DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of compound 39
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in the reply filed on 06/19/2026 is acknowledged. The traversal is on the ground(s) that the shared pyrrolo[2,1-f][1,2,4]triazine scaffold as representing "a minor portion of the claimed compounds" that "does not define a common contribution over the prior art", and concludes that the scaffold "alone does not constitute a special technical feature sufficient to establish unity". Applicant submits, respectfully, that this determination is in error for at least the following specific reasons.
First, the claimed compounds share a single special technical feature, namely, the 2,7- substituted pyrrolo[2,1-f] [1,2,4] triazine scaffold. As reflected in the title of the application and throughout the specification, this scaffold provides protein kinase inhibitory activity and is the
kinase-binding pharmacophore common to every claimed compound. The shared scaffold is not an incidental "minor portion" of the compounds but is the structural core responsible for the protein-kinase-binding activity that unifies the claimed inventions as a single general inventive concept.
Second, under PCT Rule 13.2 and 37 CFR 1.475(a), a "special technical feature" is a technical feature that defines a contribution which each claimed invention, considered as a whole, makes over the prior art. The Requirement, however, cites no prior art. The Office has therefore not established that the shared 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine scaffold is known in, or rendered obvious by, the prior art. In the absence of any reference demonstrating that the shared scaffold is previously known, the shared scaffold must be regarded as defining a contribution over the prior art, and unity of invention is present.
Third, the structural differences identified in the Requirement, such as the macrocyclic architecture of Example 36 as compared with the acyclic, alkynyl-linked architecture of Example 98, are differences among species that nonetheless share the same special technical feature. Such species-level differences in linker composition, ring size, or terminal group do not negate the corresponding special technical feature that links the claimed compounds into a single general inventive concept.
For at least these reasons, the claimed inventions are so linked as to form a single general inventive concept, and the Requirement should be withdrawn. Applicant respectfully reserves the right to petition the Requirement under 37 CFR 1.144.
This is not found persuasive because the mere presence of a structural moiety common to the claimed species does not, itself, establish that the species share the same or corresponding special technical feature within the meaning of PCT Rule 13.2. Rather the alleged common feature must define the contribution over the prior art and provide the technical relationship among the claimed species that constitute the single general inventive concept.
Applicant’s assertion that the pyrrolo[2,1-f] [1,2,4] triazine scaffold itself is the kinase-binding pharmacophore responsible for the asserted common protein-kinase inhibitory activity is not commensurate with the disclosure. The specification generally attributes kinase inhibitory and/or degradation activity to the claimed compounds, but the disclosed biological data are limited to selected compounds and selected biological systems and do not establish that the shared pyrrolo[2,1-f] [1,2,4] triazine scaffold, independently of the material different structural features appended thereto, is responsible for the asserted common activity throughout the claimed genus.
In particular, the claimed species differ substantially in the structural features surrounding the shared scaffold, including identities and substitution patterns of the A and B ring systems, linker composition and length, macrocyclic versus acyclic architecture, and terminal functional or pharmacophoric moieties. These differences are not merely incidental substituent variations. For example, Example 36 contains macrocyclic lactam-containing architecture in which the portions attached to the 2- and 7-positions form a conformationally constrained cyclic system, whereas Example 98 contains acyclic alkynyl-linked aryl architecture and a separate extended linker terminating in a phthalimide-containing moiety. Thus, although both species contain the pyrrolo[2,1-f] [1,2,4] triazine moiety, the compounds employ materially different overall molecular architecture and functional domains.
Applicant has therefore not established that the common pyrrolo[2,1-f] [1,2,4] triazine moiety constitutes the special technical feature that provides the technical relationship among these structurally distinct species. The fact that each species nominally contains that moiety does not establish that the common moiety accounts for the asserted kinase inhibitory/degradation function or otherwise constitutes the feature responsible for the single general inventive concept.
