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 the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/16/2025 has been entered.
Claims 54-59 and 62-76 are pending as of the response filed 10/16/2025. Claims 1-53 and 60-61 are cancelled. Applicant’s original election of a group I claims and species in the response dated 08/16/2024 is maintained. As noted previously, the elected species was found to be free of prior art. Claims 56, 58 and 74-76 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or nonelected species, there being no allowable generic or linking claim. Claims 54-55, 57, 59 and 62-73 are examined herein.
Applicants request for rejoinder of any withdrawn claims that require all the limitations of an allowable claim as provided in MPEP § 821.04(b) is acknowledged.
It is noted that no new claim amendments are submitted in the RCE, although the claim set is titled “Amendments to the claims”. In view of the pending claims, the 35 U.S.C. 103 rejection of record over Gallatin in view of Li2 is maintained.
Applicant’s arguments have been fully considered and are addressed below.
Claim Rejections - 35 USC § 103 - Maintained
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 54-55, 57, 59 and 62-73 are rejected under 35 U.S.C. 103 as being unpatentable over Gallatin et al. (WO 2019/046778 A1, international filing date 31 August 2018 hereinafter Gallatin) (in IDS) in view of Li et al. (WO 2019/051269 A1, international filing date 07 September 2018, hereinafter Li2) (in IDS) (both references qualify as 35. U.S.C. 102(a)(2) prior art).
Regarding instant claim 54, Gallatin teaches compounds that act as ENPP-1 inhibitors (Abstract; Para. [0111]). Gallatin teaches the exemplary compound, compound 161 (Para. [0314], Table 1, Pg. 94), shown below.
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Compound 161 overlaps the scope of instant claim 54, having a structure of Formula (Ib) wherein
R1 is hydrogen;
R4, R5 and R6 are each independently hydrogen or alkoxy (methoxy);
Z is NH;
alk is alkylene (methylene);
Ar is aryl (phenyl);
R2 and R3 are each hydrogen.
Compound 161 differs in the Q being a -SO2OH versus a -P(O)(OH)2 or -B(OH)2, as instantly claimed.
Li2 teaches compounds that are inhibitors of ENPP1 (Abstract; Para. [0069]). Li2 teaches the ENPP1 inhibitor compounds of formula (I), with variables as defined contain a hydrophilic head group (Para. [0073]).
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Li2 teaches the hydrophilic head group imparts improved water solubility and reduced cell permeability upon the molecule to which it is attached (Para. [0075). Li2 teaches that the hydrophilic head group can be selected to provide the desired permeability of the subject compound (Para. [0075). Li2 teaches various hydrophilic head groups selected from phosphonic acid or phosphonate, phosphonate ester, sulfonate, sulfonic acid, carboxylic acid, etc. (Para. [0076]). Li2 teaches particular examples of hydrophilic head groups, such as, phosphonates (RPO3H-), boric acid (RBO2H2), sulfonates (RSO3-), etc. (Para. [0077]). Li2 teaches embodiments wherein the hydrophilic head group is
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(Para. [00137],
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(Para. [00137]) or
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(Para. [0230]) (this embodiment includes an ethylene linker attached to the sulfonic acid hydrophilic head group).
Li2 teaches the following exemplary compounds with the highlighted hydrophilic head groups.
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Gallatin and Li2 to have substituted the sulfonic acid group (-SO2OH) of Gallatin with a phosphonic acid (-P(O)(OH)2) or a boronic acid (-B(OH)2), as taught by Li2 to arrive at the compounds of instant claim 54 with a reasonable expectation of success that they would act as inhibitors of ENPP1.
Gallatin teaches compounds that act as ENPP-1 inhibitors. Gallatin teaches the exemplary compound, compound 161. Compound 161 substantially overlaps the scope of instant claim 54, having a structure of Formula (Ib). Compound 161 differs in the Q being a -SO2OH versus a -P(O)(OH)2 or -B(OH)2, as instantly claimed. Li2 teaches compounds that are inhibitors of ENPP1. Li2 teaches the compounds contain a hydrophilic head group that imparts improved water solubility and reduced cell permeability upon the molecule to which it is attached. Li2 teaches that the hydrophilic head group can be selected to provide the desired permeability of the subject compound. Li2 teaches various hydrophilic head groups selected from groups that include phosphonic acid or phosphonate, phosphonate ester, sulfonate, sulfonic acid. Li2 teaches particular examples of hydrophilic head groups, such as, phosphonates (RPO3H-), boric acid (RBO2H2), sulfonates (RSO3-). Li2 teaches embodiments wherein the hydrophilic head group is
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,
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, or
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.
