DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group (I) in the reply filed on 07/15/2025 is acknowledged and maintained.
Priority
This application is a National Stage of International Application No. PCT/KR2021/000555 filed January 14, 2021, claiming priority based on Korean Patent Application No. 10-2020-0008356 filed January 22, 2000 and Korean Patent Application No. 10- 2020-0188174 filed December 30, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on November 18, 2025. Claims 1-14 are pending. Claims 1-8 and 10-13 are examined in accordance to the elected species. Claims 9 and 14 are wiredrawn.
Action Summary
Claims 5-8 and 10-13 rejected on the judicially-created basis that it contains an improper Markush and grouping of alternatives, are withdrawn in light of the deletion of preventing.
Claims 1-8 and 10-13 rejected under 35 U.S.C. 103 as being unpatentable over Levkau et al (WO2019/170796 A1) in view of Patani et al (Chem. Rev. 1996, 96, 3147−3176). The machine translation of Levkau is cited, are maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8 and 10-13 stand rejected under 35 U.S.C. 103 as being unpatentable over Levkau et al (WO2019/170796 A1) in view of Patani et al (Chem. Rev. 1996, 96, 3147−3176). The machine translation of Levkau is cited.
Levkau teaches a pharmaceutical composition comprising a modulator of sphingosine-1-phosphate signal transduction
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for treating a disease or disorder associated with Sphingosine 1-phosphate and its receptors is related, thereby in that the disease or disorder is selected from the group comprising diseases or disturbances of the bone tissue, adipose tissue and / or the glucose metabolism. (See claims 9 and 10.)
Levkau does not teach the claimed compound
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.
The only difference between the compound of Levkau and the claimed compound lies between the bycyclic ring and the phenyl ring. The compound of Levkau contains a methylene linker whereas the claimed compound contains an oxygen linker.
Patani teaches the ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties. In this review an attempt
has been made to quantitate, in specific instances, physicochemical effects such as electronegativity, steric size, and lipophilicity and to correlate these values to the observed biological activity. (See second paragraph of the left column of page 3148.) Moreover, Patani teaches the widespread application of the concept of isosterism to modify biological activity has given rise to the term bioisosterism. As initially defined by Friedman,2 bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Compounds or groups that possess near-equal molecular
shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. (See fourth paragraph of the right column of page 3148.) Furthermore, Patani teaches the concept of isosteres came about in 1925 with Grimm’s Hydride Displacement Law. This law states: “Atoms anywhere up to four places in the periodic system before an inert gas change their properties by uniting with one to four hydrogen atoms, in such a manner that the resulting combinations behave like pseudoatoms, which are similar to elements in the groups one to four places respectively, to their right.” Each vertical
column as illustrated in Table 2, according to Grimm, would represent a group of isosteres.
Erlenmeyer11 further broadened Grimm’s classification and redefined isosteres as atoms, ions, and molecules in which the peripheral layers of electrons can be considered identical.
Table 2. Grimm’s Hydride Displacement Law
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. (See Table 2.) Furthermore, Patani teaches Another illustration of divalent bioisosteric linkers
is observed in the study of inhibitors of the nuclear factor of activated T cells (NFAT)-mediated transcription of β-galactosidase. The use of an oxygen atom as a bioisosteric linker, which has a marginally smaller bond angle and much greater electronegativity, results in an
analogue with increased potency.
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. (See Table 20.)
It would have been prima facie obvious to one of ordinary skill in the art the time the invention was filed to modify the compound taught by Levkau by replacing the methylene linker between the bicyclic ring and the phenyl ring with an oxygen linker to give Applicant’s claimed compound. One would have been motivated to do so, because Patani teaches use of an oxygen atom as a bioisosteric linker, which has a marginally smaller bond angle and much greater electronegativity, results in an analogue with increased potency. One would reasonably expect the modified compound to exhibit greater potency that its counterpart successfully.
Accordingly, the limitations of “the compound is an immunosuppressant; for treating or preventing an immune disease and claims that further limit the immune disease: the compound has a kidney cell protective effect; and treating or preventing transplantation rejection or transplantation rejection disease; and claims that further limit said transplantation rejection or transplantation rejection disease. These limitations are properties claimed. Since the compound and the pharmaceutical composition are obvious over the prior, said properties are necessarily present. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on November 18, 2025.
