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 .
Status of Claims
Claims 99-117 are pending.
Priority
Instant application 18/668,916, filed 05/20/2024 claims priority as follows:
PNG
media_image1.png
117
660
media_image1.png
Greyscale
Information Disclosure Statement
All references from IDS(s) received 10/11/2024 and 11/14/2024 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 99-117 in the reply filed on 02/03/2026 is acknowledged. Applicant’s species election without traverse of the composition comprising compound 36, having the structure
PNG
media_image2.png
131
240
media_image2.png
Greyscale
, in the reply is also acknowledged.
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.
Applicant’s elected species was searched and applicable prior art was not identified. Pursuant to MPEP 803.02, the search was extended to the full scope of Formula (Ia) or (Ib) recited in claim 99:
PNG
media_image3.png
203
323
media_image3.png
Greyscale
and applicable prior art was identified.
Claims 99, 101-107, and 116 read on the expanded species of Formula (Ia) or (Ib) and are the subject of this Office Action. Therefore, claims 100, 108-115, and 117 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to compounds that do not read on the expanded species, there being no allowable generic or linking claim.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see [0568] and [0576] in the Specification filed 05/20/2024). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms “GraphPad Prism”, “PerkinElmer 2300 Enspire”, and “Sigma-Aldrich”, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The disclosure is objected to because of the following informalities:
The abstract opens with the implied introductory phrase “The present disclosure provides”.
The abstract contains a typographical error in line 4. The phrase “the bicyclic heteroaryl compounds includes those of Formula (I)” should read “the bicyclic heteroaryl compounds include those of Formula (I)”
Appropriate correction is required.
Claim Interpretation
Claim 116 recites a list of systematic chemical names which are being interpreted according to the following table:
NAME
STRUCTURE
4-((5,6-dimethoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image4.png
200
400
media_image4.png
Greyscale
4-((6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image5.png
200
400
media_image5.png
Greyscale
4-((5-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image6.png
200
400
media_image6.png
Greyscale
4-((5,6-dimethoxyindol-1-yl)methyl)phenylboronic acid
PNG
media_image7.png
200
400
media_image7.png
Greyscale
4-((5-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image8.png
200
400
media_image8.png
Greyscale
4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image9.png
200
400
media_image9.png
Greyscale
4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image10.png
200
400
media_image10.png
Greyscale
4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenylboronic acid
PNG
media_image11.png
200
400
media_image11.png
Greyscale
1-((4-(dihydroxy-boranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid
PNG
media_image12.png
200
400
media_image12.png
Greyscale
4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image13.png
200
400
media_image13.png
Greyscale
4-((5-methoxyindol-1-yl)methyl)phenylboronic acid
PNG
media_image14.png
200
400
media_image14.png
Greyscale
4-((5-cyano-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid
PNG
media_image15.png
200
400
media_image15.png
Greyscale
4-((5-carbamoyl-3-oxo-2H-indazol-1-yl)methyl)phenylboronic acid
PNG
media_image16.png
200
400
media_image16.png
Greyscale
4-((5-carbamoyl-3-chloroindol-1-yl)methyl)phenylboronic acid
PNG
media_image17.png
200
400
media_image17.png
Greyscale
4-((5-carbamoyl-3-methylindol-1-yl)methyl)phenylboronic acid
PNG
media_image18.png
200
400
media_image18.png
Greyscale
4-((5-carbamoyl-6-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image19.png
200
400
media_image19.png
Greyscale
4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image20.png
200
400
media_image20.png
Greyscale
4-((5-carbamoylindazol-1-yl)methyl)phenylboronic acid
PNG
media_image21.png
200
400
media_image21.png
Greyscale
3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid
PNG
media_image22.png
200
400
media_image22.png
Greyscale
4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image23.png
200
400
media_image23.png
Greyscale
3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid
PNG
media_image22.png
200
400
media_image22.png
Greyscale
1-(4-boronobenzyl)-1H-benzo[d]imidazole-5-carboxylic acid
PNG
media_image24.png
200
400
media_image24.png
Greyscale
4-((5-(ethoxycarbonyl)-3-methylindol-1-yl)methyl)phenylboronic acid
PNG
media_image25.png
200
400
media_image25.png
Greyscale
1-((4-(dihydroxyboranyl)phenyl)methyl)-3-methylindole-5-carboxylic acid
PNG
media_image26.png
200
400
media_image26.png
Greyscale
1-(4-boronobenzyl)-3-chloro-1H-indole-5-carboxylic acid
PNG
media_image27.png
200
400
media_image27.png
Greyscale
4-((5-methoxy-6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenyl-boronic acid
PNG
media_image28.png
200
400
media_image28.png
Greyscale
4-((6-methoxy-5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenyl-boronic acid
PNG
media_image29.png
200
400
media_image29.png
Greyscale
4-((5-(methoxycarbonyl) indazol-1-yl)methyl)phenylboronic acid
PNG
media_image30.png
200
400
media_image30.png
Greyscale
4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image31.png
200
400
media_image31.png
Greyscale
4-((5-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image32.png
200
400
media_image32.png
