Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of 18/725,596
Claims 1-11 are currently pending.
Priority
Instant application 18/725,596, filed 6/28/2024, claims priority as follows:
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.
The priority documents submitted in the file wrapper are not translated to English and as a result, priority cannot be established. Thus, the instant claims are granted the effective filing date of 12/29/2022.
Information Disclosure Statement
All references from the IDS submitted on 7/5/2024 have been considered unless marked with a strikethrough. The Examiner notes the reference struck was not formally considered because the document did not contain a translated abstract.
Objection to the Abstract
The abstract of the disclosure is objected to for insufficient length, as it is less than 50 words. The abstract should generally be within the range of 50 to 150 words in length, and chemical abstracts in particular should provide the structure of the compound of a formula thereof in addition to methods of use. See MPEP § 608.01. Appropriate correction is required.
Objection to the Specification
The specification is objected to for pixelated and illegible images. All figures of the specification are of poor quality and unable to be properly interpreted. Appropriate correction is required.
Election/Restriction
Applicant’s election of Group I, claims 1-7 and 9, drawn to compounds and compositions of formula I, with traverse in the reply filed 7/29/2026 is acknowledged. Applicant’s election of compound 57:
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In the same reply, with traverse, is also acknowledged.
The traversal of the restriction requirement and the election of species requirement is on the grounds that the combination of the N-oxide moiety and the presence of a hydroxyl-containing R1 substituent on A is the special technical feature that provides a technical interrelationship among the claimed inventions, in opposition of the Examiner’s argument that there is not a special general inventive concept in the Requirement for Restriction/Election dated 6/18/2026. Further, Applicant argues that formula I defines a common structural arrangement encompassing the heteroaromatic N-oxide portion, defines the relationship among A, L, Z, X, Y, E1, E2, E3, and G elements, and states that the difference between compounds 46 and 66 is merely a difference in degree of shared activity. This argument has been considered, but is not considered persuasive because the technical relationship between the various cores of formula I is not established in the present disclosure as the N-oxide moiety and the presence of a hydroxyl-containing R1 substituent on A do not constitute a significant structural element of formula I. A structure/function correlation cannot be established and there is an insufficient number of representative examples of various cores of formula I disclosed. For example, there is one example of a compound where E1 is N in the specification, and no examples of compounds where E2 or E3 is N. Further, there are no examples of compounds in the instant specification where E1, E2, or E3 are C(=O), C(=S), or C(=NR4), much less examples of the large number of possibilities of the A-L-Z-X-Y chain. In fact, certain interpretations of the A-L-Z-X-Y chain can constitute a larger structural portion of the compound than the E1, E2, and E3 pyridine N-oxide core. With a change in biological activity observed with a core change in E1 from CH to C-Me, it is unknown what a larger change such as an atom or large functional group can constitute. Further, as the Examiner states below in the 103 rejection, an alternative argument can be made that breaks unity of invention because the special technical feature/inventive concept is known in the art. Thus, Applicants argument with respect to the traversal above is not persuasive and the restriction is made FINAL.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and no prior art was identified. Thus, the search was expanded to a compound of instant formula I:
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When A is a 9-membered heteroaryl substituted with R1, where R1 is R8 substituted with one hydroxy, R8 is -NRbRc, Rb is hydrogen, and Rc is C3 alkyl, L is O, Z is a 6-membered aryl substituted with one R3, where R3 is halogen, X is NR4, where R4 is hydrogen, Y is (CRaRb)n1-C(=O), where n1 is 0, E3 is CRaRb, where Ra is hydrogen, E2 is CRaRb, where Ra is hydrogen, E1 is CRaRb, where Ra is C1 alkyl, and G is (CRaRb)n1-6-membered aryl, where n1 is 0 and the aryl is substituted with a halogen. See the 103 rejection below. The full scope of the claims has not yet been searched in accordance with Markush search practice. Claims 1-5, 7, and 9 read on the expanded species. Claims 6, 8, and 10-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable generic or linking claim.
Claim Objections
Claims 1 and 2 are objected to for pixelated and illegible images, and thus are unable to be interpreted. The Examiner notes this claim has not been adequately examined because the images are of poor quality. Appropriate correction is required.
Claim 7 is objected to because the figures are pixelated and illegible, and thus are unable to be interpreted. The Examiner notes this claim has not been adequately examined because the images are of poor quality. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-5, 7, and 9 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.
