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 .
DETAILED ACTION
1. This application is a 371 of PCT/CN2021/103263 06/29/2021; FOREIGN APPLICATIONS: CHINA 202010622053.2 06/30/2020.
Claims 1-10 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, the compound A1
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, in the reply filed on January 5, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). According to applicants’ representative “at least claim 6 reads on the elected species”. The species requires M to be a substituted C6 aromatic ring (benzene), where R1 is cyano and unsubstituted alkoxy, B is a 6 membered unsaturated carbon ring (benzene), R6 is H, X is CH2, R2is H, R and R’ are the cyclic structure with the R3 group at the top of page 61, where n is 2 and R3 is carboxyl or -C(O)OR5, where R5 is H.
Objections
3. Claims 1 and 5 are objected to for the following typographical informalities: The claims have a large number of words jumbled together missing spaces including “guanyl,substituted”, “(includingtrifluoromehtyl)”, “ringB”, “substitutedmeans”, etc. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 1-5, 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 1 and 4 have the phrase “(preferably a benzene ring)”. The term "preferably" is a relative term which renders the claim indefinite. It is improper to speak of preferred embodiments within a claim since this is the purpose of a dependent claim. The phrase is also in parenthesis along with “(includingtrifluoromethyl)” [sic] also in claim 5, along with “(containing trifluoromethyl)”
By placing the phrases in parenthesis, it is unclear if this is required of the claim or optional, or merely non-limiting example. Compare to the phrase “C1 to C6 alkyl (5- to 7- membered heteroaryl)” which has not been rejected as the examiner views the parenthesis as required and functioning as a bracketing of the structural element linked to the alkyl.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
5. Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takeuchi US 8,957,051. Takeuchi teaches anticipatory compounds including but not limited to 2-[[[4-[5-(4-phenylbutyl)-1,2,4-oxadiazol-3-yl]-1-naphthalenyl]methyl]amino]-ethanol on column 5 lines 34-35. This is a compound of claim 1 where M is a substituted alkyl1 substituted with one R1 group where the R1 group is C6 aromatic ring (benzene) or C7 (benzyl) or R1 is substituted alkyl where the substituent is C6 aryl (benzene) or C7 aryl (benzyl)2, B is a 6 membered unsaturated carbon ring (benzene), R6 is H, X is CHR2, R2 is H, one of R and R’ is H the other is substituted alkyl where the substituent is hydroxyl. Compositions are described at column 9 lines 29ff.
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.
6. Claim(s) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen US 7,199,142 AND Li US 20160137616 in view of Fujiwara “Identification of the Hydrophobic Ligand Binding Pocket of the S1P1 Receptor” THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 4, pp. 2374–2385, January 26, 2007. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Chen prepared a number of sphinogsine 1 phosophate (Edg1) receptor ligands, the same utility of the claimed compounds, including those of the general formula I on column 4:
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This formula corresponds to the instant formula I where the M group is equivalent to the Y-phenyl ring, and X is CHR2, and the nitrogen forms a saturated ring, such as aeztidine and pyrrolidine as in claim 2-3 with a polar group like a carboxylate as R3. A number of specific examples that have substituion patterns that correspond to the compound in claim 6 are given in the table on columns 11/12 to column 23/24, shown here:
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Li teaches compounds with the same utility as S1P ligands with a 1,3,4-oxadiazole core attached to a fused phenyl, in particular naphthyl and quinoline as generic formula I on page 1:
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This structure corresponds to the claimed formula I where B is phenyl or pyridyl, X is CHR2, M is substituted alkenyl, substituted alkyl and R and R’ are substituted with carboxyl. An additional ring forming subgenus of the structure of claims 2-3, i.e. azetidine etc., is disclosed
As a Formula II on page 5:
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A number of example compounds are disclosed including those on pages 7-9 with phosphate and carboxylate groups as instant R3. A few relevant examples are shown here:
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Fujiwara studied the binding pocket of S1P agonists, “Here we report on the experimental validation of a computational model of the ligand binding pocket of the S1P1 GPCR surrounding the aliphatic portion of S1P. The extensive mutagenesis-based validation confirmed 18 residues lining the hydrophobic ligand binding pocket, which, combined with the previously validated three head group interacting residues, now complete the mapping of the S1P ligand recognition site. We identified six mutants (L3.43G/ L3.44G, L3.43E/L3.44E, L5.52A, F5.48G, V6.40L, and F6.44G) that maintained wild type [32P]S1P binding with abolished ligand-dependent activation by S1P.” [abstract]
Comparing the endogenous agonist S1P1 to the synthetic 1,2,4-oxadiazole ligand SEW2871 in Table 3 on page 2382 a model pharmacophore was developed as shown in Figure 5, shown here:
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“To further characterize the interaction of SEW2871 with S1P1, we probed the hydrophobic interactions between residues found to line the S1P1 binding pocket with SEW2871. The activation data for mutations in the S1P1 binding pocket for the SEW2871 and S1P ligands shown in Table 3 revealed numerous similarities and differences with regard to the relative positions of alkyl and aromatic agonists in the binding pocket.” [page 2383].