Applicant argues, inter alia, that the restriction requirement did not cite prior art establishing that the shared pyrrolo[2,1-f] [1,2,4] triazine scaffold was known or otherwise failed to define a contribution over the prior art. Applicant’s argument is persuasive to the extent that the restriction requirement did not identify prior art establishing that the asserted common scaffold doe not itself constitute a special technical feature defining a contribution over the prior art. However, as set forth in the rejection under 35 U.S.C. 103 below, the prier art establishes that the shared pyrrolo[2,1-f] [1,2,4] triazine scaffold was known in the art. Accordingly, in view of the prior art discussed in the 103 rejection below, the shared scaffold does not by itself, constitutes a special technical feature defining a contribution over the prior art sufficient to link the elected and non-elected compound species into a single general inventive concept. Rather, once the known common scaffold is considered in view of the prior art, the species continue to differ in the potentially distinguishing technical features previously identified, including their ring systems, substitution patterns, linker composition and lengths, macrocyclic versus acyclic architectures, terminal functional domains, and overall molecular topology. Thus, the species do not share the same or corresponding special technical feature defining a contribution over the prior art as required by PCT Rule 13.2
Accordingly, the lack-of-unity/restriction requirement is maintained. However, because the present action identifies and relies upon prior art not expressly identified in the original restriction requirement in addressing Applicant’s traversal, the requirement is not made Final at this time.
Claims 8-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Priority
This application is 371 of PCT/KR2022/019157 11/30/2022, which claim priority to Foreign Application No. KR10-2022-0162449, filed on 11/29/2022and KR10-2021-0169177, filed on 11/30/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/28/2024, 09/01/2025, and 02/25/2026 has been considered by the examiner.
Status of Claims
Claims 1-18 are pending. Claims 8-10 are withdrawn. Claims 1-7 and 11-18 are examined in accordance to the elected species.
Claim Objections
Claim 13 is objected to because of the following informalities: the phrase “comprising the compound according to claim 1 as an effective ingredient” is awkward and should preferably be amended to “as an active ingredient,” consistent with the terminology employed in the specification, or otherwise corrected for grammatical clarity. Appropriate correction is required.
Claim 18 is objected to because of the following informalities: the phrase “wherein the diseases selected from the group consisting of …” lacks the verb “is.” Applicant is required to amend the limitation, for example to read “wherein the disease is selected from the group consisting of ….” Or otherwise provide grammatical proper language.
Claim Rejections - 35 USC § 112
Claims 1-7 and 11-18 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 claim 1 is improper because the alternatives encompassed by Chemical Formula 1 do not constitute a recognized physical or chemical class and do not share a substantial structural feature that has been shown to be essential to their asserted common utility. Although the specification generally attributes kinase-inhibitory and/or anticancer utility to the claimed compounds, the existence of an asserted common utility alone is insufficient where the members do not share a substantial structural texture essential to that utility.
Although the claimed compounds may contain the recited pyrrolo[2,1-f][1,2,4]triazine moiety, the specification does not establish that this moiety constitutes a substantial structural feature responsible for the asserted common kinase-inhibitory and/or anticancer activity throughout the claimed genus. Rather Chemical Formula 1 permits substantial and independent structural variation at A, B, La, Lb, Q1-Q4, Za, Zb, M, and E, including materially different carboxylic and heterocyclic ring systems, linker architectures, open-chain and ring-closed rearrangements, and target-binding/degradation moieties.
Moreover, the biological data are limited to selected compounds and selected kinase/cancer systems and do not establish that the structurally diverse alternatives encompassed by Chemical Formula 1 possess the asserted common utility by virtue of a shared substantial structural feature. Accordingly, the members encompassed by the Markush grouping have not been to share the requisite structural relationship necessary to support their inclusion in a single Markush group.
Likewise, claim 11 is additionally included in this rejection. Although claim 11 limits the claimed subject matter to the specifically enumerated compounds 1-126, the limitation to expressly disclosed species does not, by itself, establish proper Markush grouping. The enumerated compounds encompass substantially different molecular architecture, including macrocyclic and acyclic structure, materially different linker systems, ring systems, substitution patterns, and terminal functional domains, and the biological data do not establish that these structurally diverse species possess the asserted common utility by virtue of the shared pyrrolo[2,1-f] [1,2,4] triazine moiety.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-7 and 12-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass a genus of 2,7-substituted pyrrolo[2,1-f] triazine compounds represented by Chemical Formula 1. Although the specification expressly set forth Chemical Formula 1 and provides definitions for the variables thereof, the disclosure does not reasonably convey to one of ordinary skill in the art that the inventor had possession, as of the filling date, of the full structural genus presently encompassed by the claims.