Claim 1 recites that variables E1, E2, and E3 are each absent or each independently selected from CRaRb, N, C(=O), C(=S), and C(=NR4). However, if E1, E2, and E3 are CRaRb, C(=O), C(=S), or C(=NR4) in instant formula I or a tautomer thereof, then the carbons of the ring will have incorrect valency with five bonds. Thus, the limitations are indefinite and unclear. Dependent claims 2-5, 7, and 9 do not resolve this issue by clarifying the variables and are therefore also rejected.
Claim 1 also recites, “R1 is not hydroxyalkyl”, in the provisos at the end of the claim. There is insufficient antecedent basis for this limitation in the claim, as the claim previously recites, “R1 is selected from R8 substituted with one or more hydroxy” and doesn’t explicitly recite R1 as hydroxyalkyl. Dependent claims 2-5, 7, and 9 do not resolve this issue and are therefore also rejected.
Claim 1 recites the phrase, “for example” in the provisos at the end of the claim. The phrase is indefinite because the phrase is exemplary language and it is not clear if the contents after the term are required, or just examples of what is required. Dependent claims 2-5, 7, and 9 do not resolve this issue and are therefore also rejected. Appropriate correction is required.
Claim 1 recites the term, “may be” in the provisos at the end of the claim. Similar to above, this term is ambiguous, and it is unclear if what follows this term is required, or just examples of what is required. It is unclear what occurs when than the limitation after the term “may be”, is other than what is recited. Dependent claims 2-5, 7, and 9 do not resolve this issue and are therefore also rejected. Appropriate correction is required.
Claims 2-5, 7, and 9 recite multiple instances of, “preferably” in reference to preferred variables, compounds, and forms of pharmaceutical composition. The term is indefinite because the phrase is exemplary language and it is not clear if the contents after the term are required, or just examples of what is required. Appropriate correction is required.
Claims 2 and 7 recite, “Y is selected from C(=O)”; however, claim 1 recites Y is absent or can be selected from (CRaRb)n1-C(=O), C(=S), C(=NR4), SO2, SO, NR4, O, S, and CR4R5. Thus, there is insufficient antecedent basis for this limitation in the claim. Dependent claims 3-5 and 9 do not resolve this issue and are therefore also rejected. Appropriate correction is required.
Claim Rejections - 35 USC § 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 1-5, 7, and 9 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 claims 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, the claims of the instant application embrace compounds of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuteride, prodrug molecule, hydrate, or solvate thereof. Particularly, the term “prodrug molecule” recited in claims 1-5, 7, and 9 invokes the 35 U.S.C. 112(a) rejection. Even a cursory calculation of the number of compounds embraced in the instant claims would result in thousands of compounds.
Level of skill and knowledge in the art
The level of skill and knowledge in the art is high.
Partial Structure
Compounds of formula I have been disclosed and example compound species that would be within the general formula have been disclosed. However, as to the claimed prodrug molecules, no specific examples are given that would demonstrate possession or put the public in possession of all the claimed prodrug molecules of formula I. It is generally accepted that prodrug molecules may vary by chemical formulae and may also differ in properties and the arrangement of atoms in the molecule.
Physical and/or chemical properties/functional characteristics
The compounds of formula I, and prodrug molecules thereof, are compounds which are allegedly useful in the treatment of diseases associated with a protein kinase in a subject. Although the art recognizes generally accepted definitions, the terms are not explicitly defined by the specification in such a way as to demonstrate that the inventor had possession of the prodrug molecules of formula I.
A review of the prior art identifies the reference Najjar (Najjar, A. & Karaman, R. Expert Opinion on Drug Discovery, 2018, 14(3), 199-220) discloses successes and failures of prodrugs of known pharmaceuticals, one example of which is also an ester (abstract and page 212, section 3). Najjar teaches hetacillin, an ester prodrug of ampicillin, which was withdrawn since it did not have a superior advantage when compared to ampicillin. In light of Najjar, it is unknown which of the prodrugs of compounds of formula I claimed by Applicant is will be active or inactive. Further, one of ordinary skill in the art would not be able to predict which compounds, of the vast number that are claimed, will be active or inactive absent evidence. There is no structure/function correlation in the specification showing which prodrugs would or would not be active.
Since Applicant has not set forth compounds or substituents on formula I in the specification which Applicant considers prodrug molecules, it is not clear what compounds fall under formula I. Applicant has not described which prodrug molecules have the ability to treat diseases associated with a protein kinase in a subject, and which do not. Stated differently, there is no structure/function correlation and no representative number of specific examples of prodrug molecules that demonstrate which compounds retain activity. Further, one of ordinary skill in the art would not be able to predict the biological activity of the claimed prodrug molecules of formula I.
