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
Claims 20 and 21 are withdrawn from consideration as being directed to a non-elected invention for the reasons set forth in the CTNF of 11/3/2025.
Status of Claims
Cancelled: 9
Withdrawn: 20 and 21
Examined Herein: 8, 10-19
Priority
Priority to CN201910007703.X filed on 1/4/2019 and PCT/CN2020/070009 filed on 1/2/2020 is
acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/22/2021 and 1/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings filed on 4/22/2021 are accepted.
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 8 and 10-19 are rejected under 35 U.S.C. 103 as being unpatentable over Kung (US 2006/0269474 A1, Published 11/30/2006), in view of Brown (Bioisosteres in Medicinal Chemistry, 2012, First Edition, Wiley-VCH Verlag GmbH & Co. KGaA).
With respect to claim 8, 11, 14, 17, and 18, Kung discloses the following compounds, which are specific embodiments of the compound of Formula I. [Kung, 0025-0036]
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[Structures drawn by the Examiner using CAS Draw based on specific embodiments of Formula I described by Kung in Paragraph 0025-0036]
With respect to claim 10, 12, 13, 15, 16, 18, and 19, Kung discloses the aforementioned compounds also includes pharmaceutically acceptable salts thereof. [Kung, 0025]
Kung does not disclose instant compound 87-92.
However, with respect to claim 8, Brown discloses N and CH are isosteres based on Grimm’s hydride displacement law. [Brown, Page 16, Table 2.2] Grimm’s hydride displacement law states the addition of hydrogen to an atom produces a pseudoatom with similar physical properties as those present in the column immediately behind in the periodic table. [Brown, Page 15, Paragraph 3 and Page 5, Paragraph 2-3] Brown also discloses -CH= and -N= are bioisosteres. [Brown, Page 7, Table 1.3]
Modifying the compound disclosed by Kung by replacing one or more of the CH groups of the -CH=CH-CH=CH- moiety with N, results in instant compound 87-92 of claim 8 and 10-19.
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[Structures drawn by the Examiner using CAS Draw based on specific embodiments of Formula I described by Kung in Paragraph 0025-0036, in view of the teachings of Brown]
It would be obvious to one of ordinary skill in the art to modify the compounds disclosed by Kung by replacing one or more of the CH groups of the -CH=CH-CH=CH- moiety with N and have a reasonable expectation of success. Kung discloses several embodiments of a compound of Formula I, each comprising a -CH=CH-CH=CH- core. Brown discloses N and CH are isosteres based on Grimm’s hydride displacement law, which states the addition of hydrogen to an atom produces a pseudoatom with similar physical properties as those present in the column immediately behind in the periodic table. So, Kung discloses compounds each comprising a -CH=CH-CH=CH- core and Brown discloses CH is a pseudoatom of N and has similar physical properties. Thus, the combined teachings of Kung and Brown suggest that replacing one or more of the CH groups in the -CH=CH-CH=CH- moiety with N results in a moiety with similar physical properties. Therefore, it is reasonable to expect the compounds disclosed by Kung may be modified by replacing one or more of the CH groups of the -CH=CH-CH=CH- moiety with N. One would have been motivated to do so because it is prima facie obvious to combine teachings when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the instant case, Kung discloses the compounds of Formula I are pharmaceutical compounds that inhibit the aggregation of amyloid proteins to form amyloid deposits. [Kung, 0019, 0021] Brown discloses the discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity. [Brown, Page 15, Paragraph 1] Therefore, one would have been motivated by the expectation that the aforementioned modification could improve some of the properties, such as pharmacological activity, selectivity, and pharmacokinetics of the pharmaceutical compounds disclosed by Kung.