Greyscale
4-((5-carbamoyl-4-methoxyindol-1-yl)methyl)phenylboronic acid
PNG
media_image33.png
200
400
media_image33.png
Greyscale
4-((4-carbamoylindol-1-yl)methyl)phenylboronic acid
PNG
media_image34.png
200
400
media_image34.png
Greyscale
4-((4-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image35.png
200
400
media_image35.png
Greyscale
4-((7-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image36.png
200
400
media_image36.png
Greyscale
4-((4-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image37.png
200
400
media_image37.png
Greyscale
4-((7-fluoro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image38.png
200
400
media_image38.png
Greyscale
4-((7-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image39.png
200
400
media_image39.png
Greyscale
4-((4-methoxy-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image40.png
200
400
media_image40.png
Greyscale
4-((6-(methylcarbamoyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image41.png
200
400
media_image41.png
Greyscale
4-((4-amino-5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image42.png
200
400
media_image42.png
Greyscale
4-((5-carbamoyl-4-methoxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image43.png
200
400
media_image43.png
Greyscale
4-((5-carbamoyl-4-hydroxy-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image44.png
200
400
media_image44.png
Greyscale
4-((5-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image45.png
200
400
media_image45.png
Greyscale
4-((6-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image46.png
200
400
media_image46.png
Greyscale
4-((4-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image47.png
200
400
media_image47.png
Greyscale
4-((7-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image48.png
200
400
media_image48.png
Greyscale
4-((4-(difluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image49.png
200
400
media_image49.png
Greyscale
4-((4-(fluoromethyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image50.png
200
400
media_image50.png
Greyscale
Claim Objections
Claim 116 is objected to because of the following informalities: the following chemical names contain typographical errors:
4-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((6-cyano-1,3-benzodiazol-1-yl)methyl)phenylboronic
4-((6-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((6-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((5-carbamoyl-1H-indol-1-yl)methyl)phenyl)boronic acid
4-((5-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid
4-((6-carbamoyl-1H-benzo[d]imidazol-1-yl)methyl)-3-methylphenyl)boronic acid
Due to the typographical errors, chemical structures could not be generated for these names. In many instances, the recited name appears to comprise at least one extra parenthesis. In at least one instance, the compound reads “phenylboronic” but should read “phenylboronic acid”. Appropriate correction of each name is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 99 and 102 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims:
The claims are broadly directed to pharmaceutical compositions comprising a compound of formula (1a) or (1b). Claim 102 specifically requires the compound to have the structure of formula (1b). The formula (Ib) genus is structurally broad: it permits that one of y and z is N and the other is CR7, or both y and z are CR7; any alk1 linker (an alkylene in which one carbon may be replaced by oxygen, optionally substituted with halo); and the full range of R2 through R7 substituents. The combinatorial scope of (Ib) alone encompasses millions of distinct chemical structures, none of which are exemplified.
Nature of the invention:
The invention relates to small-molecule ENPP1 inhibitors for pharmaceutical use. It is well established that pharmaceutical and medicinal chemistry is an unpredictable art where the relationship between molecular structure and biological activity cannot be reliably predicted. The repositing of a pharmacophore (here, moving a boronic acid from being directly on the aryl ring to being tethered through an alkylene chain, while simultaneously changing how the aryl ring connects to the heterocyclic core) is the type of structural modification that routinely and unpredictably alters binding affinity, selectivity, metabolic stability, and pharmacological utility.
State of the prior art and predictability in the art:
A review of the prior art reveals that: (i) no ENPP1 inhibitor with the formula (Ib) connectivity had ever been reported; (ii) the closest structural analogs in the literature exclusively followed the (Ia) connectivity pattern; (iii) no prior art guidance existed to predict whether the structural rearrangement from (Ia) to (Ib) would preserve ENPP1 inhibitor activity.
See, for example, ONYEDIBE (Molecules, vol. 24, no. 22, Nov. 2019, p. 4192). ONYEDIBE discloses ENPP1 inhibitors (see entire document). The inhibitors are either nucleotide-based substrate analogs (Figure 8), or non-nucleotide inhibitors (Table 3). In particular, the non-nucleotide inhibitors generally bear no structural resemblance to compounds of Formula (Ib).
The closest structural prior art includes LLONA 1 (WO 2016055582 A1; published April 14, 2016) and LLONA 2 (Journal of Medicinal Chemistry, vol. 59, no. 3, Feb. 2016, pp. 1140–48; IDS). LLONA 1 and LLONA 2 describe a series of benzimidazole derivatives as inhibitors of dCTPase (DCTPP1), a different pyrophosphatase enzyme. The compounds all have the connectivity of formula (Ia) recited in the instant claims. No compounds with the connectivity shown in formula (Ib) are disclosed.
Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Moreover, the specification itself acknowledges the unpredictability of the claimed method, stating: “it is unclear how the antidepressant phenotype observed in FGFR3 A385E/+ mice and FGFR3 N534K/+ mice could be translated in human condition” (page 26, lines 10-12).
Level of ordinary skill in the art:
The person of ordinary skill would be a medicinal chemist with an advanced degree (e.g. Ph.D.) and possess several years of professional experience, with some familiarity for synthesizing heterocyclic compounds and enzyme inhibition assays. While this person would possess a high level of skill to synthesize (Ib)-type compounds if given adequate direction, that skill alone does not substitute the missing structural guidance and activity data needed to predict which (Ib) compounds, if any, would be functional ENPP1 inhibitors.
The amount of direction provided:
The specification provides limited direction for Formula (Ib) compounds. Scheme 1 on page 64 appears to disclose a prophetic approach to synthesizing the compounds. However, there is no discussion anywhere in the specification of how moving the boronic acid from the aryl ring to the alkylene tether would be expected to affect ENPP1 binding or inhibitory potency.
Existence of working examples:
The specification provides zero working examples of any formula (Ib) compound. Table 1 provides approximately 150 compounds exclusively following the (Ia)-type connectivity pattern. All biological data reported in Table 2 are for (Ia)-type compounds. No activity data exists for any (Ib)-type structure. The complete absence of working examples for an entire structural genus recited in an independent claim is a strong indicator of non-enablement.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. To practice the invention with respect to Formula (Ib) compounds, a skilled artisan would need to:
(i) reduce Scheme 1 to practice for (Ib)-type compounds, which would involve identifying and sourcing or synthesizing the appropriate starting materials and optimizing the reaction steps. Each of these steps may require screening of conditions, catalysts, and protecting group strategies. The specification does not report yields, side products, or purification details for any (Ib) product, so the skilled artisan would be working without the benefit of reduced-to-practice experimental guidance;
(ii) synthesize and characterize representative (Ib) compounds across the breadth of the claimed genus (varying the bicyclic ring system variables y and z, alk1 linker, and R2 to R7 substituents);
(iii) test each compound for ENPP1 inhibitory activity to determine whether any (Ib) compound possesses meaningful activity, since no biological data is present; and
(iv) formulate active compounds into pharmaceutical compositions.
The biological experimentation step is the most burdensome: in the absence of any activity data or SAR rationale for (Ib) compounds, the skilled artisan would be embarking on a screening campaign with no guarantee of success.
Therefore, in view of the factors discussed above, claims 99 and 102 are rejected as failing to comply with the enablement requirement.
Consistent with MPEP 2164.04 and in the interest of compact prosecution, the examiner recommends either cancelling any reference to compounds of Formula (Ib) from the claims; or providing evidence demonstrating that the (Ib) genus was enabled at the time of filing.
Claim Rejections - 35 USC § 103
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 99, 101, 103-107, and 116 are rejected under 35 U.S.C. 103 as being unpatentable over:
LLONA 1 (WO 2016055582 A1; published April 14, 2016) in view of
LLONA 2 (“Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1.” Journal of Medicinal Chemistry, vol. 59, no. 3, Feb. 2016, pp. 1140–48; IDS).
The instant claims are drawn to pharmaceutical compositions comprising compounds having a structure of Formula (Ia):
PNG
media_image51.png
206
187
media_image51.png
Greyscale
and a pharmaceutically acceptable carrier. The compounds are disclosed as inhibitors of the pyrophosphatase ENPP1 for treating cancer, wherein the variables R2-R7, alk, y, and z are defined in the claims.
LLONA 1 teaches compounds of Formula (I):
PNG
media_image52.png
228
231
media_image52.png
Greyscale
and pharmaceutical formulations thereof comprising the compound in admixture with one or more pharmaceutically acceptable adjuvant, diluent and/or carrier. The compounds are disclosed as inhibitors of the pyrophosphatase DCTPP1 for treating cancer, wherein the variables R4-R7, X2, X1, and A are defined in, for example, a first aspect defined on pages 5-9, claim 1, or a second aspect defined on pages 9-12.
In the first aspect, Formula (I) teaches that at least one of R4 or R7 represents -NO2. In the second aspect, Formula (I) teaches that at least one of R4 or R7 represents -C(H)(CF3)OH, -C(CF3)2OH, -C(OH)2CF3, -NO2 or -C(O)R8. Otherwise, X1 and X2 each represent N or a substituted methine group; R4 and R7 represent H, alkyl, halo, cyano, azido, nitro, amino, alkoxy, sulfide; and R5 and R6 represent H, alkyl, halo, cyano, azido, or nitro.