Predictability of the art
Medicinal chemistry is an experimental science with a low predictability level. Small changes in the structure of a compound can lead to large differences in their pharmacological activity. Regarding prodrug molecules, predicting if a certain claimed compound retains the activity and function of the original drug is filled with experimental uncertainty because prodrug molecules contain variation by chemical and physical properties of the molecules.
Method of making the claimed invention
Although the specification provides a method for making the compounds of formula I, no method for making all of the compounds, including the prodrug molecules, encompassed by the instant claims has been disclosed. Methods of synthesizing compounds are, in general, known to a person of ordinary skill; however, methods of making the myriad of compounds encompassed by the instant claims is beyond the skill of the artisan, particularly when certain elements, such as prodrug molecules are merely described partially.
As such, the instant specification and instant claims do not provide sufficient description such that one could anticipate what additional elements may be present in the prodrug molecules of formula I because the examples illustrated in the experimental section are limited to only compounds of formula I.
Substantial and undue experimentation would be needed to practice Applicant’s invention because the specification lacks sufficient detail to show how to use the prodrug molecules of the instant invention. Further, there is no guarantee that all of the prodrug molecules embraced by the scope of the claims would be use in treatment of a disease associated with a protein kinase in a subject.
Even with the undue burden of experimentation, there is no guarantee that one would obtain the product of a desired prodrug molecules of an instant compound of formula I. Although some functional characteristics are disclosed or would be known to a person of ordinary skill in the art, in the absence of a disclosed structure, there can be no correlation between the function and structure of the claimed prodrug molecules in the instant application.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claim(s) are broad and generic with respect to all possible compounds encompassed by the claims: the possible structural variations are limitless to any prodrug molecules of the elected compound species. In the instant case, however, the specification does not disclose a sufficient variety of species to reflect this variance in the genus. Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims, such as prodrug molecules of formula I.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention. This rejection would be overcome by amending the claims to remove the term “prodrug molecule”.
Claim Rejections – Improper Markush
Claims 1-5, 7, and 9 are rejected on the basis that they contain 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.
With respect to claim 1, the Markush groupings of formula I:
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are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons: The Markush groups A, L, Z, X, Y, E1, E2, E3, and G of formula I contain variables that can be independently selected from various atoms, substituents, saturated and unsaturated carbon and heteroatom chains, and saturated and unsaturated carbon and heteroatom rings. From this definition, the A, L, Z, X, Y, E1, E2, E3, and G variables contain atoms, functional groups, and various cycloalkyl, aryl, heterocycloalkyl, and heteroaryl rings, and therefore share no common core. In fact, many interpretations of the A-L-Z-X-Y chain can constitute a great portion of the structure that is more significant than the E1, E2, E3, and G pyridine N-oxide core in both structural volume and molecular weight. A skilled artisan would recognize the variation in ring choice, atom selection, and functional group installation can lead to variations in biological and chemical properties such as bond angles and binding pose of the substrate in the target. They do not belong to the same recognized physical or chemical class or to the same art-recognized class.
Furthermore, the claims recite the limitation, prodrugs thereof in reference to the compounds of formula I. The prodrugs of formula I also share no common core, and are therefore not members or the same recognized physical or chemical class, or the same art-recognized class, or have a common use.
The instant specification discloses compounds that have the property of c-Met inhibition (pages 155-156), and further discloses that the compounds or compositions of the disclosure are for the treatment of a disease associated with a protein kinase (page 41). The scope of the compounds tested compared to the instant claims is small; there is one example of a compound where E1 is N, and no examples of compounds where E2 or E3 is N. Further, there are no examples of compounds in the instant specification where E1, E2, or E3 are C(=O), C(=S), or C(=NR4), much less examples of the large number of possibilities of the A-L-Z-X-Y chain. As stated above, certain interpretations of the A-L-Z-X-Y chain and the variable G can constitute a larger structural volume and molecular weight of the compound than the E1, E2, and E3 pyridine N-oxide core. No other data supporting varying atoms, functional groups, and various cycloalkyl, aryl, heterocycloalkyl, and heteroaryl rings of the common core is disclosed and therefore no structure-function relationship between the varying atoms, functional groups, and various cycloalkyl, aryl, heterocycloalkyl, and heteroaryl rings is corroborated. In addition, no prodrugs are presented as support for the instant claims. In this case, the claims are so expansive that a common utility cannot be expected. Dependent claims 2-5, 7, and 9 do not resolve the issue and are therefore also rejected.
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 1-5, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Array Biopharma Inc. (WO 2020/047184 A1, herein after “Array”) in further view of Takeda Pharmaceutical Company Limited (WO 2009/136663 A1, herein after “Takeda”). This rejection applies to the expanded species.
