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 1-7, 10-13 are pending.
Response to Amendments
2. The objection to claims 1 and 5 for typographical informalities is withdrawn based upon the amendments. The rejection of claim(s) 1-5, 7 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subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention for parenthesis and preferably is withdrawn based upon the amendments.
The rejection of claim(s) 1 and 7 under 35 U.S.C. 102(a)(1) as being anticipated by Takeuchi US 8,957,051 is withdrawn based upon the amendments.
The rejection of claim(s) 1, 3-7 under 35 U.S.C. 103 as being unpatentable over Chen US 7,199,142 AND Li US 20160137616 in view of Fujiwara is maintained. Applicants’ arguments have been fully considered but are unpersuasive. According to the argument “the nucleic ring1 cannot be easily replaced with a fused ring” [Arguments at page 20/27]. As evidence of a teaching away applicant shows that both fused pyrimidines and quinolines are not potent ligands by referencing the compounds A56 to A58 in the specification. However as applicant shows Li’s compounds are potent ligands. Regardless, the change applicant is alleging as being taught away from in the prior art is not a claimed change since the claims are not drawn to quinolines or quinazaolines since all the Xs are CH.
Applicant the argues unexpected results based upon comparisons with two compounds siponmod and ozanimod on pages 23-25, however a good portion of this data, specifically the argued selectivity data is not in the specification. According to the applicants’ representative “Some of the bioactivity effect is newly added to further support the technical effect.” "Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection.…The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) [MPEP 2145]. If data is to be relied upon that is not in the specification, it must be submitted in the form of a sworn declaration. Assuming the data were properly submitted, the compounds used for comparison are not the closest prior art. Both siponimod and ozanimod are not the based of the rejection and differ structurally from the closest prior art compounds.
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Highly relevant examples of Chen were cited in the rejection. These compounds have the same terminal cyclic amino group, azetidine, and other structural features. In order to rebut a prima facie case of obviousness with an argument of unexpected results, it is the closest prior art that must be compared (See MPEP 716.02(e)). Finally even if such evidence were presented, the evidence of unexpected results "must be reasonably commensurate with the scope of the claims," although every claimed embodiment need not be tested. In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011); see also Allergan, Inc. v. Apotex, Inc., 754 F.3d 952, 965 (Fed. Cir. 2014). "Appellant bears the burden of establishing a nexus between the full scope of the claimed invention and the proffered evidence of nonobviousness." Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 1392 (Fed. Cir. 1988). Unexpected results must be “commensurate in scope with the degree of protection sought by the claimed subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
The rejection of claim(s) 1, 3-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang CN 109956912 A AND Li US 20160137616 in view of Fujiwara is maintained. The arguments against Wang is just a recapitulation of the arguments against Chen and are unpersuasive for the same reasons. However Wang has evidence of the improved property. 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.” The argued increased selectivity over ozanimod AKA RPC1063. appears to be an expected results. Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989).
Applicant’s election of group I and the species, the compound A1
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, in the reply filed on January 5, 2026 was previously 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. Applicant has amended the claim 1 to remove substitution as a possibility for the C6-C10 aromatic ring but has left it in for the aromatic heterocycle, so technically generic claim 1 does not read on the elected species. Out of courtesy to the applicant the examiner has examined claims with a benzene ring and withdrawn claims that do not, and rejected the improper claims under 112 (d). As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 2, which does not read on the elected species is withdrawn. Newly submitted claims 11-13 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the product may be used in assays for screening GPCRs.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 11-13 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
3. Claims 4-6, are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The M ring as a “C6-C10 aromatic ring” in claim 1 is not substituted, however in the dependent claim including the species in claim 6, the ring is substituted. Claim 4 uses a different structure an “A” circle which has an R1 group and an n, which is not allowed for the “C6-C10 aromatic ring” in claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
4. Claim(s) 1, 3-7 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 of claim 4 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, 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.
5. Claim(s) 1, 3-7 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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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 RPC1063.2”
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
6. 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 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 It is unclear how what the term “nucleic ring” means. “Nucleic” refers to a biomolecule relating to the nucleus of a cell. It is primarily used in the term nucleic acid, which defines the complex organic acids—most notably DNA and RNA. The word nucleic is associated with nucleic acids like purine and pyrimidine nucleobases which were discovered in high abundance in the nucleus, however none of these rings are in the claims. Claim 1 is drawn solely to naphthalene as the ring referred to as “nucleic” and it has never been associated with nucleic acids or the nucleus of a cell.
2 Ozanimod (Scripps-Receptos compound RPC1063) is sold under the brand name Zeposia.
Prosecution Insights