With respect to claim 8 and 10-19, the limitations, “a dihydrazone compound having high affinity to Aβ protein and Tau protein,” "a diagnostic or detecting reagent for
neurodegenerative diseases caused by Aß protein or Tau protein deposition" and "a nuclear medicine
imaging agent, optical imaging agent or staining agent", recite an intended use. The body of
the claims, “…wherein the compound is selected from… compounds 87-94,” "...wherein an active ingredient is the compound of claim 8," and "...a compound according to claim 8," fully and intrinsically sets forth all of the limitations of the claimed invention, which are the compounds 87-94 or a pharmaceutically acceptable salt or ester thereof. Thus, the preamble merely states the purpose or intended use of the invention and does not state any distinct definition of any of the claimed invention's limitations. As a result, the preamble is not considered a limitation and is of no significance to claim construction. MPEР 2111.02. Since the structural limitations of claim 8, 10, and 12 have been met over Kung and Brown, the limitations of claim 8 and 10-19 have also been met.
Claims 8, 11, 14, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Al-Karawi (From mesogens to metallomesogens. Synthesis, characterisation, liquid crystal and luminescent properties, 2017, Liquid Crystals, 44:14-15, 2285-2300), in view of Brown.
With respect to claim 8, 11, 14, 17, and 18, Al-Karawi discloses the following compound
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[Al-Karawi, Page 2288, Scheme 1]
Wherein,
R and R1 are independently CnH2n+1, n=1-10.
So, in the embodiment where R is CnH2n+1, n=1 and R1 is CnH2n+1, n=3, the resulting compound is depicted below.
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[Structures drawn by the Examiner using CAS Draw based on a specific embodiment of the compound described by Al-Karawi in Scheme 1]
Al-Karawi does not disclose instant compound 87.
However, with respect to claim 8, 11, 14, 17, and 18, Brown discloses N and CH are isosteres based on Grimm’s hydride displacement law. [Brown, Page 16, Table 2.2] Grimm’s hydride displacement law states the addition of hydrogen to an atom produces a pseudoatom with similar physical properties as those present in the column immediately behind in the periodic table. [Brown, Page 15, Paragraph 3 and Page 5, Paragraph 2-3] Brown also discloses-CH= and -N= are bioisosteres. [Brown, Page 7, Table 1.3]
Modifying the compound disclosed by Al-Karawi by replacing the O atom of the -CH3-O moiety with NH and the CH3 group of the -O-CH2-CH2-CH3 moiety with F, results in instant compound 88.
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[Structures drawn by the Examiner using CAS Draw based on a specific embodiment of the compound described by Al-Karawi in Scheme 1, in view of the teachings of Brown]
It would be obvious to one of ordinary skill in the art to modify the compound disclosed by Al-Karawi by replacing the O atom of the -CH3-O- moiety with -NH and the -H3 group of the -O-CH2-CH2-CH3- moiety with -F and have a reasonable expectation of success. Al-Karawi discloses a compound that comprises a -CH3-O- moiety and a -O-CH2-CH2-CH3 moiety. Brown discloses O and -H and CH3 and F are isosteres based on Grimm’s hydride displacement law, which states the addition of hydrogen to an atom produces a pseudoatom with similar physical properties as those present in the column immediately behind in the periodic table. So, Al-Karawi discloses a compound that comprises a -CH3-O- moiety and a -O-CH2-CH2-CH3 moiety and Brown discloses O and CH3 are pseudoatoms of -NH and -F, respectively, and have similar physical properties. Thus, the combined teachings of Al-Karawi and Brown suggest that replacing one or more of the O and CH3 atoms in the compound disclosed by Al-Karawi with NH and F atoms, respectively, results in a compound with the same physical properties. Therefore, it is reasonable to expect the compound disclosed by Al-Karawi may be modified by replacing the O atom of the -CH3-O- moiety with NH and the CH3 group of the -O-CH2-CH2-CH3 moiety with F. One would have been motivated to do so because it is prima facie obvious to combine teachings when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the instant case, Al-Karawi discloses the compound is an azine type compound, which constitutes an important class of compounds with pharmacological and biological activities; specifically, as anticonvulsant, antidepressant, anti-inflammatory, antiviral or antitumor agents. The specific role of azine compounds as binding molecules of biological receptors makes them suitable candidates for drug development. [Al-Karawi, Page 2286, Col. 1, Paragraph 3] Brown discloses the discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity. [Brown, Page 15, Paragraph 1] Therefore, one would have been motivated by the expectation that the aforementioned modification would improve some of the properties, such as pharmacological activity, selectivity, and pharmacokinetics of the bioactive compound disclosed by Al-Karawi.