“The computational model of SEW2871-S1P1 was utilized to lend a chemical rationale to these experimental observations. Fig. 4D illustrates the importance of the positioning of aromatic residues around the periphery of the SEW2871 binding pocket. Specifically, Trp-6.48 is positioned in the binding pocket such that it makes favorable p-p stacking interactions with the thiophene and oxazolidine moieties of the ligand. Mutation of this residue to alanine has two separate effects, both of which are potentially deleterious to ligand binding (1). These p-p interactions between the indole functionality and the aromatic domains of SEW2871 are lost (2)”
Page 2382 column 1 highlight the additional importance of Phe-5.48 residue, “The F5.48Y mutation, however, amplifies this finding to indicate that mutation to a residue that occupies significantly less volume than the phenyl moiety results in loss of activation. It seems likely, therefore, that it is the interaction of Phe-5.48 with other hydrophobic residues that confers its importance in the activation process.” In conclusion, “Hence, it is plausible that Phe-5.48 serves as an important amino acid in the activation process, and amino acid replacements to residues that occupy significantly less volume than phenylalanine contribute to loss of S1P1 activation.” [page 2384 col. 1]
Ascertainment of the difference between the prior art and the claims
The following compounds in claim 6 only differ by the substitution of a phenyl with a naphthalene from the compounds of Chen shown above.
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Compound A21 is the naphthalene analog of the Chen compound 6, Chen compound 7 is the same to A14, 8 to A66 and 9 to A62.
Finding of prima facie obviousness
Rational and Motivation
(MPEP 2142-2143)
Naphthalene is frequently used as an isosteric, replacement for a phenyl (benzene) ring in medicinal chemistry to enhance metabolic stability, lipophilicity, and binding affinity. As a larger, more hydrophobic, and rigid aromatic system, it can fill hydrophobic pockets in proteins that a smaller phenyl ring cannot, often leading to increased potency. In this case, Li has shown that naphthalene and other fused bicyclic aromatics (quinoline), function the same way as a phenyl ring in these ligands. Fujiwara shows the criticality of the hydrophobic pocket in the binding site of the structurally related 1,2,4-oxadiazole SEW2871 and similar binding is expected for the prior art compounds of Chen. A more favorable p-p stacking interaction between the ligand and Phe-5.48 and Trp-6.48 would be expected upon going from phenyl to naphthalene. The person having ordinary skill in the art would formulate the compounds with naphthalene instead of phenyl to enhance metabolic stability, lipophilicity, and binding affinity in the hydrophobic pocket with more favorable p-p stacking interaction between the ligand and Phe-5.48 and Trp-6.48. Ex parte WESTFAHL, 136 USPQ 265 (Bd. Pat. App. & Int. 1962): “In the present case, the examiner does not rely upon any theory of homology but has cited a reference (Richter II) teaching that naphthalene is very similar to benzene and forms a series of analogous derivatives.”
Finally at least for the generic claims, the compounds differ from Li only by the position of the nitrogen atoms in the oxadiazole, Li being drawn to the 1,3,4-oxadiazoles, while the instant claims and Chen are drawn to the 1,2,4-oxadiazoles. Positional isomers, having the same radical on different positions of the molecule, have been determined to be prima facie obvious, requiring no secondary teaching, this includes internal ring isomers, see for example Ex parte Ullyot 103 USPQ 185 (4-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline obvious over a reference teaching 4-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline), however reliance on this is not necessary since Chen is a secondary teaching who has already shown that 1,2,4-oxadiazole works the same way, as does Fujiwara in the SEW2871 compound. There is an expectation of the same or similar properties upon moving the position of the nitrogen atom in the oxadiazole. The fact that the position isomer was already shown to provide the same activity is strong evidence of the obviousness of the change.