The rejection is not based merely upon the numerical size of the genus, nor upon a requirement that Applicant expressly exemplify every species encompassed by Formula 1. Indeed, the specification provides 126 synthesized compounds and those examples are evidenced that Applicant possessed the specifically disclosed compounds and structural families represented thereby. Rather, the deficiency is that the claimed genus encompassed substantial qualitative structural variation resulting from the independent selection and combination of, inter alia, A, B, La, Lb, and Q4, whereas the disclosed species do not reasonably represent the structural diversity encompassed by those alternatives and their combinations.
A and B
Claim 1 defines A and B independently as C6-C10 aryl; C3-C10 cycloalkyl; C3-C10 heteroaryl; or C3-C10 heterocyclyl. Thus, Formula 1 does not merely encompass closely related homologous substitutions. A and B may independently comprise chemically and structurally different classes of rings, including aromatic carbocycles, saturated carbocycles, heteroaromatic systems, and nonaromatic heterocyclic systems. The specification provides definition and examples of the meanings of “heteroaryl” and “heterocyclic,” but such generic definitions identify the universe encompassed by the terminology, they do not themselves demonstrate possession of Formula 1 compounds spanning the full range of independently selectable A/B combinations.
Claims 2 and 3 narrow A and B to enumerate ring systems. Nevertheless, substantial structural breadth remains because A and B continue to be independently selectable from multiple chemically distinct ring systems and because the remaining linker and substituent variables are not correspondingly limited to the exemplified combination.
La and Lb
The deficiency is particularly apparent from La and LB
La is not limited to a single peripheral substituent. Claim 1 permits La to be hydrogen, hydroxy, halogen, C1-C3 alkyl, -Za-Q3-E, or -Za-Q1-M. In the latter embodiment, when Lb is -Zb-Q2, M may connect to Q2. Lb similarly encompasses numerous simple substituents as well as -Zb-Q2, which may incorporate with the La/Za/Q1/M arrangement to produce. A ring. These alternatives materially change the architecture of the claimed compounds and encompass open-chain structures, linker-containing structures, E-containing structures, and macrocyclic/ring-closed structures. The specification’s synthetic disclosure demonstrates possession of particular linker and ring-closure architectures but does not provide representative species spanning the full structural variation resulting from all claimed La/Lb alternatives in combination with the independently variables A and B groups.
Q4
The same deficiency is present with respect to Q4.
Q4 “may be present or absent,” and, when present, may comprise the recited carbon-containing linking groups. Accordingly, the claim encompasses compounds having materially different connectivity between the pyrrolotriazine core and B. This is merely variation in a terminal substituent. Q4 affects the connectivity and spatial relationship of substantial portion of the molecule. The disclosed species do not reasonably represent the breadth resulting from the claimed Q4 alternatives in combination with the independent A, B, La and Lb alternatives.
The 126 disclosed compounds
The Examiner acknowledges that the specification provides detailed synthetic preparation and structural identification for compound 1-126. Those species demonstrate possession of those compounds and of structural subject matter reasonably represented thereby. However, the mere number of disclosed species does not resolve the written-description inquiry where the claimed genus contains substantial qualitative structural variation not adequately represented by these species. Here, the disclosed compounds occupy particular structural families involving selected A/B ring systems, linker arrangements, ring-closed structures, and selected E-containing constructs. The specification does not identify a structural principle demonstrating that the disclosed species are representative of the full genus generated by independently selecting the substantial broader A, B. La, Lb, Q4 and associated linker alternatives.
Claims 2-4 narrow selected variables but do not restrict the remaining Formula 1 variables sufficiently to cure the above deficiency.
Claims 5-7 restrict the compound to Chemical Formula 2 and progressively restrict certain A/B, R-groups, and E-alternatives. Nevertheless, Formula 2 continues to encompass substantial structural variation in the remaining independently variable groups, including linker length and composition and the numerous alternative E structures. Accordingly, the disclosed examples do not provide representative species reasonably commensurate with the full breadth remaining in these claims.
Claim 12 restricts the type of pharmaceutically acceptable salts but does not materially restrict the underlying Formula 1 compound genus and therefore does not cure the deficiency.
Claims 13-18 incorporate the compound of claim 1 directly or through dependency, and their additional pharmaceutical-use, kinase-function, or cancer limitations do not cure the lack of written-description for the underlying structural genus.