With respect to claim 8 and 11, 14, 17, and 18, the limitations, “a dihydrazone compound having high affinity to Aβ protein and Tau protein,” "a diagnostic or detecting reagent for
neurodegenerative diseases caused by Aß protein or Tau protein deposition" and "a nuclear medicine
imaging agent, optical imaging agent or staining agent", recite an intended use. The body of
the claims, “…wherein the compound is selected from… compounds 87-94,” "...wherein an active ingredient is the compound of claim 8," and "...a compound according to claim 8," fully and intrinsically sets forth all of the limitations of the claimed invention, which are the compounds 87-94 or a pharmaceutically acceptable salt or ester thereof. Thus, the preamble merely states the purpose or intended use of the invention and does not state any distinct definition of any of the claimed invention's limitations. As a result, the preamble is not considered a limitation and is of no significance to claim construction. MPEР 2111.02 Therefore, since the structural limitations of claim 8, have been met over Al-Karawi and Brown, the limitations of claim 8 and 11, 14, 17, and 18 have also been met.
Response to Arguments
Applicant’s arguments, filed 2/3/2026, with respect to the rejection of claims 8 and 10-19 under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant asserts the following:
“The theory of isosteres is preliminary and theoretical, isosteres cannot be directly equated with bioisosteres, let alone with similar biological activities between isosteres… The Applicant believes that the theory of isosteres is preliminary and theoretical and cannot be directly equated with bioisosteres. The teaching of Brown, based on Grimm's hydride displacement law, indicates that N and CH are isosteres, meaning they are similar in electron configuration and certain physical properties (e.g., volume, polarity). However, the theory of isosteres primarily concerns the physical properties of atoms or groups (e.g., electron distribution, electronegativity, bond length). In fact, similarity in physical properties does not equate to identical biochemical properties… Therefore, this does not guarantee similar biological activity. Bioisosteres requires that the substituted compound maintains or enhances activity within a biological system. This involves complex pharmacodynamic, pharmacokinetic, and toxicity parameters that cannot be predicted by the theory of isosteres. In other words, although isosteres may have similar electron configurations, their behavior in biological systems can be unpredictable.” [Remarks 2/3/2026, Page 9]
According to MPEP § 2141, obviousness must be based on a reasonable expectation of success provided by the prior art, not on theoretical possibility or mere "obvious to try." This means that if the prior art does not provide sufficient guidance or prediction, the replacement or modification may be considered non-obvious. Brown does not provide an expectation of success because its teaching is theoretical. The replacement with isosteres or bioisosteres is often unpredictable, which often yield unpredictable results, including changes in stucture-activity relationships, selectivity, and pharmacokinetic properties. Even with stuctural similarity, successful replacement requires repeated trials. In other words, its success is highly dependent on experimental verification and summarization. Brown's theory does not provide any specific examples of compounds or imaging applications, and Al-Karawi does not suggest any biological imaging uses either. Therefore, the examiner cannot demonstrate that this substitution would have a reasonable expectation of success.” [Remarks 2/3/2026, Page 15, Paragraph 4 – Page 16, Paragraph 1]
Grimm's hydride displacement law, isosterism, and bioisosterism are well recognized scientific principles. Brown explicitly discloses isosterism is a principle.