Determining the scope and contents of the prior art
The reference Array teaches pyrazolo[3,4-b]pyridine compounds as inhibitors of receptor tyrosine kinases TAM and c-Met (title, abstract). Specifically, Array teaches compound 129 (page 305):
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Which partially maps to instant formula I:
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When A is a 9-membered heteroaryl substituted with R1, where R1 is R8 substituted with one hydroxy, R8 is -NRbRc, Rb is hydrogen, and Rc is C3 alkyl, L is O, Z is a 6-membered aryl substituted with one R3, where R3 is halogen, X is NR4, where R4 is hydrogen, Y is (CRaRb)n1-C(=O), where n1 is 0, E3 is CRaRb, where Ra is hydrogen, E2 is CRaRb, where Ra is halogen, E1 is CRaRb, where Ra is hydrogen, and G is (CRaRb)n1-6-membered aryl, where n1 is 0 and the aryl is substituted with a halogen. The Examiner notes that the definition of E1-E3 is indefinite and unclear as stated above in the 112(b), and in the interest of compact prosecution, Ra is defined as the sole variable to ensure correct valency of the carbons. Furthermore, compound 129 of Array is taught in DMSO, which indicates a pharmaceutical composition (page 206), and is disclosed as a TAM inhibitor (page 212).
The reference Takeda teaches fused heterocyclic derivatives with inhibitory activity against various receptor tyrosine kinases including, but not limited to VEGFR2, c-Met, and TEK (abstract). Specifically, Takeda teaches Example 29 (pages 251-252):
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Which partially maps to instant formula I:
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When A is a 9-membered heteroaryl, L is O, Z is a 6-membered aryl substituted with one R3, where R3 is halogen, X is NR4, where R4 is hydrogen, Y is (CRaRb)n1-C(=O), where n1 is 0, E3 is CRaRb, where Ra is hydrogen, E2 is CRaRb, where Ra is halogen, E1 is CRaRb, where Ra is C1 alkyl, and G is (CRaRb)n1-6-membered aryl, where n1 is 0 and the aryl is substituted with a halogen. The Examiner notes that the definition of E1-E3 is indefinite and unclear as stated above in the 112(b), and in the interest of compact prosecution, Ra is the sole variable defined to ensure correct valency.
Furthermore, Takeda teaches the pyridone counterpart of Example 29 as Example 27 (pages 294-250):
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Which partially maps to instant formula I in the same manner as Example 29. Both Examples 27 and 29 were placed in DMSO (pages 250 and 252), indicating a pharmaceutical composition, and were demonstrated to have inhibitory activity in assays against kinases VEGFR2 and c-Met (pages 317 and 321). In fact, Examples 27 and 29 were shown to have 100% inhibitory activity in the kinase assays, indicating both cores are successful in inhibiting VEGFR2 and c-Met kinase.
Ascertaining the differences between the prior art and the claims at issue
The compound of Array fails to teach the pyridine N-oxide as the core of Example 129 or another compound
The compounds of Takeda fail to teach a compound with the 3-[[(1R)-2-hydroxy-1-methylethyl]amino]- 1H-Pyrazolo[3,4-b]pyridine moiety.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of heteroaromatic nitrogen-oxide compounds. An artisan possess the technical knowledge necessary to make adjustments to the heteroaromatic nitrogen-oxide compounds to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said heteroaromatic nitrogen-oxide compounds and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (B), it would have been prima facie obvious to one having ordinary skill in the art to substitute the pyridone core of Example 129 of Array with the pyridine N-oxide core of Examples 29 of Takeda because both compounds are known to have biological activity in receptor tyrosine kinases, and structurally similar compounds are expected to have similar properties. Further, the compounds of Array and Takeda teach the identical meta-substitution pattern of the internal heteroaryl core and are decorated with an oxygen atom extending from the ring in between the substituents, indicating the importance of this design in receptor tyrosine kinases that would direct a skilled artisan to the particular framework. Additionally, Takeda teaches that Example 29, with an N-oxide core, has comparable properties to Example 27, with a pyridone core, thus further strengthening the argument that the cores are interchangeable. A skilled artisan would have been motivated before the effective filing date to make such a substitution to identify additional compounds with activity in receptor tyrosine kinases, and ultimately diseases associated with a protein kinase selected from a disease associated with c-Met, VEGFR-2, AXL, TAM, NTRK, or RET. The Examiner notes this argument can be expanded to encompass multiple compounds of the instant invention, and that expanding to different species using the art and substitution argument will lead to a final rejection.
Conclusion
Claims 1-5, 7, and 9 are rejected. Claims 1-2 and 7 are also objected to. Claims 6, 8, and 10-11 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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