DETAILED ACTION
This office action is in response to applicant’s filing dated June 16, 2026.
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 1-3, 5-7, 9, 10, 12, 16-18, 22, 30, 31, 36, 40-42, and 44 are pending in the instant application. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on June 16, 2026 are acknowledged. Claims 5 - 7, 9, 10, 12, 16, 17, 31, 36 and 44 remain withdrawn, as being drawn to an unelected invention or species. Acknowledgement is made of Applicant's amendment of claims 1 and 40.
Claims 1 – 3, 18, 22, 30 and 40 – 42 are under consideration in the instant office action.
Drawings
Acknowledgement is made of the corrected substitute drawings received on June 16, 2026. These drawings are accepted. Therefore, drawing objection is withdrawn.
Objections and/or Rejections and Response to Arguments
Applicants' arguments, filed on June 16, 2026, have been fully considered.
Acknowledgement is made of the Applicant’s amendment of claim 1 by removing indefinite terms “such as” and “preferably”.
Accordingly, the rejection of claim 1 under 35 U.S.C. 112(b) as being indefinite is withdrawn.
Acknowledgement is made of the Applicant’s arguments about structures of exemplary compounds recited in claim 41 and their biological activity (Remarks, page 12). The arguments are found persuasive.
Accordingly, the rejection of claim 41 under 35 U.S.C. 103 as being unpatentable over Kalleda and Galvão is withdrawn.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Objections
Claim 41 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 3, 18, 22, 30 and 40 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Kalleda et al (WO 2006/034473 A2, hereinafter Kalleda) in view of Galvão et al (J. Phys. Chem. A 2013, 117, 12668−12674, hereinafter Galvão).
Regarding claims 1 – 3, 22, 30 and 40 and 42, drawn to a method of treating, preventing or reducing neuropathic pain in a patient, comprising administering a formulation, comprising compounds of Formula I
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, such as compound of Formula Ia
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, having a structure
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, where X and Y is carbon, Z is nitrogen and R3 is absent. According to the description above, compound of Formula Ia has a structure of substituted 3H‐pyrimidin‐4‐one:
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, where R1 is hydrogen, R2 is unsubstituted or substituted aryl or heteroaryl or R2 is NR5R6, where R5 and R6 are independently a hydrogen, wherein at least one of R5 and R6 is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R4 is substituted aryl or substituted heteroaryl. Instant claims are further drawn to a compound, having a structure according to Formula I, such as to Formula Ia and a formulation comprising compound of Formula Ia and a pharmaceutically acceptable carrier.
Kalleda teaches substituted pyrimidine compounds and pharmaceutical compositions thereof, where the composition comprises substituted pyrimidine compounds and a pharmaceutically acceptable carrier (page 181, lines 15 – 17). Kalleda further teaches a method of treating a condition or disease state mediated by the low expression of Perlecan, such us a neuritis or multiple sclerosis (page 158, line 15 and 159, line 25), comprising administering an amount of at least one of said compound, effective to induce Perlecan expression (page 135, lines 17 – 19). Effective amounts are administered to humans and animals in dosages that are safe and effective (page 160, lines 27 – 29). The substituted pyrimidine compounds taught by Kalleda have a structure such as (II-H1):
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, where R1 is substituted or unsubstituted aryl or substituted/unsubstituted heteroaryl, where heteroaryl comprises at least one heteroatom selected from N, O, S; R2 is hydroxyl; R4 is substituted or unsubstituted alkyl, aryl, heterocyclyl, heteroaryl, where heteroaryl or heterocyclyl comprises at least one heteroatom selected from N, O, S; when R1 or R4 is substituted, the substituents are selected from alkyl, alkoxy (e.g. -OMe), -NR102 (R10 is hydrogen), (page 48, lines 1 – 25 and page 49, lines 1 – 3). Kalleda further teaches compounds of formula (II-G2i):
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, where R4 is hydroxy; R11 and R12 is alkyl, alkoxy, halogen; n and m is 0 to 3. Compounds of formula (II-G2i) taught by Kalleda satisfy the structure of compound of formula Ia of instant claims, where variables R4, R11 and R12 as described above. Kalleda also teaches compound of formula
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, where A, B and C variables are given in Table 3 (page 144 – 146), which structures satisfy the instantly claimed compounds encompassed by formula Ia.