Claim 11 is not included in this rejection. Claim 11 expressly limits the claimed compound to compounds numbered 1-126, which as specially disclosed and structurally identified in the specification. Accordingly, the present record reasonably demonstrates possession of these numerated species.
Functionality defined Genus Written description
Claims 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 15 requires Formula 1 compound to possess “inhibition efficacy of over 80% against protein kinase at 1 µM.”
Claim 16 extends this functional limitation to one or more members of an extensive genus comprising numerous structurally and functionally distinct protein kinases.
Claim 17 narrows the kinase genus to CDK, NEK, Wee1, GCN2, but still defines the claimed compounds by the required kinase-inhibition function.
The specification generally states that compounds of Formula 1 possess protein-kinase inhibitory/degradation activity and provides biological experiments for selected compounds. However, the disclosure does not provide a representative number of Formula 1 species exhibiting the claimed greater than 80%-at-1µM inhibition function across the breadth of the claimed kinase genus, nor does it identify structural characteristics common to Formula 1 compounds that permit one skilled in the art to recognize, from structure, which compounds will possess that function against the recited kinases. The experimental disclosure instead reports selected cellular GI50 activity, FLT3-dependent Ba/F3 cellular activity, and target-protein degradation studies. Such disclosure demonstrates biological activity for the particular compounds and experimental systems tested, but it does not establish possession of the considerably broader genus defined by the claimed quantitative kinase-inhibition function. Moreover, the specification does not disclose structure-function correlation by which changes among the numerous Formula 1 variables-including the target-binding portion, linkers, ring systems, and E-containing structure-can be correlated with greater than 80% inhibition at 1 µM against the full range of kinases recited in claim 16 or even each kinase families recited in claim 17. Accordingly, the disclosure provides at most, particular species or subgenera having demonstrating activity, rather than a representative disclosure reasonably commensurate with the full functionality defined genus of claims 15-17.
This rejection is separate from the structural-genus rejection above. Even assuming arguendo that the specification adequately describes the structural boundaries of Formula 1, the specification must still reasonably convey possession of the subset of that enormous structural genus satisfying the newly imposed quantitative kinase-inhibition function.
Claims 13-18 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 working examples demonstrating anticancer activity of selected compounds of Table 2 in colorectal cancer, non-small cell lung cancer, triple-negative breast cancer, and FLT-3-related leukemia, does not reasonably provide enablement for the substantially broader scope of the claims, which encompasses numerous additional biological distinct cancers and cancer prevention. 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.
The rejection is not based upon the absence of demonstrated anticancer activity. Rather, the rejection concerns whether the limited demonstrated embodiments reasonably enable the substantially broader scope of claims 13-18, which encompasses prevention, alleviation, or treatment of cancer generally and numerous biologically and molecularly distinct malignancies for which no corresponding working examples are provided. The specification does not provide sufficient guidance or a predictive relationship by which one of ordinary skill in the art could reasonably extrapolate activity observed in the tested colorectal, NSCLC, TNBC, and FLT3-leukemia to numerous other cancers encompassed by the claims. As evidenced by Sawyers and Bhuller et al., responsiveness to kinase-targeted therapy is dependent upon the particular kinase dependency, molecular alteration, tumor genetics, cellular context, resistance mechanisms, and other tumor-specific factors.
Therefore, one of ordinary skill would have been required to undertake substantial empirical screening to determine which claimed compounds, if any, are effective against numerous unrelated cancers encompassed by the claims. Such experimentation would amount to identifying additional operative embodiments throughout the claimed genus rather than merely optimizing known operative embodiments.
Claim 13 is directed to a pharmaceutical composition comprising a compound according to claim 1 as an effective ingredient for preventing, alleviating, or treating cancer. Claims 14-18 further limit the claimed subject matter by reference to abnormal cell growth due to protein kinase activity, kinase-inhibitory activity, particular protein kinases, and/or particular cancers.