Applicant’s argument
Applicant argues that the compound disclosed in Levkau contains a phthalazin ring linked to a phenyl ring via a methylene group (-CH2-). Levkau does not disclose, suggest, or exemplify any oxygen-linked (-0-) structure between those rings, nor does it provide any reason or motivation for such modification. To the contrary, Levkau focuses on methylene or other carbon-based linkers in its exemplified compounds. In contrast, the claimed compound of the present application (see paragraph [0099] and the structural formula of Formula 1) includes a phenoxy linkage (-0-) connecting the phthalazin and phenyl moieties. This change is not a mere substitution of an atom, and it represents a different chemical connectivity that alters both the electronic and resonance characteristics of the aromatic system. Importantly, nothing in Levkau or Patani provides any teaching that an oxygen atom may be introduced in place of the methylene linkage in this specific scaffold or that such a modification would be chemically tolerated or desirable.
Examiner’s response
In response, Applicant’s argument Is not persuasive. It may well be true that Levkau does not disclose, suggest, or exemplify any oxygen-linked (-0-) structure between those rings, nor does it provide any reason or motivation for such modification. However, Patani clearly provides the motivation for replacing the -CH2- linker taught by Levkau with an -O- linker. Moreover, contrary to Application’s assertion that such replacement or change is not a mere substitution of an atom, and it represents a different chemical connectivity that alters both the electronic and resonance characteristics of the aromatic system. The Examiner contends oxygen bridging two rings (diaryl ethers) can be effectively replaced with a carbon atom (specifically a methylene, (CH2), or ketone, as a bioisostere to alter metabolism and enhance potency, as identified in Patani.
Applicant’s argument
Applicant argues that Patani is a general review article discussing theoretical concepts of bioisosterism and does not concern phthalazin derivatives or any compounds structurally similar to those in Levkau. Patani provides no experimental data or guidance suggesting that a methylene-to-oxygen replacement in a heteroaryl-aryl linkage of a phthalazin scaffold would preserve stability, activity, or chemical compatibility. In fact, the cited discussion in Patani is directed to general cases where substitution occurs within small aliphatic chains or pharmacophoric fragments, not within rigid heteroaromatic cores as in Levkau. One skilled in the art would therefore have no reasonable expectation that the same principle could be applied to the multi-ring phthalazin framework of Levkau without disrupting the overall conformation or electronic interaction of the system.
Examiner’s response
In response, Applicant’s argument Is not persuasive. It may well be true that Patani is a general review article discussing theoretical concepts of bioisosterism and does not concern phthalazin derivatives or any compounds structurally similar to those in Levkau. However, Patani is not only a general review article discussing theoretical concepts of bioisosterism. Patani is a highly regarded, comprehensive, and practical guide for medicinal chemists that emphasizes specific, literature-derived examples of bioisosteric replacements to enhance drug development. While it covers concepts, the primary focus is on how bioisosteres are used in current medicinal chemistry literature to improve lead compounds. It connects bioisosteric changes to physical chemistry properties (e.g., lipophilicity, electronegativity, steric) and their impact on biological activity, rather than just describing theory. It provides extensive examples of both classical and nonclassical bioisosteres, making it a "go-to" practical resource rather than just an overview. The article explicitly outlines how these replacements are used to optimize drug potency and safety, often linking them to Quantitative Structure-Activity Relationships (QSAR). Moreover, it may also well be true the cited discussion in Patani is directed to general cases where substitution occurs within small aliphatic chains or pharmacophoric fragments, not within rigid heteroaromatic cores as in Levkau. However, Patani clearly teaches that such replacement is based on the Grimm’s hydride displacement law. Said law is based on experimental observations of non-metallic hydrides and the emerging octet theory. By studying the physicochemical properties of molecules. The law is crucial for predicting the behavior of compounds, showing that hydrides could simulate the behavior of neighboring elements in the periodic table. Even though Patani does not teach phthalazin derivatives, that does not mean the law cannot apply to phthalazin derivatives. In fact, Applicant has not shown such replacement would not give rise to similar biological activity. Therefore, one skilled in the art would have a reasonable expectation that the Grimm’s hydride displacement law in principle could be applied to the multi-ring phthalazin framework of Levkau with success.
Conclusion
No claims are allowed.
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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/JEAN P CORNET/Primary Examiner, Art Unit 1628