Additionally, LLONA 1 teaches an embodiment of Formula (I) wherein variable A is defined as follows (see claim 13):
PNG
media_image53.png
110
602
media_image53.png
Greyscale
LLONA 1 also teaches the following specific compounds (see Table 3):
PNG
media_image54.png
565
1020
media_image54.png
Greyscale
PNG
media_image55.png
431
930
media_image55.png
Greyscale
PNG
media_image56.png
489
836
media_image56.png
Greyscale
PNG
media_image57.png
496
797
media_image57.png
Greyscale
PNG
media_image58.png
559
770
media_image58.png
Greyscale
PNG
media_image59.png
408
704
media_image59.png
Greyscale
PNG
media_image60.png
473
787
media_image60.png
Greyscale
and
PNG
media_image61.png
283
413
media_image61.png
Greyscale
.
With respect to claims 99 and 101, the LLONA 1 compounds of Formula (I) where A is -CH2-A1 and A1 is phenyl substituted by -B(OH)2 overlap substantially with the compounds of instant Formula (Ia). Additionally, both genera of compounds are disclosed as having utility for the treatment of cancer and operate by a similar mechanism of action (inhibition of a pyrophosphatase).
LLONA 1 fails to disclose compounds where A is -CH2-A1 and A1 is phenyl substituted by -B(OH)2 having no nitro group on the benzimidazole aryl ring, as required by the instant claims.
However, LLONA 2 discloses pyrophosphatase inhibitors having structures from LLONA 1 or additional variants thereof and their utility for cancer treatment. In particular, LLONA 2 discloses compound 38 having no nitro group (see Table 4):
PNG
media_image62.png
182
343
media_image62.png
Greyscale
LLONA 2 explores the activity associated with the various substituents on the benzimidazole ring, and teaches that the pyrophosphatase inhibitors of this class retain submicromolar activity when the nitro group is absent (see pg. 3, col. 2, para. 1):
PNG
media_image63.png
120
638
media_image63.png
Greyscale
Thus, LLONA 2 provides a clear teaching that the nitro group is not essential to provide the pyrophosphatase inhibitory activity and thus utility in treating cancer.
Applying KSR Prong (B), it would have been prima facie obvious to substitute the nitro group in Formula (I) taught by LLONA 1 with a hydrogen taught by LLONA 2 to arrive at a pharmaceutical formulation comprising the compounds recited in the instant claims. A skilled artisan would have reasonably predicted that this substitution would achieve compounds having pyrophosphatase inhibitory activity based on the teachings of LLONA 2.
With respect to claim 103, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) where R7 is alkyl, hydrogen, methyl, or isopropyl. See for example the groups listed when X1 is C(R2) in Formula (I) of LLONA 1.
With respect to claim 104, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) where alk is methylene. As disclosed above, LLONA 1 teaches compounds of Formula (I) where A is -CH2-A1.
With respect to claim 105, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) where R2 and R3 are hydrogen. As disclosed above, LLONA 1 teaches compounds of Formula (I) where A1 is phenyl substituted at the para position by -B(OH)2.
With respect to claims 106 and 107, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) having the variables defined for R4, and with respect to claim 107, having said variables located at the position indicated for R4. See for example the groups listed for R5 in Formula (I) of LLONA 1. Additionally for claim 107, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) having the variables defined for R5 and R6. See for example the groups listed for R4-R7 in Formula (I) of LLONA 1.
With respect to claim 116, LLONA 1 in view of LLONA 2 teaches compounds of Formula (Ia) wherein the benzimidazole ring is substituted by halogen, alkyl, alkoxy, hydroxy, or cyano. MPEP 2144.09 notes that a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. In the instant case, the teachings of LLONA 1 in view of LLONA 2 would have enabled a skilled artisan to arrive at compounds of instant claim 116 with a reasonable expectation that said compounds would have similar utility disclosed in LLONA 1 and LLONA 2.
For example, starting from compound 38 of LLONA 2, a skilled artisan would have reasonably predicted that substituting:
the 2-methyl substituent for -H (defined for R2 of Formula (I) in LLONA 1); and
one -Cl substituent with -H (defined for R5 or R6 of Formula (I) in LLONA 1)
would achieve compounds having utility as dCTPase inhibitors with the following structures:
4-((5-chloro-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
4-((6-chloro-1,3 -benzodiazol-1-yl)methyl)phenylboronic acid
PNG
media_image64.png
200
400
media_image64.png
Greyscale
PNG
media_image65.png
200
400
media_image65.png
Greyscale
Each of the above compounds is recited in instant claim 116. Accordingly, for at least these reasons, claims 140-141 are obvious over LLONA 1 in view of LLONA 2.
Conclusion
Claims 99, 101-107, and 116 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights