1-inhibitory effect. Such activity depends not merely upon the presence of a nominal 7-azaindole scaffold, but upon the combined influence of:
the identify and attachment position of each substituent;
ring size and topology;
heteroatom identity and placement;
hydrogen-bond donor and acceptor geometry;
steric fit within the kinase pocket;
conformational orientation;
electronic characteristics;
intracellular permeability and retention; and
competing physiochemical properties.
The common 7-azaindole core may provide a structural starting point, but the claimed
invention is not limited to a narrow series in which only a predictably interchangeable terminal group is varied. The claims permit extensive alterations adjacent to and extending from the core at multiple position. The nature of the invention is therefore one in which operative biological activity depends upon experimentally determined structure-activity relationships rather than merely upon the ability to synthesize a compound satisfying the generic formula.
Factor 3: State of the prior art
This factor weighs against full scope enablement. In the present case, Morozova et al. (European Journal of Medicinal Chemistry 266 (2024) 116101) reports the development potent ULK1 inhibitors based on the same general 7-azaindole scaffold. The reference describes a structure-based drug-design and SAR program in which analogs were synthesized and evaluated for biochemical activity, intracellular target engagement, functional activity, and other properties. Morozova reports excellent activity for selected analogs and not for others, but the reference does not teach the presence of the 7-azaindole scaffold alone is sufficient to confer activity. Rather, it describes systematic optimization and the identification of a lead only after iterative design and testing. (See Abstract; Tables 1 and 2; and Experimental section.) Morozova’s conclusion similarly states that development of the lead compound was achieved through extensive rational design and systematic evaluation, aided by docking and crystallographic binding-mode analysis.
Thus, the art reflects that identification of potent, cell-active ULK1 inhibitors on this scaffold was an empirical medicinal chemistry endeavor. The art did not provide a generally applicable rule by which a skilled artisan could select arbitrary combinations within the present Markush definitions and reasonably predict that those compounds would retain asserted utility.
Factor 4: Level of ordinary skill
This factor favors Applicant to a degree, but does not outweigh the remaining factors.
A person of ordinary skill would likely possess substantial training and experiment in medicinal chemistry, synthetic organic chemistry, kinase pharmacology, and assay interpretation. Such a person would know conventional synthetic transformations and would be capable of:
preparing many analogs within the claimed formulas;
selecting protecting groups;
modifying synthetic routes;
performing biochemical kinase assays;
performing cellular target-engagement assays; and
analyzing SAR data.
The high level of skill would reduce the difficulty of making and testing individual
compounds. However, enablement does not turn solely on whether each experiment is technically familiar. A skilled artisan’s ability to conduct routine synthesis and screening does not supply the missing predictive guidance concerning which of the extremely numerous claimed combinations will possess the disclosed utility. High skill may make a research program feasible, but it does not necessarily make the scope enabled where the artisan must discover operable species through extensive trial-and-error screening. Thus, this factor provides some support for enablement but does not resolve the breadth and predictability concerns.
Factor 5: Predictability of the art
This factor weighs strongly against enablement. optimization of ULK1 inhibitor was governed by experimentally determined structure-activity relationships, and the biological activity of compounds across broad structural modifications could not reliably predicted solely from the common scaffold. The prior art demonstrates that optimization of UKL1 inhibitors required iterative structure-relationship studies involving synthesis and biological evaluation to determine which structural modifications retained the desired ULK1 inhibitory activity. Accordingly, one of ordinary skill in the art would not reasonably predict that arbitrary combinations of the numerous independently variable Markush substituents recited in the claims would uniformly retain the asserted ULK1 inhibitory utility without experimental verification.
Factor 6: Amount of direction or guidance in the specification
This factor weighs against enablement of the full scope. The specification provides substantial direction concerning:
the generic formulas;
lists of permitted substituents classes;
synthetic procedures for numerous compounds;
assay protocols; and
activity results for disclosed species. This is meaningful guidance and supports
enablement of certain exemplified compounds and closely related analogs. The specification, however, does not provide a sufficiently general predictive rule identifying which combinations across the claimed scope will remain operative for the disclosed ULK1-inhibitor use. In particular, the disclosure does not provide:
a defined pharmacophore applicable to the entire claimed genus;
quantitative boundaries governing steric size, electronic character, hydrogen-bond geometry, or ring orientation;
an established correlation permitting activity to be predicted across the claimed bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, and bicyclic heterocycle alternatives;
guidance showing that the OR5 and NR6R7 branches of Formula II behave interchangeably;
guidance addressing the effect of combining remote extremes separately listed Markush alternatives;
criteria that reliably distinguish active from inactive untested members before synthesis and screening; or
an experimentally validated SAR model spanning the full scope. The broad definitions
tell the artisan what structures fall within the claim, but they do not adequately teach which of those structures will possess the disclosed use. The artisan is therefore left to select candidates from the broad genus, synthesize them, test them, analyze the resulting SAR, and then select further candidates based upon the newly acquired information. That is material different from routine verification of a result that the disclosure already makes reasonably predictable.