The specification provides working examples demonstrating biological activity of selected compounds in a limited number of cancer-cell systems. In particular, selected compounds were tested against HCT116 and Colo205 colorectal cancer cells, H1975, H23, and H358 non-small cell lung cancer cells, and MDA-MB-231 triple-negative breast cancer cells. The specification additionally provides activity data using FLT3-dependent cellular systems. Thus, the rejection is not based upon the absence of demonstrated anticancer activity. For purpose of the present rejection, the Examiner does not dispute enablement with respect to the cancer types and molecular contexts reasonably represented by these working examples. Rather, the enablement deficiency concerns the substantially broader scope of the claims. Claim 13 encompasses prevention, alleviation, or treatment of cancer generally suing the claimed compounds, while claim 18 expressly encompasses numerous biologically and molecularly distinct malignancies substantially beyond the cancer systems tested, including, inter alia, stomach cancer, lung cancer, liver cancer, colon cancer, rectal cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, sclerotic adenosis, uterine cancer, cervical cancer, oral cancer, esophageal cancer, thyroid cancer, parathyroid cancer, renal cancer, sarcoma, prostate cancer, ureter cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, hematologic malignancies such as Hodgkin's disease and non- Hodgkin's lymphoma, and fibrosarcoma. Although, the specification provides biological background concerning kinase signaling and cancer, the disclosure does not provide working examples or sufficient predictive guidance demonstrating that the activity observed in the tested colorectal, non-small-lung, triple-negative breast cancer, and selected FL3-dependent leukemia can reasonably be extrapolated to the numerous additional cancers encompassed by the claims. Whether the experimentation required to practice the full scope of the claimed invention would have been undue is evaluated in view of the factors set forth in in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). The relevant are discussed below:
Quantity of Necessary Experimentation
The quantity of experimentation required to practice the full scope of the claims would be substantial. In the absence of a predictive relationship between the demonstrated cancer systems and the numerous additional cancers encompassed by the claims, one of ordinary skill in the art would be required to empirically determine whether a claimed compound possesses therapeutically relevant activity against each materially different cancer or molecular context. Such experimentation would require, at a minimum, selection of appropriate compounds, identification of the relevant kinase or molecular pathway for the particular cancer, evaluation of compound activity against the relevant target and cancer cells, and determination of whether the observed biochemical or cellular activity is sufficient to support the claimed preventive, alleviating, or therapeutic effect.
The required experimentation therefore would not merely constitute routine optimization of conditions for embodiments already shown to be operative. Rather, substantial screening would be necessary to determine which additional compound/cancer combinations encompassed by the claims are operative embodiment in the first instance. This factor weighs in favor of undue experimentation.
Amount of Direction of Guidance Presented
The specification provides meaningful guidance regarding preparation of the disclosed compounds and discusses the relationship between protein kinase and cancer. The disclosure also provides more particular guidance concerning certain molecular systems, including FLR3 and EGFR. However, the specification does not provide a general principle or structure-kinase relationship by which one of ordinary skill in the art could determine, without substantial empirical testing, which claimed compounds will be therapeutically effective against the numerous untested cancers encompassed by the claims. In particular, the specification does not establish that the various cancer encompassed by the claims share a common kinase dependency or molecular mechanism such that the activity demonstrated in the tested colorectal, non-small-cell lung, triple-negative breast cancer, or FLT3-dependent systems would reasonably predict therapeutic activity against the remaining cancers. Accordingly, the guidance provided by the specification is insufficient to bridge the substantial gap between the demonstrated embodiments and the full claimed scope. This factor weighs in favor of undue experimentation.
Presence of Absence of Working Examples
The specification contains working examples, and this factor is acknowledged as weighing in favor of Applicant. However, the working examples are limited in relation to the breadth of the claimed therapeutic genus. The cancer-cells testing is directed to colorectal cancer, non-small-cell lung cancer, and triple-negative breast cancer cell lines with additional testing in selected FLT3-dependent cellular systems. The claims encompass numerous additional solid and hematologic malignancies for which corresponding working examples are not provided. Accordingly, although the presence of working examples favors Applicant, the examples represent only a limited portion of the claimed therapeutic scope and do not, by themselves, establish enablement throughout the substantially broader cancer genus.
Nature of the Invention and Predictability of the Art
The claimed invention concerns kinase-related compounds for prevention, alleviation, or treatment of cancer. The evidence of record demonstrates that this is biological complex and context-dependent field in which therapeutic response to kinase-targeted agents cannot reliably be predicted merely from activity observed against a different cancer or cellular system.