According to MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the -P(O)(OH)2, -B(OH)2 and -SO2OH groups, all serve as hydrophilic head groups and are therefore, considered equivalents.
Therefore, one of ordinary skill in the art would have been motivated to substitute the sulfonic acid hydrophilic head group of compound 161 of Gallatin with a -P(O)(OH)2 or -B(OH)2 hydrophilic head group to arrive at the compounds of instant invention, with a reasonable expectation of success. The motivation being to provide the desired water solubility and permeability of the subject compound (Li2, Para. [0075]).
The substitution of the sulfonic acid hydrophilic head group of compound 161 of Gallatin with a -P(O)(OH)2 as taught by Li2, will result in the following compound (which reads on the fourth compound of instant claim 72).
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This renders the limitations of instant claims 55, 57 and 59, 62-72, prima facie obvious.
Regarding instant claim 73, the teachings of Gallatin in view of Li2 render obvious the compound having a structure of Formula (Ib) prima facie obvious. Gallatin teaches a pharmaceutical composition comprising a compound disclosed in Gallatin and a pharmaceutically acceptable excipient (Para. [0010]; Paras. [0331]-[0332]).
Miscellaneous
In an effort to provide compact prosecution, while the species election is being maintained, the examiner would like to bring the Applicant’s attention to the following additional species of Gallatin that render obvious the compounds of formula (Ic) as in instant claim 54 in view of Li2.
It is noted that the reference to compounds 179 and 234 of previous record are withdrawn in consideration of Applicant’s arguments.
Gallatin teaches the exemplary compound 332 (Para. [0314], Table 1, Pg. 107), shown below.
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Compound 332 overlaps the scope of instant claim 54, having a structure of Formula (Ic) wherein
R1 is hydrogen;
R4, R5 and R6 are each independently hydrogen or alkoxy (methoxy);
Z is NH;
alk1 is alkylene (methylene);
Ar is aryl (phenyl);
R2 and R3 are each hydrogen.
Compound 332 differs in the Q being -COOH versus a -P(O)(OH)2 or -B(OH)2, as instantly claimed.
In view of the teachings of Li2 discussed above and applying the same reasoning as applied to compound 161, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Gallatin and Li2 to have substituted the -COOH group of compound 332 of Gallatin with a phosphonic acid (-P(O)(OH)2) or a boronic acid (-B(OH)2), as taught by Li2 to arrive at the compounds of instant claim 54 with a reasonable expectation of success that they would act as inhibitors of ENPP1.
Response to Arguments
Applicants argue on pages 8-11 of the response dated 10/16/2025, that “Because there is a desire to obtain highly active compounds, one of ordinary skill in the art would not select a compound with the lowest activity as a lead compound”. Applicants direct attention to example 4 of MPEP 2143(I)(E) and examples 9 and 11 of MPEP 2143(I)(B) alleging that the Office has not provided sufficient motivation to select compounds 161 and 332 of Gallatin and thus have not established a prima facie case of obviousness in combining it with the teachings of Li2 to arrive at the compounds of the instant invention.
Applicant's arguments have been fully considered but they are not persuasive.
Regarding the Takeda case of example 4 of MPEP 2143(I)(E), which concerns pioglitazone, a two-step modification - involving homologation and ring-walking - of the lead compound identified as "compound b" was needed to produce the compound of interest, pioglitazone. “Compound b”, the closest prior art of interest, a thiazolidinedione compound (TZD) exhibited some negative properties that would have directed one of ordinary skill in the art away from that compound. Therefore, the Federal Circuit found that the claimed invention was not obvious in view of the prior art using the obvious-to-try rationale.
According to MPEP 2123 (II), “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”.