Factor 7: Existence of working examples
This factor favors Applicant, but only for the chemical region represented by the examples. The specification contains numerous ULK1 binding or activity data obtained using Radiometric HotSpot, LanthaScreen, for selected compounds, NanoBRET. The biological table demonstrates that activity varies materially across the tested compounds and that NanoBRET results provided for only a subset. These working examples are substantial and should not be minimized. They establish that:
numerous claimed species can be made;
numerous claimed compound species possess measurable ULK1 activity; and
the disclosed assays can be used to evaluate additional compounds. They do not,
however, establish that the examples are representative of the full combinatorial genus. The examples are concentrated in selected structural families and do not systematically traverse all material different alternatives and combinations encompassed by the claims. In an unpredictable SAR setting, numerous clustered examples may still fail to enable structurally remote portions of a far broader genus. The working examples therefore weigh in Applicant’s favor, but their evidentiary weigh is limited by the breadth and structural diversity of the untested claim scope.
Factor 8: Quantity of experimentation required
This factor weighs strongly against enablement. To practice the full scope for the disclosed ULK1-inhibitory use, a skilled artisan would have to undertake, across the untested portion of the genus:
selection of candidate combinations among numerous A, R1, R2, R3, R4, X, and Y alternatives;
route planning and synthesis;
purification and structural confirmation;
biochemical testing;
determination of whether biochemical activity translate to intracellular target engagement;
analysis of failed and successful analogs;
development of new SAR hypotheses;
synthesis and testing additional generations; and
repetition of that process across material different ring, heteroatom, attachment-position, and substituent subclasses.
The individual synthetic and assay techniques may be conventional. Nevertheless, the
required combination is not merely confirmatory because the specification does not permit a skill artisan in advance which claimed combinations will be operative. Morozova illustrates the nature of the required effort, its authors used iterative structure-based design, synthesis, biochemical testing, NanoBRET cellular target-engagement testing, docking, crystallographic analysis, and further optimization to identify selected active compounds and a lead having the desired overall profile. The task left by the present disclosure is therefore not simply to reproduce a disclosed procedure a reasonable number of times. It is to conduct an empirical SAR discovery program across exceptionally broad multidimensional genus. The amount of such experimentation considered together with the absence of predictive guidance and the demonstrated sensitivity of the scaffold to small structural changes, is undue.
Conclusion
A skilled artisan therefore would not be able, based upon the specification and ordinary knowledge alone, to make and use the full scop0e of the claims for the disclosed ULK1-inhibitory utility without undertaking an extensive research program. Accordingly, the experimentation required is merely routine confirmation of predictable results. It constitutes undue experimentation directed to discovering which members of the claimed genus are operative.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 14, 16, 28, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alam et al. (WO2013/092467 A1).
Alam teaches compounds of Formula (I), or a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I), and a pharmaceutically acceptable carrier.
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wherein Ar is - phenyl, unsubstituted or mono- or bi-substituted independently with halogen,
- heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl and halogen, or
- unsubstituted cycloalkyl; and
Ar' is - phenyl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, -C(0)OCH3, -S02N(CH3)2, -CN and alkoxy,
- heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, heteroaryl, -C(0)NHCH3, -C(0)NH(CH2)2OH, -S02CH3 and haloalkyl, or a pharmaceutically acceptable salt thereof, the compound or composition is useful for treatment of autoimmune and inflammatory diseases associated with IL-2 inhibition via modulation of calcium release-activated calcium (CRAC) channels. Also disclosed are methods of making and using the compounds for treatment of diseases associated with CRAC channels. (See Abstract and claims 1 and 12.) Alam also teaches preferred compounds of the formula (I) includes
Compound 11
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and compound 12
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. (See page 46.) Although, the structure of compound 12 does not appear to contain 2-hydroxy-ethyl) amide, such structure contains 2-hydroxy-ethyl) amide as evidenced by the chemical name (5-[2-(2,6-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide).