7. Claim(s) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang CN 109956912 A (translation appended) AND Li US 20160137616 in view of Fujiwara “Identification of the Hydrophobic Ligand Binding Pocket of the S1P1 Receptor” THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 4, pp. 2374–2385, January 26, 2007.
Determination of the scope and content of the prior art
(MPEP 2141.01)
Wang prepared a number of sphinogsine 1 phosophate (Edg1) receptor ligands, the same utility of the claimed compounds, including those of the general formula I on page 2:
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This formula corresponds to the instant formula I where the M group is equivalent to the phenyl ring, and X is CHR2, and the nitrogen is a chain or forms a saturated ring, such as aeztidine and pyrrolidine as in claim 2-3 with a polar group like a carboxylate as R3. A number of specific examples that have substituion patterns that correspond to the elected species and other compounds in claim 6 on pages 3-6, a few highly relevant examples with the -O-iPr group and CN group on the terminal phenyl are shown here:
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Others have the -O-c-Pentane group in addition to the -CN group.
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This is the substitution pattern in the compound A70 in claim 6.
According to the experimental section in the translation, “As can be seen from Table 1, the compounds of the present invention have strong S1P1 receptor agonistic activity and S1P1/S1P3 receptor selectivity, and some compounds are equivalent or higher than the level of the positive control. (RPC1063)……The above experimental results show that the oral administration of the compound of the present invention has better in vivo pharmacokinetic properties, and the Cmax and AUC (0-t) are higher than the positive drug RPC1063.3”
The Li US 20160137616 and Fujiwara teachings are discussed above in the 103 rejection over Chen, Li and Fujiwara and are not reproduced but are incorporated here.
Ascertainment of the difference between the prior art and the claims
The prior art compounds in claim 6 only differ by the substitution of a phenyl with a naphthalene from the genus and specific compounds of Wang shown above.
Finding of prima facie obviousness
Rational and Motivation
(MPEP 2142-2143)
Naphthalene is frequently used as an isosteric, replacement for a phenyl (benzene) ring in medicinal chemistry to enhance metabolic stability, lipophilicity, and binding affinity. As a larger, more hydrophobic, and rigid aromatic system, it can fill hydrophobic pockets in proteins that a smaller phenyl ring cannot, often leading to increased potency. Naphthalene is frequently used as an isosteric replacement for a phenyl (benzene) ring in medicinal chemistry to enhance metabolic stability, lipophilicity, and binding affinity. As a larger, more hydrophobic, and rigid aromatic system, it can fill hydrophobic pockets in proteins that a smaller phenyl ring cannot, often leading to increased potency. In this case, Li has shown that naphthalene and other fused bicyclic aromatics (quinoline), function the same way as a phenyl ring in these ligands as a phenyl alternative. Fujiwara shows the criticality of the hydrophobic pocket in the binding site of the structurally related 1,2,4-oxadiazole SEW2871 and similar binding is expected for the prior art compounds of Wang. A more favorable p-p stacking interaction between the ligand and Phe-5.48 and Trp-6.48 would be expected upon going from phenyl to naphthalene. The person having ordinary skill in the art would formulate the compounds with naphthalene instead of phenyl to enhance metabolic stability, lipophilicity, and binding affinity in the hydrophobic pocket with more favorable p-p stacking interaction between the ligand and Phe-5.48 and Trp-6.48.
Conclusion
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/ Primary Examiner, Art Unit 1621
1 The prior art butyl-phenyl group on the 4 position of the 1,2,4-oxadiazole can be generated a number of ways with different number of carbon atoms in the initial M alkyl since the substituent on the alkyl can generate an aryl substituted with an alkyl a number of ways, i.e. if the alkyl is C1, the substituent could be a C2 or C3 alkyl substituted with an aryl or the group could be a C3 or C4 alkyl substituted with benzyl (CH2-Ph) or benzene (Ph) respectively.
2 Benzyl is explicitly listed in the list of substituents at the end of the claim and is also the only known uncharged C7 aryl in the group “C6-C10aryl” see, THE VAN NOSTRAND CHEMIST'S DICTIONARY 1953, entry for “aryl” Pg. 44. “ARYL. A radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen, so producing a univalent unit. Examples are phenyl C6H5- derived from benzene; tolyl (or benzyl) C7H7 derived from toluene, etc.”
3 Ozanimod (Scripps-Receptos compound RPC1063) is sold under the brand name Zeposia.