Sawyer et al. (Genes & Development 17:2998–3010 © 2003) teaches that kinase inhibitor therapy works consistently where the tumor is dependent upon the relevant kinase and emphasizes the importance of identifying the molecular lesion and renders the particular cancer responsive to kinase inhibition. (See page 3002; left col.) Sawyer further describes the experience of EGFR inhibitors, which demonstrated activity against a broad panel of EGFR-expressing tumor cell lines but produce dramatic clinical responses in only a small fraction of lung tumors. (See Table 1 and page 3001.) The reference explains that EGFR express itself did not account for the differential responses and concludes that targeted kinase therapy requires patient selection based upon molecular lesion. (See page 3001.)
Sawyers additionally explains that successful inhibition of kinase activity in surrogate tissues does not ensure inhibition of kinase activity in tumor cells, (see page 3003) further demonstrating that activity in one biological context cannot necessarily be extrapolated to another.
Bhullar et al. (Molecular Cancer (2018) 17:48. Pages 1-20) likewise explain that the human genome encodes approximately 538 protein kinases and that the clinical efficacy of kinase-targeted compounds is affected by specific tumor genetics, tumor micro-environment, drug resistance, and pharmacogenomics. Bhullar et al. further explains that therapeutic response to kinase inhibitors vary widely among individual patients across patient populations and depend upon multiple diverse factors (See Abstract.)
Thus, the state of the art demonstrates that kinase-targeted anticancer efficacy is dependent upon the particular molecular target, tumor genotype, cellular context, resistance mechanisms, and other cancer-specific factors. The results obtained in the limited cancer systems tested in the specification therefore would not reasonably permit one of ordinary skill to predict therapeutic activity throughout the substantial broader cancer scope of claims 13-18 without empirical testing. The nature and unpredictability of the art weigh strongly in favor of undue experimentation.
State of the Prior Art
The prior art establishes that protein kinases constitute a large and functionally diverse family and that different cancers depend upon different kinases and signaling pathways. Bhullar et al explains that hundreds of kinases play overlapping and intricate roles in cellular transformation, tumor initiation, survival, and proliferation, and identify different kinases as being associated with different cancer types and molecular abnormalities. (See page 1.)
Furthermore, Sawyer explains that responsiveness to kinase inhibitors depends upon the existence and nature of the relevant kinase-dependent state and that the inability to identify responsive molecular subgroups significantly complicates development of kinase therapies. (See page 3006.)
Accordingly, the state of the prior art does not provide a predictable basis for extrapolating the limited working examples of the specification to all of the additional cancers encompassed by the claims. This factor weighs in favor of undue experimentation.
Relative Skill of Those in the Art
The Examiner acknowledges that those of ordinary skill in medical chemistry, molecular oncology, and kinase pharmacology possessed a relatively high level of skill and would have been capable of preparing candidate compounds and performing kinase and cancer-cell assays. However, the level of skill in the art does not provide the predictive information absent from the specification. Although the skilled artisan would have possessed the technical ability to perform the necessary screening, such ability does not eliminate the need to perform extensive empirical experimentation to determine which compounds are effective against which of the numerous cancers claimed. Accordingly, the high level of skill in the art does not overcome the enablement deficiency.
The Breadth of the Claims
The breadth of the claims is substantial relative to the scope of the working examples and guidance provided.
Claims 13 is not limited to colorectal cancer, non-small cell lung cancer, tripe-negative breast cancer, or FLT3-related leukemia. Rather, claim 13 encompasses cancer generally. Claims 18 confirms the breadth of this genus by expressly encompassing numerous biologically distinct solid and hematologic malignancies.
Conclusion
Considering the Wands factors as a whole, the Examiner acknowledged that the specification provides substantial synthetic disclosure, numerous exemplified compounds, working biological examples demonstration activity in particular cancer-related systems. The rejection therefore is not based upon a conclusion that the disclosed compounds lack anticancer activity or that no cancer indication is enabled. Rather the deficiency concerns the scope of the enablement. Therefore, claims 13-18 are rejected under 35 U.S.C. 112(a) for lack of enablement.
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 1-7 and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Breslin et al. (WO2010/071885A1) in view of Crew et al. (WO2020/041331A1).