Although compounds of Kalleda are drawn in the hydroxy form of pyrimidine ring and compounds of instant claims are drawn in the keto form, the compounds of instant claims and compounds of Kalleda have the same core structure, since it is well known that 4-hydroxypyrimidine and 4(3H)-pyrimidinone are two tautomeric forms, existing in keto−enol tautomeric equilibrium as shown in the reference of Galvão:
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(page 12668, Fig. 1). Thus, compound of Formula Ia of instant claims can be redrawn in its enol form as:
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.
Regarding limitations of claim 18, drawn to a method where the effective amount is sufficient to inhibit phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) compared to a control that does not contain the compound of Formula I, as determined by an in-cell Western assay that detects inhibition of VEGFR2 activation, The prior art is silent regarding "inhibition of phosphorylation of (VEGFR2)". However: " inhibition of phosphorylation of (VEGFR2) " will naturally flow from the teachings of (or method made obvious by) the prior art (see above rejection), since the same compound (compound of formula (II-H1) is being administered to the same subjects (subjects suffering from neuritis). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding " inhibition phosphorylation of (VEGFR2)", by practicing the method made obvious by the prior art: "the administration of an effective amount of compound of formula (II-H1) to a patient suffering from neuritis", one will also be "inhibiting phosphorylation of (VEGFR2) ", even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage ("inhibition of phosphorylation of (VEGFR2)" of the method made obvious by the prior art ("the administration of an effective amount of compound of formula (II-H1) to a patient suffering from neuritis").
MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Thus, since Kalleda teaches compounds, which compounds have the same core and all the structural elements as instantly claimed compounds, and where the compounds taught by Kalleda are useful for the same method (method of treating neuritis), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to modify teachings of prior art and make various known compounds useful for the same method, to arrive at claimed compounds. The one of ordinary skills would be motivated to do so in search of an active agent with improved desired properties to treat neuritis with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- The combination of Kalleda and Galvão does not describe the claimed method with sufficient specificity, as broad and general disclosures cannot serve as a basis for concluding that those disclosures render obvious the specific selection of features in a claimed subject matter. See In re Kubin, 561 F.3d at 1359-60; accord Leo Pharmaceutical Prod. V. Rea, No. 2012-1520, slip op. at 17-18 (Fed. Cir. August 12, 2013); Cyclobenzaprine, 676 F.3d at 1070 (Fed. Cir. 2012).
- Kalleda describes the following structure for treating a variety of diseases and disease states:
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. The definitions of R1, R2, and R4 within Formula II-H1 are open-ended and encompass a vast, effectively uncountable number of compounds. Thus, one of ordinary skills in the art would not be led to the specified form and structural features of claim 1 in view of the broad disclosure of Formula II-H1 of Kalleda. A skilled artisan turning to Kalleda is confronted with (i) a myriad of structural features and forms from which to select (Kalleda, entire disclosure), and (ii) a multitude of diseases and disease states (Kalleda, page 158, line 7, until page 160, line 2) with no guidance as to which one(s) of these compounds and forms will be useful for treating neuropathic pain.
- Kalleda provides no guidance as to which tautomer of Formula II-H1 should be selected. Kalleda broadly discloses compounds of Formula II-H1, as well as salts thereof, including pharmaceutically acceptable and non-pharmaceutically acceptable salts, prodrugs, diastereomeric mixtures, enantiomers, tautomers, and racemic mixtures. However, Kalleda provides no meaningful guidance for selecting a tautomer in preference to a salt, prodrug, diastereomer, enantiomer, or racemic form, nor does it provide any direction for selecting a particular tautomer of Formula II-H1. Keto and enol forms are constitutional isomers (tautomers) that rapidly interconvert, yet display distinct chemical behavior: the keto form typically functions as an electrophile, whereas the enol form behaves as a nucleophile, reflecting fundamentally different reactivity profiles arising directly from their structural differences.
- Kalleda fails to provide the necessary specificity to direct a person of ordinary skill in the art toward the presently claimed compounds. Applicant refers to Ruiz V. A.B. Chance Co., 357 F.3d 1270 (Fed. Cir. 2004) that cautioned that a claimed subject matter must be considered "as a whole”.