The organization of this book follows a logical sequence, starting with Part One on the principles of bioisosterism. [Brown, Page XV, Paragraph 2]
The first part of this book covers the historical aspects of bioisosterism, from its founding principles of isosterism. [Brown, Page XVII, Paragraph 3]
In this chapter, the principles of bioisosterism will be considered. [Brown, Page 31, Paragraph 1]
Isosterism and bioisosterism have been very active fields of research, since their principles are directly applicable to structure optimization efforts [Brown, Page 103, Paragraph 1]
To that end, the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle. MPEP 2144.02. Accordingly, the Office’s reliance on the principle of isosterism and bioisosterism is appropriate. Moreover, MPEP 2143.02(I) states that prior art that suggests that compounds would have been expected to have similar activity because the structural difference between them involves a known bioisosteric replacement provides a sufficient basis for a reasonable expectation of success. See also MPEP 2144.09(III).
Moreover, the Office does not equate isosteres with bioisosteres but -CH= and -N= are both isosteres and bioisosteres. [See Brown, Page 7, Table 1.3 & Page 16, Table 2.2]
Furthermore, Brown does not teach that physical properties equate to identical chemical properties or that isosterism guarantees similar biological activity, nor does the instant rejection recite these teachings.
While Applicant asserts that bioisosteric replacement involves complex pharmacodynamic, pharmacokinetic, toxicity parameters, changes in structure-activity relationships, selectivity, pharmacokinetic properties, and repeated trials is indicative of unpredictability, Brown acknowledges the discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity. [Brown, Page 15, Paragraph 1] Accordingly, the factors identified by Applicant do not undermine the reasonable expectation of success established by Kung and Brown. Rather, these considerations are expected during the discovery and development of clinically evaluating a lead compound.
Furthermore, unpredictability does not preclude obviousness. A rejection should not be withdrawn solely on the basis that the invention lies in a technological area ordinarily considered to be unpredictable.” MPEP 2145(E). Applicant appears to assert that because the outcome of bioisosteric replacement may vary, such modification is unpredictable, and therefore no reasonable expectation of success exists. However, obviousness does not require absolute predictability, but rather a reasonable expectation of success in combining or modifying the prior art. A reasonable expectation of success does not require conclusive proof of efficacy. MPEP 2143(I). Consistent with this standard, the cited references need only to support the likelihood of success in modifying the compound disclosed by Kung to yield a bioisosterically modified molecule. The instant rejection does not guarantee improved properties, such as pharmacological activity, selectivity, and pharmacokinetics will be the outcome of the bioisosteric replacement. However, in view of Brown’s teaching that N and CH are bioisosteres and isosteres based on Grimm's hydride displacement law and that isosteres are used to improve properties of clinically evaluated lead compounds, the likelihood of success in modifying Kung is reasonable. The variability of the effect of the modification does not negate the expectation of success, as modulation inherently requires changes in biological properties, rather than uniform outcomes.
With respect to predictability, the relevant inquiry is not whether a POSITA could forecast every possible outcome of the modification, but whether they would reasonably expect that the proposed modification would yield a compound consistent with the prior art’s teachings. Applicant’s arguments rely on generalized assertions of outcome variability but do not explain why the cited references would not support a reasonable expectation that the modification would yield a bioisosterically modified molecule with modulating properties. To that end, a POSITA would have had a reasonable expectation of success in bioisosterically replacing CH with N, in part, because Brown discloses that bioisosteric replacements are a mainstay of medicinal chemistry and routinely used to optimize bioactive compounds. Accordingly, bioisosteric modifications are routinely used to modulate pharmacological properties of biomolecules, even if the precise extent of the effect may vary.
Applicant asserts “Brown provides a general principle but does not disclose any specific compounds or examples directed to imaging applications. It does not teach how to replace the stilbene core (-CH=CH-CH=CH-) with a dihydrazone core (-C=N-N=C-), nor does it suggest that such a replacement would be successful in AP/Tau protein imaging. In fact, Brown emphasizes that the replacement with bioisosteres requires experimental verification, not merely theoretical speculation. The Examiner oversimplifies Brown's teaching, ignoring its theoretical nature.” [Remarks 2/3/2026, Page 10, Paragraph 1]
Grimm's hydride displacement law, isosterism, and bioisosterism are well recognized scientific principles. To that end, the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle. MPEP 2144.02. Accordingly, the Office’s reliance on the principle of isosterism and bioisosterism is appropriate. Moreover, MPEP 2143.02(I) states prior art that suggests that compounds would have been expected to have similar activity because the structural difference between them involves a known bioisosteric replacement provides a sufficient basis for a reasonable expectation of success. See also MPEP 2144.09(III).