Breslin teaches a pharmaceutical composition comprising at least one compound of the
compound of formula (I)
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448
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or a pharmaceutically acceptable salt form thereof together with at least one pharmaceutically acceptable carrier, diluent, or excipient therefor. (See lines 10 and claim 1.) Moreover, Breslin teaches the compounds can also be combined in a pharmaceutical composition that also comprises compounds that are useful for the treatment of cancer or another ALK- or JAK2 -mediated disorder including breast cancer lung cancer. (See lines 3-15.) Preferably the salts are pharmaceutically acceptable salts including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. (See lines 6-20.) Breslin further teaches compound 627 and compound 369 as depicted below
Compound 627 Compound 369
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wherein compound 627 exhibits ALK potency of “++++”, which Breslin defines as anIC50 of less than 0.1 µM. (See pages 486 and 593, and pages 327-329.)
Breslin Example 627 therefore teaches the target-binding portion corresponding to elected compound 36, including:
The pyrrolo[2,1-f] [1,2,4] triazine core;
at one side of the pyrrolotriazine core, a phenyl bearing an
N-methyl methane sulfonamide substituent;
at the other side, a phenylamino substituent bearing a piperazine ring and;
substitution at the distal nitrogen of the piperazine ring.
Breslin does not expressly teach the elected compound 39
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wherein the methyl substituent at the distal piperazine nitrogen of Example 627 is replaced with the linker terminating in the phthalimide/glutarimide E3-ligase-binding moiety recited in the elected compound 39. Breslin however, demonstrates that the distal piperazine nitrogen of this same pyrrolotriazine pharmacophore is amenable to substitution other than methyl. For example, Breslin expressly teaches the corresponding compound 369. Thus, Breslin teaches that the distal piperazine nitrogen is a substitutable position while retaining the relevant pyrrolotriazine target-binding architecture.
Crew teaches bifunctional or PROTAC compounds comprising a protein-binding moiety (PTM) coupled, directly or through a chemical linker, to and E3 ubiquitin-ligase-binding moiety (ULM). Crew teaches that the ULM may specifically comprise a cereblon-binding moiety (CLM) and explains that interaction of the PTM and E3-ligase-binding portions places the target protein in proximity to the ubiquitin ligase, thereby facilitating degradation of the target protein. Crew expressly represents such compounds as PTM-L-CLM, wherein L is a chemical linker. (See paragraphs [0008] – [0010].) More particularly, Crew’s synthesis of compound 27
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teaches that the structural linker/El ligase portion pertinent to the presently claimed elected compound. At paragraphs [00578]-[000597], Crew reacts a target-binding compound having an available piperazine nitrogen with 5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]pentyl 4-methylbenzene-1-sulfonate in the presence of K2CO3 and NaI. The resulting exemplary Compound 27 thereby attached the cyclic amine nitrogen at the target-binding portion through a pentyl linker and ether linkage to the phthalimide/glutarimide cereblon-binding moiety.
Crew further exemplifies the foregoing linker/E3-ligase-binding architecture in multiple compounds, including Exemplary Compounds 31 and 32,
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(see page 376) wherein an available nitrogen atom of a cyclic-amine-containing protein-targeting moiety is substituted with an alkyl liner terminating through an ether linkage in a phthalimide/glutarimide cereblon-binding moiety. Thus. Crew demonstrates that attachment of the cereblon-binding portion through an N-linked alkyl linker represents a generally employed structural arrangement for constructing its heterobifunctional degradation compounds, rather than an isolated modification unique to Exemplary Compound 27.
Accordingly, Breslin and Crew collectively teach all of the structural components of elected Compound 39. Breslin Example 627 supplies the pyrrolo[2,1-f][1,2,4]triazine kinase-binding portion having the N-methyl methane sulfonamide-substituted phenyl and piperazinyl phenylamino substituent, whereas Crew teaches functionalizing an available cyclic amine nitrogen with the pentyl-oxy-phthalimide/glutarimide cereblon-binding portion employed in a bifunctional degradation compound.
It would have been obvious to one of ordinary skill in the art at the effective filing date of the claimed invention to modify the pyrrolo[2,1-f][1,2,4]triazine kinase-binding compound of Breslin Example 627 by replacing the methyl substituent at the distal piperazine nitrogen with the linker/cereblon-binding moiety taught by Crew, thereby providing the corresponding bifunctional degradation compound.
One of ordinary skill in the art would have been motivated to replace the methyl substituent on the distal piperazine nitrogen of Breslin Example 627 with the N-linked alkyl/cereblon-binding substituent taught by Crew in order to convert Breslin’s known kinase-binding compound into a heterobifunctional degradation compound. Crew expressly teaches the use of a protein-targeting moiety connected through a linier to an E3-ligase-binding moiety and repeatedly exemplifies attachment to an alkyl-oxy-phthalimide/glutarimide cereblon-binding portion through an available nitrogen of a cyclic amine-containing target-binding moiety, including in Exemplary Compounds 27, 31, and 32. Breslin, in turn, establishes that the distal piperazine nitrogen of its pyrrolotriazine kinase-binding pharmacophore is amenable to substitution. Accordingly, modification at that nitrogen according to Crew would have represented the application of Crew’s expressly taught bifunctionl-degrader architecture to Breslin’s known kinase-binding ligand for the purpose taught by Crew-recruitment of an E3 ubiquitin ligase to a protein targeted by the protein-targeting moiety.
One of ordinary skill in the art would have had a reasonable expectation of success because Breslin demonstrates that substitution at the distal piperazine nitrogen is tolerated, while Crew repeatedly demonstrates that cyclic amine nitrogen can serve as an attachment site for alkyl linkers terminating in the disclosed cereblon-biding phthalimide/glutarimide moiety. Crew’s successful preparation of multiple compounds employing this architecture, including Exemplary Compounds 27, 31, and 32, would have provided the skilled artisan with a reasonably expectation that the corresponding N-linked modification of Breslin’s piperazine-containing kinase ligand could likewise be successfully prepared and employed as a heterobifunctional degrader.
With respect to claims 14, the claim recites that the pharmaceutical composition is for “use in prevention, alleviation, or treatment of cancer, which is a disease induced by abnormal cell growth due to protein kinase activity as recited in claim 14. This language constitutes statements of intended use and does not impart further structurally distinguish the claimed pharmaceutical composition from a composition comprising the otherwise identical compound rendered obvious by Breslin in view of Crew. The proposed modified compound possesses the same structural feature relied upon for the claimed composition and would retain the same functionality of the intended use discussed above. Accordingly, the recited intended use does not render the otherwise obvious composition patentable.
With respect to claim 15. Claim 15 further requires that the compound has an inhibition efficacy of greater than 80% against protein kinases at 1 µM. Breslin expressly teaches that Example 627 possesses potent kinase inhibitory activity. In particular, Breslin reports Example 627 as having an ALK potent designated “++++.” Breslin defines “++++” as an IC50 of less than 0.1 µM. (See pages 327-329.) Thus, Breslin demonstrates that Example 627 inhibits ALK at concentration substantially below 1 µM concentration recited in claim 15. As discussed above, Crew teaches bifunctional protein-degradation compounds comprising a target-protein-binding moiety linked to and E3-ligase-binding moiety and provides Compound 27 as an Exemplary compound containing the linker/E3-ligase-binding architecture relied upon. One of ordinary skill in the art would have a reasonable expectation of success that the resulting or obvious compound would retain substantial ALK inhibitory activity because the proposed modification retains the Breslin kinase-binding moiety for its known kinase-binding function while appending the linker/E3-ligase-binding functionality taught by Crew. Breslin’s demonstrated ALK IC50 of less than 0.1 µM.
The recitation that the pharmaceutical composition is “for use in prevention, alleviation, or treatment of cancer” does not further distinguish the claimed composition from the otherwise obvious composition because this language states the intended use of the composition. The proposed modified compound possesses the same structural feature relied upon for the claimed composition and would retain the protein-kinase inhibitory property discussed above. Accordingly, the recited intended use does not render the otherwise obvious composition patentable.
With respect to claim 17. Claim 16 further specifies that one or more of the protein- kinase is from the group consisting of CDK, NEK, Wee1, and GCN2. Although Breslin does not expressly report data for CDK, NEK, Wee1, or GCN2 for Example 627. The combined teachings of Breslin and Crew render obvious the same compound/composition recited by the claim. The identity and properties of a chemical compound are inseparable. Thus, once the claimed compound itself is rendered obvious, properties necessarily possessed by that same compound are inherently present notwithstanding that the prior art may have recognized or expressly reported those properties. Accordingly, the modified compound resulting from the combination of Breslin and Crew, being the same compound encompassed by claim 17, necessarily possesses the biotechnical properties inherent to that compound, including its inhibition of the kinase or kinases recited in claim 17. The recognition or discovery of an inherent property of an otherwise obvious composition does not render the composition patentable.
Conclusion
Claims 1-7 and 11-18 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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