- Galvão does not cure the deficiencies of Kalleda. Galvão characterizes keto-enol equilibrium behavior in the gas phase. The experiments conducted in the gaseous-phase and the associated equilibrium behavior cannot be directly applied to compounds in all states of matter, particularly condensed phases or biological environments. It is well understood that tautomeric equilibria are highly sensitive to environmental factors, including solvent polarity, hydrogen bonding, pH, and protein or receptor binding interactions. These factors can significantly shift both the position of equilibrium and the dominant tautomeric form. Accordingly, conclusions drawn from gas-phase studies do not reliably predict the predominant tautomer under biologically relevant conditions, where solvation and microenvironmental effects can stabilize one form over another.
- Further, Kalleda and Galvão disclose a very broad genus of compounds and fail to provide any information about what structural features are needed to obtain compounds that interfere with the NRP-1/VEGF-A signaling pathway and thereby treat, prevent, or reduce neuropathic pain.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, instant claims are extremely broad regarding the scope of
genus Formula I:
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, which encompasses any 6-membered cyclic compound, including cyclohexane and benzene. Instant formula Ia (
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) is also very broad regarding position of the second nitrogen atom (variables X, Y and Z) in the cycle as well as variety of structures of variables R2 and R4. One of the possible structures encompassed by instant formula Ia is
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(or its enol form
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). Kalleda teaches compound of formula (II-H1):
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, such as compounds of formula (II-G2i):
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. The core structure and the respective substituents disclosed in Kalleda are equivalent to those defined in the description of the instant genus Formula Ia. Thus, compounds disclosed in Kalleda are structurally similar to the instantly claimed compounds, thereby rendering the claimed compounds obvious to one of ordinary skill in the art. The person of ordinary skills would have been motivated to modify prior art teachings, to make various structural analogs by selecting and combining known elements. Such a modification would be driven by a reasonable expectation of success that the resulting compounds would possess similar or improved chemical and biological properties. As states in MPEP 2143.I(B): “structural similarity can provide the necessary reason to modify prior art teachings. The Federal Circuit also addressed the kind of teaching that would be sufficient in the absence of an explicitly stated prior art-based motivation, explaining that an expectation of similar properties in light of the prior art can be sufficient, even without an explicit teaching that the compound will have a particular utility”.
Furthermore, compounds disclosed in Kalleda are useful to treat relevant conditions (e.g. neuritis). Although Kalleda discloses multiple conditions to be treated with compounds shown above, a positive recitation cannot be seen as a negative teaching merely because there are additional utilities. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123 states: "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
Regarding the argument about the selection of a particular tautomer is not persuasive, because if the compound exists in two tautomeric forms (keto-enol tautomeric forms for the claimed compounds), the disclosed compounds encompass all tautomeric forms, as keto and enol tautomers always exist in dynamic equilibrium, where C=O group and C-OH group easily interconvert by tautomeric proton transfer. Although it is possible to make one of the forms (keto or enol) predominant by varying conditions (e.g. solvent, pH etc.), it is not possible to isolate one particular tautomer under standard conditions. This dynamic interconversion is inherent to the definition of keto-enol tautomerism and represents a foundational principle of organic chemistry. Thus, reference to one tautomeric form encompasses the equilibrium mixture thereof (Keto-Enol Tautomerism: Definition, Examples, and Mechanism). The reference of Galvão is cited for illustrative purposes, to show keto−enol tautomeric equilibrium between 4-hydroxypyrimidine and 4(3H)-pyrimidinone, since according to the reasonings set forth above, keto−enol tautomeric equilibrium always exists under standard conditions, and not limited to a gaseous phase.
Regarding the argument that Kalleda fails to provide any information about structural features of compounds that interfere with the NRP-1/VEGF-A signaling pathway, it is not persuasive because as set forth above, Kalleda teaches compounds of similar structure, thus, all necessary properties are inherently present, because compounds of identical or similar composition cannot exert mutually exclusive properties (see also MPEP 2112.01).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 1 – 3, 18, 22, 30, 40 and 42 as obvious over teachings of Kalleda and Galvão is maintained.
Conclusion
Claims 1 – 3, 18, 22, 30, 40 and 42 are rejected. Claim 41 is objected to.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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