While Applicant asserts experimental verification is indicative of unpredictability, Brown discloses the discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity. [Brown, Page 15, Paragraph 1] Accordingly, experimental verification is not indicative of unpredictability. Rather, such verification is an expected part of the discovery and development for clinically evaluated lead compounds.
Applicant asserts the following:
“In fact, the effects of replacement with bioisosteres are influenced by numerous factors, such as the three-dimensional structure of the target protein, the binding mode of the drug to the target, and metabolic pathways. These factors are highly complex and variable in actual biological systems, and it is difficult to predict them based solely on simple similarities in electronic structures. For example, certain isosteric replacements may alter molecular conformation, affect binding affinity to the target, or initiate new metabolic pathways leading to changes in toxicity.” [Remarks 2/3/2026, Page 10, Paragraph 2] “Kung's compounds are based on a stilbene core (C=C double bond), whereas the compounds of the present application are based on a dihydrazone core (-C=N-N=C- bond). Although N and CH are considered similar according to the theory of isosteres, replacing CH groups with N changes the entire molecular structure, as detailed below: Changes of Polarity… Hydrogen Bonding Capacity…Metabolic Stability…” [Remarks 2/3/2026, Page 10, Paragraph 3-6, Page 11, Paragraph 1]
“Replacing the stilbene core with dihydrazone core constitutes a fundamental alteration of the core structure. This alteration is highly likely to cause a significant increase in molecular polarity and a decrease in lipophilicity, thereby disrupting its ability to cross the blood-brain barrier-a prerequisite for a brain PET tracer. In the absence of positive teachings or successful precedents, the risk associated with such a replacement is exceedingly high. Those skilled in the art could not have a reasonable expectation of success, but could only anticipate loss of activity or unpredictable changes.” [Remarks 2/3/2026, Page 11, Paragraph 4 - Page 12, Paragraph 1]
“Brown's isosteres is theoretical and cannot predict biological activity. Based on Grimm's hydride displacement law, Brown discloses O and NH and CH3 and F are isosteres based on Grimm's hydride displacement law, meaning they are similar in physical properties (e.g., volume, electronegativity). However, this applicability is confined to physicochemical comparisons at the atomic or group level and does not guarantee similar biological activity. The chemical and biological effects after replacement with isosteres are unpredictable: O to NH replacement: replacing an O atom with NH may increase hydrogen bond donor capacity and change the molecular polarity, thereby affecting blood-brain barrier penetration or metabolic stability. For instance, the NH group could be susceptible to oxidation or participate in nonspecific binding, reducing imaging specificity. CH3 to F replacement: replacing CH3 with F may increase electronegativity and metabolic stability, but it could also introduce toxicity or change pharmacokinetics (e.g., the fluorine atom might prolong half-life, whereas the present application requires rapid clearance to optimize imaging contrast).” [Remarks 2/3/2026, Page 14, Paragraph 1-3]
Arguments presented by applicant cannot take the place of evidence in the record. An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness. MPEP 2145(I). Merely stating the chemical and biological effects that could occur after replacement with isosteres, is not sufficient to rebut the present prima facie case of obviousness.
Furthermore, unpredictability does not preclude obviousness. A rejection should not be withdrawn solely on the basis that the invention lies in a technological area ordinarily considered to be unpredictable.” MPEP 2145(E). Applicant appears to assert that because the outcome of bioisosteric replacement may vary, such modification is unpredictable, and therefore no reasonable expectation of success exists. However, obviousness does not require absolute predictability. The variability of the resulting effect of modifying the compound disclosed by Kung to yield a bioisosterically modified molecule does not negate the reasonable expectation of success, as modulation inherently requires changes in biological properties rather than uniform outcomes.
With respect to predictability, the relevant inquiry is not whether a POSITA could forecast every possible outcome of the modification, but whether they would reasonably expect that the proposed modification would yield a compound consistent with the prior art’s teachings. Applicant’s arguments rely on generalized assertions of outcome variability but do not explain why the cited references would not support a reasonable expectation that the modification would yield a bioisosterically modified molecule with modulating properties. To that end, one skilled in the art would have had a reasonable expectation of success in bioisosterically replacing CH with N, in part, because Brown discloses that bioisosteric replacements are a mainstay of medicinal chemistry and routinely used to optimize bioactive compounds. Accordingly, bioisosteric modifications are routinely used to modulate pharmacological properties of molecules, even if the precise extent of the effect may vary.
Applicant asserts “The prior art does not provide a motivation to make the specific replacement: "Kung teaches that the stilbene core structure is effective. Brown's theory of isosteres is a fundamental chemical principle explaining atomic properties, it itself provides no motivation to modify a core phannacophore that has been proven effective, nor does it specify which particular carbon atoms within the -CH=CH-CH=CH- tetracarbon chain should be replaced." In fact, when replacing CH groups in "-CH=CH-CH=CH-" with N, there are many substitution modes, such as monosubstitution, disubstitution, trisubstitution, and tetrasubstitution. For disubstitution, there are at least six different disubstitution modes. The compounds produced by these different substitutions are distinct in structure, electronic properties, and conformation. There is no evidence indicating that those skill in the art would be motivated to specifically select the two central carbon atoms of"-CH=CH-CH=CH-" to form the dihydrazone core (-C=N-N=C-) claimed in the present application, as opposed to the many other possibilities.” [Remarks 2/3/2026, Page 11, Paragraph 2-3]
Grimm's hydride displacement law, isosterism, and bioisosterism are well recognized scientific principles. To that end, the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle. MPEP 2144.02. Accordingly, the Office’s reliance on the principle of isosterism and bioisosterism is appropriate. Moreover, MPEP 2143.02(I) states that prior art that suggests that compounds would have been expected to have similar activity because the structural difference between them involves a known bioisosteric replacement provides a sufficient basis for a reasonable expectation of success. See also MPEP 2144.09(III).
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. MPEP 2144(I).
The instant rejection does not rely on an “obvious to try” rationale nor does it state that a POSITA would be motivated to specifically select the two central carbon atoms of "-CH=CH-CH=CH-" to form the dihydrazone core (-C=N-N=C-) claimed in the present application. The instant rejection states that one of ordinary skill in the art would be motivated to modify the compounds disclosed by Kung by replacing one or more of the CH groups of the -CH=CH-CH=CH- moiety with N.
While Applicant characterizes the possible substitutions as extensive, replacing one or more of the CH groups of the -CH=CH-CH=CH- core with N actually yields a finite and limited number of substitution patterns.
Mono-substitution
-N=CH-CH=CH-; which is equivalent to -CH=CH-CH=N-, as the -CH=CH-CH=CH- core is symmetric
-CH=N-CH=CH-; which is equivalent to -CH=N-CH=CH-, as the -CH=CH-CH=CH- core is symmetric
Di-substitution
-N=N-CH=CH-; which is equivalent to -CH=CH-N=N-, as the -CH=CH-CH=CH- core is symmetric
-CH=N-N=CH-
-N=CH-N=CH-; which is equivalent to -CH=N-CH=N-, as the -CH=CH-CH=CH- core is symmetric
Tri-substitution
-N=N-N=CH-; which is equivalent to -CH=N-N=N-, as the -CH=CH-CH=CH- core is symmetric
-N=CH-N=N-; which is equivalent to -N=N-CH=N-, as the -CH=CH-CH=CH- core is symmetric
Tetra-substitution
-N=N-N=N-
Each of these possibilities is encompassed by the motivation to modify the compounds disclosed by Kung by replacing one or more of the CH groups of the -CH=CH-CH=CH- moiety with N, and do not each require an independent motivation. Moreover, the existence of these possibilities does not negate the motivation to perform the bioisosteric replacement.