Compound 11 anticipated the instant claims because it reads the instant Formula (I)
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Wherein:
A = C6-monocyclic heteroaryl (pyridine) substituted with X and X is C1-alkhyl (methyl);
R2 = hydrogen;
R1 = alkyl (methyl);
R3 = C6-monocyclic aryl (phenyl) substituted with one or more X and X is halo (F).
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 non-obviousness.
Claims 1, 2, 6, 14, 16-17, 28-29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Alam et al. (WO2013/092467 A1) as applied to claims 6, 17, and 29 as set forth in the above rejection in view of Patani et al. (Chem. Rev. 1996, 96, 3147−3176).
Claims 1, 2, 14, 16, 28, and 30 have already been addressed in the rejection set forth above. Accordingly, the analysis below is directed only to claims 6, 17, and 29, which present additional limitation not previously addressed.
The teachings of Alam have been discussed supra.
Alam does not teach the expanded compounds that read on claims 6, 17, and 29.
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and
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However, Alam teaches Ar can be halogen-substituted-phenyl; Ar’ can be heteroaryl, substituted with one or two substituents independently selected from lower alkyl, heteroaryl, -C(0)NHCH3, -C(0)NH(CH2)2OH, -S02CH3 and haloalkyl. Alam further teaches pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients. (See lines 12-16 of page 20.) Alan expressly defines both Ar’ and Ar as including heteroaryl substituent where pyridyl and thiazolyl are representative heteroaryl groups. (See lines 4-11.)
Patani teaches the ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties. In this review an attempt
has been made to quantitate, in specific instances, physicochemical effects such as electronegativity, steric size, and lipophilicity and to correlate these values to the observed biological activity. (See second paragraph of the left column of page 3148.) Moreover, Patani teaches the widespread application of the concept of isosterism to modify biological activity has given rise to the term bioisosterism. bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. (See fourth paragraph of the right column of page 3148.) Furthermore, Patani teaches
. (See Table 48.) Patani further teaches Fluorine and Hydroxyl, Amino, or Methyl Groups as
Replacements for Hydrogen (Grimm’s Hydride Displacement Law), (See page 3152; section 4.)
Alam teaches pyrrolo[2,3-b] pyridine compounds in which Ar’ can be heteroaryl, substituted with one or two substituents independently selected from lower alkyl, heteroaryl, -C(0)NHCH3, -C(0)NH(CH2)2OH, -S02CH3 and haloalkyl. Alam further teaches specific compounds, including compounds 11 and 12, wherein the pyridine ring bears methylamine and 2-hydroxyethyl amide substituent, respectively. Alan expressly defines both Ar’ and Ar as including heteroaryl substituent where pyridyl and thiazolyl are representative heteroaryl groups. (See lines 4-11.)
Patani teaches bioisoteric replacement is a well-established medicinal chemistry strategy in which substituents having similar steric, electronic, and physiochemical properties are routinely exchanged to preserve or optimize biological activity while modifying other desirable properties, including potency, selectivity, lipophilicity, and metabolic stability. Patani further teaches fluorine, hydroxyl, amino, and methyl groups are recognized bioisosteric replacements and that substitution of such groups is routinely employed in medicinal chemistry to modify biological activity while maintaining interaction with the same pharmacological target.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was file to modify the 2-haloalkyl amide-substituent attached to the pyridine ring of compound 12 by selecting the corresponding substituted hydroxyalkyl amide while further selecting unsubstituted thiazolyl from Alam’s expressly disclosed unsubstituted heteroaryl genus and selecting a mono-halogen-substituted phenyl group from Alam’s expressly halo-substituted phenyl genus. The modifications involve the selection of expressly disclosed alternatives from Alam’s generic disclosure together with routine medical chemistry optimization taught by Patani. One of ordinary skill in the art would have been motivated to make these routine medicinal chemistry modifications in view of Patani’s teaching that bioisosteric replacement and substitution of chemically similar functional groups are conventional optimization techniques employed to preserve or optimize biological activity while modifying desirable physiochemical properties, including potency, selectivity, lipophilicity, and metabolic stability, with a reasonably expectation that the modified compounds would retain activity against the same pharmacological target.
Furthermore, upon selecting the corresponding substituted hydroxyalkyl amide, the resulting substituent necessarily contains a stereogenic center. Alam contemplates individual isomers, racemic mixtures, and non-racemic mixtures. Accordingly, selection, preparation, isolation or evaluation of the individual stereoisomers, including the present claimed stereochemical configurations, would have constituted nothing more than routine optimization of the finite number of predictable stereochemical possibilities available to one of ordinary skill in the medicinal chemistry arts.
Conclusion
Claims 1, 2, 6, 14, 16-17, 28-29, and 30 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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