In the instant case, contrary to the lead compound in the Takeda case, the quinazoline compounds of Gallatin, namely, compound 161 and compound 332 are taught to have ENPP-1 inhibitory activity (same activity as the instant compounds) with close-structural-similarity to the instant compounds, differing only in the Q moiety attached to the quinazoline derivative – i.e., requiring a one-step modification (Q being a -SO2OH or -COOH versus a -P(O)(OH)2 or -B(OH)2 of the instant claims). Additionally, Gallatin does not in any way discredit the use of these compounds as inhibitors of ENPP-1 activity – no teaching away. Therefore, Gallatin provides sufficient motivation to select compounds 161 and 332 as lead compounds for further modification. Moreover, the rejection of the instant claims over Gallatin in view of Li2 does not use an obvious-to-try rationale. Thus, the ruling in the Takeda case is not applicable to the instant obviousness rejection.
Regarding the Eisai case of example 9 of MPEP 2143(I)(B), which concerns the pharmaceutical compound rabeprazole, the prior art compound lansoprazole was useful for the same indications as rabeprazole, and differed from rabeprazole only in that lansoprazole has a trifluoroethoxy substituent at the 4-position of the pyridine ring, while rabeprazole has a methoxypropoxy substituent. The conversion of the trifluoroethoxy to a methoxypropoxy substituent is not a one-step modification, unlike the modification of compounds 161 and 332 of Gallatin to arrive at the compounds of the instant invention. Moreover, the trifluoro substituent of lansoprazole was taught to be a beneficial feature since it conferred lipophilicity to the compound and thus the proposed modification would have destroyed an advantageous property of the prior art compound. So, the summary judgment of nonobviousness of such a modification by both the Federal circuit and district court, is not applicable to the instant case. The 103 rejection and the discussion above, make it clear that the teachings of the prior art, Gallatin and Li2, render obvious the substitution of a -SO2OH or -COOH with a -P(O)(OH)2 or -B(OH)2 to arrive at the compounds of the instant invention with a reasonable expectation of success.
Additionally, quoting from the Eisai case, “The Federal Circuit in Eisai makes it clear that from the perspective of the law of obviousness, any known compound might possibly serve as a lead compound …Office personnel might also base an obviousness rejection on a known compound that pharmaceutical chemists would not select as a lead compound due to expense, handling issues, or other business considerations”. Thus, the Eisai case makes it clear that contrary to Applicant’s contention in pages 9-10 of their remarks dated 10/16/2025 that “… one of ordinary skill in the art (i.e., a medical chemist), would select a compound with promising activity in Gallatin over examples 161 and 332, for lead optimization. … Applicant respectfully submits that a compound having high potency would be chosen as the lead compound over examples 161 and 332”, for the purpose of an obviousness rejection, a compound with lower activity may be chosen as a lead compound.
Regarding the Altana case of example 11 of MPEP 2143(I)(B), which concerns the compound pantoprazole, a proton pump inhibitor. Quoting from the Altana case, “Altana’s patent discussed a compound referred to as compound 12, which was one of eighteen compounds disclosed … compound 12 was disclosed as one of the more potent of the eighteen compounds disclosed … and experts had opined that one of ordinary skill in the art would have selected the eighteen compounds to pursue further investigation into their potential as proton pump inhibitors”. Again, contrary to Applicant’s contention that a compound having higher potency would be chosen as the lead compound by one of ordinary skill in the art, the Altana case makes it clear that less potent compounds may be chosen as the lead compounds as well. Moreover, the Altana case states that “Obviousness of a chemical compound in view of its structural similarity to a prior art compound may be shown by identifying some line of reasoning that would have led one of ordinary skill in the art to select and modify the prior art compound in a particular way to produce the claimed compound. The necessary line of reasoning can be drawn from any number of sources and need not necessarily be explicitly found in the prior art of record”.
Additionally, according to MPEP 2144 (I), “The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings)”.
In the instant case, the quinazoline compounds of Gallatin, namely, compound 161 and compound 332 are taught to have ENPP-1 inhibitory activity with close-structural-similarity to the instant compounds, differing only in the Q moiety attached to the quinazoline derivative. Irrespective of the fact that they are reported to have an activity of “C” in the ENPP1 inhibition assay (i.e., a lower activity), Gallatin establishes that both compound 161 and compound 332 are hit compounds that exhibited activity against the target of interest, i.e., ENPP-1 inhibitory activity (Abstract; Para. [0111]). This is essentially the same utility/activity as the compounds of the instant invention (see Para. [0004] of the instant specification). Based on the discussion above, a compound with lower activity/potency, could be chosen as a lead compound for further modification. Compound 161 and compound 332, with the closest-structural-similarity and similar utility to the instant compounds have been exemplified by Gallatin and are considered good candidates for further optimization. Thus, there is enough motivation/incentive for a person of ordinary skill in the art at the time the application was effectively filed, to further explore compound 161 and compound 332 of Gallatin as promising therapeutic candidates that act as ENPP-1 inhibiting agents.