Applicant asserts the following:
“The compounds of the present application achieve unexpected technical effects, demonstrating non-obviousness.” [Remarks 2/3/2026, Page 12, Paragraph 3-5]
“The superior properties of the compound 88 are unexpected: Compound 88 demonstrates high affinity for AP/Tau protein (e.g., Ki values in the nanomolar range), excellent brain uptake (high %ID/g values in mouse models), and rapid clearance (Table 3). These effects are not predictable from Brown's general theory. MPEP 716.02” [Remarks 2/3/2026, Page 14, Paragraph 4]
“The present application achieved the superior performance of compound 88 through extensive experimentation, demonstrating non-obviousness. For instance, compound 88 exhibits unexpectedly high affinity, brain uptake, and clearance rate, these effects not suggested by Al Karawi or Brown.” [Remarks 2/3/2026, Page 16, Paragraph 2]
Allegations of unexpected results must be supported by factual evidence that demonstrates a greater than expected result was achieved and that the results are significant. MPEP 716.02(a-c). The results must also be commensurate in scope with the claim(s) and compared against the closest prior art. MPEP 716.02(d-e). Applicant has not provided evidence in accordance with this standard. Specifically, Applicant has not compared the claim(s) with the closest prior art. Therefore, Applicant’s allegations are unsupported and are not persuasive.
Applicant asserts “Kung discloses stilbene derivatives for imaging amyloid plaques, but all examples are based on a -CH=CH-CH=CH- core. Kung does not disclose or suggest replacing the core with a -C=N-N=C- core. Brown discusses general concepts of isosteres and bioisosteres, does not involve in imaging agents or central nervous system targets, and does not disclose specific compounds or suggest the application of isosteres or bioisosteres replacement technique in diagnostic or detecting reagent, nuclear medicine imaging agent, to achieve the specific effects of the present application.” [Remarks 2/3/2026, Page 12, Paragraph 6 -Page 13, Paragraph 1]
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. MPEP 2144(IV). Therefore, a POSITA need not be motivated to obtain a compound with utility as diagnostic or detecting reagent, a nuclear medicine imaging agent, or to achieve the specific effects of the present application.
Applicant asserts “Al-Karawi's compounds are designed for liquid crystal applications, not for biological imaging or the diagnosis/detection of neurodegenerative diseases…. since Al-Karawi's compound was designed for liquid crystal materials, those skilled in the art would have no motivation to structurally modify it with bioisosteres to obtain a compound with a completely different function(high affinity to AB/Tau protein) from its lead compound (which possesses liquid crystalline property). Therefore, there is no rational motivation for those skilled in the art to combine Al-Karawi (liquid crystals) with Brown (isosteres), as the objectives of the liquid crystal and bioimaging fields are disparate. Replacement with isosteres that might improve physical properties in the field of liquid crystals, but it may be ineffective or even detrimental in biological imaging.” [Remarks 2/3/2026, Page 15, Paragraph 2-3]
Al-Karawi defines the cited compound as a multifunctional azine compound and further discloses azine-type compounds possess pharmacological and biological activities, function as binding molecules of biological receptors, and are suitable candidates for drug development. [Al-Karawi, Page 2286, Col. 1, Paragraph 3]
In view of this teaching by Al-Karawi, a POSITA would have recognized the cited compound as a multifunctional azine compound that may be a suitable candidate for drug development and would have been motivated to modify the compound via bioisosteric replacement in view of Brown. Brown discloses the developing a candidate for clinical evaluation involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics, via bioisosteric replacement. [Brown, Page 15, Paragraph 1]
Moreover, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. MPEP 2144(IV). Therefore, a POSITA need not have been motivated to obtain a compound with high affinity to AB/Tau protein, utility for biological imaging, or the diagnosis/detection of neurodegenerative diseases.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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