Finally, contrary to Applicant’s contention that there is no motivation to select the specific compounds, compound 161 and compound 332 of Gallatin from among the 400+ compounds listed in Table 1 of Gallatin, it is noted that selecting a single lead compound from a pool of 400 potential candidates is not considered a particularly tough choice in the context of typical drug discovery processes - in fact, it is a relatively standard and manageable number of compounds to screen.
Therefore, the examiner asserts that the lead compound analysis has been applied appropriately in the obviousness rejection.
Applicants argue on pages 12-13 of the response dated 10/16/2025, that “Because Li2 does not attribute any improved solubility to compounds with phosphonate groups or boronic acid groups over compounds with sulfonic acid groups or carboxylic acid groups, there is no motivation to make this modification”.
Applicant's arguments have been fully considered but they are not persuasive.
Regarding Applicant’s contention that there is no motivation to make said modification, it has been established that compounds 161 and 332 can serve as lead compounds despite their lower activity level of “C” (see discussion above). MPEP 2144.08 (II)(A)(4)(d) states that “Consider the properties and utilities of the structurally similar prior art species or subgenus. It is the properties and utilities that provide real world motivation for a person of ordinary skill to make species structurally similar to those in the prior art. Dillon, 919 F.2d at 697, 16 USPQ2d at 1905; In re Stemniski, 444 F.2d 581, 586, 170 USPQ 343, 348 (CCPA 1971).”
In the instant case, the close-structural-similarity of the compounds of Gallatin in relation to the instant compounds, in combination with their ENPP-1 inhibitory activity provide real world motivation for a person of ordinary skill to make species structurally similar to those in the prior art, to arrive at the compounds of the instant invention, in view of the teachings of Li2.
Moreover, regarding Applicant’s argument that “The Office, however, does not identify a reasonable expectation how the skilled artisan could expect to retain the activity level of examples 161 and 332 when exchanging a sulfonic acid group or a carboxylic acid group with a phosphonate group or a boronic acid group”, it must be recognized that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The examiner emphasizes that a determination of obviousness based on teachings from multiple references does not require an actual substitution, say, substitution of a sulfonic acid group or a carboxylic acid group with a phosphonate group or a boronic acid group, to render such a substitution, prima facie obvious. Li2 teaches the sulfonic acid group, carboxylic acid group, phosphonate group and boronic acid group, as hydrophilic head groups that impact the solubility/permeability characteristics of the compounds (from among a small list of about 15 hydrophilic head groups). The compounds of Li2 have structural similarity to the instant compounds and are taught to be inhibitors of ENPP-1. Therefore, a person of ordinary skill in the art would be motivated to substitute the hydrophilic head groups of compound 161 and 332 of Gallatin, as taught by Li2, to arrive at the instant compounds with a reasonable expectation of success.
According to MPEP 2145 (IV), “One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually”. The 103 rejection outlined above clearly articulates the rationale behind combining the teachings of Gallatin and Li2 to arrive at the compounds of the instant invention. Therefore, the said modification, i.e., substituting the hydrophilic head group, -S(O)2OH of Gallatin’s compound 161 OR the hydrophilic head group, -COOH of Gallatin’s compound 332, with the hydrophilic head groups taught by Li2, -P(O)(OH)2 or -B(OH)2 to obtain the instantly claimed compounds is prima facie obvious to a skilled artisan, in the absence of evidence to the contrary.
Applicants have not demonstrated that the claimed compounds exhibit properties that are unexpectedly better than what one would expect from the prior art. Therefore, the examiner asserts that the choice of the lead compound to arrive at the instantly claimed compounds, as outlined in the 103 rejection over Gallatin and Li2 is proper. As such, for the reasons of record, the 35 U.S.C. 103 rejections are maintained.
Applicants are encouraged to provide a clear and convincing evidence of nonobviousness or unexpected results to overcome the 35 U.S.C. 103 rejection of record.
Allowable Subject Matter
The elected species was found to be free of prior art.
Conclusion
Claims 54-55, 57, 59 and 62-73 are rejected.
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached on 9:00-5:30pm EDT.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.S.R./
Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627