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 .
Status
Claims 3, 5, 7, 10-20, 23, 24, 26 and 28 are pending, wherein Claim 28 is newly added. Claims 10-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention. Therefore, Claims 3, 5, 7, 23, 24, 26 and 28 are presented for examination.
Election/Restrictions
Applicant elected Invention I (a compound) with traverse in the reply filed on 6/26/2023.
Priority
This application claims priority to U.S. Provisional Patent Application No. 63/275,987, filed November 5, 2021, and U.S. Provisional Patent Application No. 63/229,265, filed August 4, 2021.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s remarks.
Withdrawn Claim Rejections
Claim 7 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tashmukhamedova et al. (“Preparation of acylated and alkylated 2,3-benzo-15-crown-5.” Bioorganicheskaya Khimiya (1980), 6(2), 281-4.)
Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the 35 U.S.C. rejections above made of record in the previous Office Action, specifically, the addition of the limitation to Claim 7 that requires if m=2, then n=9.
Claim Rejections - 35 USC § 103
Rejection Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Slightly modified to address amendment - Claims 7, 26, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over by Kikukawa et al. (J. Chem. Soc. Perkin Trans. II 1987.)
Claimed invention
Claim 7 is drawn to a self-assembling compound for the formation of ion channels in biological membranes, the self-assembling compound being one of a monoacylated benzo(crown-ether) (MAkBCE) compound:
MAkBCE
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, wherein
m is 2 or 3 and
n is 4 or 9;
wherein is m is 2 then n is 9.
Claim 26 limits formula (IIB) of Claim 7 wherein m is 3 and n is 9.
Claim 28 limits formula (IIB) of Claim 7 wherein m is 3 and n is 4.
Prior art
Kikukawa teaches the crown ether, Compound 2b
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. See p. 136, 1st column. This compound corresponds to formula (IIB)
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, wherein m is 3 and n is 6. Kikukawa further teaches that the crown ethers are useful for solvent extraction and complexation of alkali metal cations. See title.
However, Compound 2b differs from the claimed compound because n is 6 instead of 9 (as required in Claim 26) or 4 (as required by Claim 28).
However, Kikukawa teaches that Compound 2b possessed the highest extraction percentage for potassium ion as compared to the other substituted benzocrown ethers (Table 1 at p. 138). It can further be seen that the substituted benzocrown ethers can maintain a similar extraction percentage capability for potassium ion even when the length of the alkyl chain differs by a large number of repeating -CH2- groups. For example, Table 1 shows that Compounds 2c and 2d, which are structural homologs amongst each other, possess similar extraction percentages of 56.7% and 56.5% for potassium ion even though these compounds differ structurally by 12 repeating -CH2- groups:
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Compound 2c: R = n-C4H9O,
Compound 2d: R = n-C16H33O.
Compound 2b (where n=6 as it corresponds to instant formula IIB) is a homolog of instant compounds of formula IIB (where n = 9 or 4). “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.” See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP § 2144.09. In the current case, the compound of formula IIB
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(where m is 3 and n is 9 or 4) would have been obvious because Compound 2b (where m is 3 but n is 6) is a homolog differing only by 2 or 3 regular successions of the same chemical group, i.e., by -CH2- groups. The POSA would have initially selected Compound 2b for further modification because it possessed the highest extraction percentage for potassium ion as compared to the other substituted benzocrown ethers. Therefore, the POSA would have found it obvious to modify Compound 2b by altering the length of the alkyl chain by changing the number of -CH2- groups therein, including wherein n is 9 or 4. The POSA would have reasonably expected the suggested compound to be useful for potassium ion extraction.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that compounds 2c and 2d differ in moiety class from compound 2b and thus their performance is not predictive of 2b derivatives. However, consistent with In re Wilder, the rejection relies on homologous relationship involving regular -CH2- repeating groups variation. Like In re Wilder, the rejection recognizes such variation as a basis for presuming similar properties. MPEP § 2144.09 further explains that such regular homologous changes are generally regarded as predictable modifications. Further, Kikukawa discloses compound 2b (corresponding to instant alkyl chain wherein n is 6, instead of 4 or 9) and compounds 2c (R = n-C4H9O) and 2d (R = n-C16H33O). Despite a twelve-carbon difference in substituent chain length between 2c and 2d, the reported potassium ion extraction efficiencies are nearly identical (56.7% and 56.5%). This demonstrates that substantial variation in carbon-length did not produce significant change in extraction performance. A POSA would reasonably infer from this data that a more modest chain-length adjustment in the n-alkyl chain would likewise not materially affect function.
Applicant also argues that the differences in extraction percentages from compounds 1a-e to the homolog compounds 2a-e do not possess similar properties. This is not persuasive because the changes addressed in this rejection is not the crown size (15-crown ethers (1a-e) vs 18-crown ethers (2a-e)), it is rather changes in the methylene chain length. Therefore, Applicants arguments distinguishing between ring size variation and side-chain homologation do not overcome the rejection.
B. Rejection maintained - Claims 3, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Luboch et al. (“The synthesis of some aromatic crown ether derivatives and their ion-selective electrode properties.” Tetrahedron (1990); 46(7): 2461-2472.)
Claimed invention
Claim 3 is drawn to a self-assembling compound for the formation of ion channels in biological membranes, the self-assembling compound being one of a monoacylated benzo(crown-ether) (MAcBCE) compound:
MAcBCE
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, wherein
m is 2 or 3, and
n is 4, 6 or 9,
wherein if m is 2, then n is 9.
Claim 7 is drawn to a self-assembling compound for the formation of ion channels in biological membranes, the self-assembling compound being one of a monoacylated benzo(crown-ether) (MAkBCE) compound:
MAkBCE
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,
wherein m is 2 or 3 and n is 4 or 9
wherein if m is 2, then n is 9.
Prior art
Luboch reports on the synthesis of aromatic “crown ether” derivatives and their ion-selective properties. See Luboch, title. Luboch teaches benzo-15-crown-5 and benzo-18-crown-6 derivatives. Specific examples include
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. See Fig. 1 at p. 2462.
Compounds 5 and 6 in the figure read on the following structures:
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(compound 5);
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(compound 6).
Luboch teaches highly lipophilic crown ether compounds including compounds 5 and 6 are ion carriers that exhibit the best selectivity towards potassium with log kK,Na values of approximately -3.3 to -3.5. Luboch teaches a rise in lipophilicity is also advantageous as it causes an increase stability. See Luboch, pp. 2461 and 2468.
Claims 3 and 5 are obvious
Compound 5
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differs from the instant compounds of formula IB
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because, in Compound 5 of the reference, n would be 8, which falls outside the scope of the claims.
However, the compounds of Claims 3 and 5 would have been obvious because of the close structural similarities between Compound 5 and compounds of formula IB. Compound 5 (where n=8) is a homolog of instant compounds of formula IB (where n = 4, 6 and 9). “Compound which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.” See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP § 2144.09.In the current case, the compound of formula IB
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(where m is 2 and n is 9) would have been obvious to a person of ordinary skill in the art (POSA) because it is a homolog of Compound 5 (where m is 2 but n is 8) differing only by regular successions of the same chemical group, i.e., by -CH2- groups. The POSA would have initially selected Compound 5 for further modification because it was one of the compounds Luboch identified as providing the best selectivity for potassium. Therefore, the POSA would have found it obvious to modify Compound 5 by altering the length of the alkyl chain by changing the number of -CH2- groups therein, including wherein n is 9. Further given the teaching that a rise in lipophilicity is also advantageous as it causes an increase stability, the artisan would have found it obvious to further change the carbon chain length of Compounds 5 and 6 to adjust the lipophilicity in order to optimize stability. The POSA would have reasonably expected the suggested compounds to be useful as potassium ion carriers.
Claim 7 is obvious
Compound 6
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differs from the instant compounds of formula IIB
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because, in Compound 6 of the reference, n would be 8, which falls outside the scope of the claims.
However, the compounds of Claim 7 would have been obvious because of the close structural similarities between Compound 6 and compounds of formula IIB. Compound 6 (where n=8) is a homolog of instant compounds of formula IIB (where n = 4 or 9). “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.” See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP § 2144.09.In the current case, the compound of formula IIB
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(where m is 2 and n is 9) would have been obvious because it is a homolog of Compound 6 (where m is 2 but n is 8) differing only by regular successions of the same chemical group, i.e., by -CH2- groups. The POSA would have initially selected Compound 6 for further modification because it was one of the compounds Luboch identified as providing the best selectivity for potassium. Therefore, the POSA would have found it obvious to modify Compound 6 by altering the length of the alkyl chain by changing the number of -CH2- groups therein, including wherein n is 9. Further given the teaching that a rise in lipophilicity is also advantageous as it causes an increase stability, the artisan would have found it obvious to further change the carbon chain length of Compound 6 to adjust the lipophilicity in order to optimize stability. The POSA would have reasonably expected the suggested compounds to be useful as potassium ion carriers.
Response to arguments
Applicant relies on the same arguments above against Kikukawa (which is not used in this rejection) would not suggest changing the length of the alkyl chain. Applicant adds that Kikukawa teaches that compound 1a (R=H) has an extraction percentage of 14.2 while compound 1b (R=C8H17) has an extraction percentage of 11-5; thus, decreasing extraction. However, this line of argument is not persuasive for reasons set forth above. Additionally, Luboch provides its own internal data directly supporting the value of lipophilic side chain (affected by chain length) in optimizing stability:
“A rise in lipophilicity is also advantageous as it causes an increase of the membrane stability.” See p. 2468.
Accordingly, the POSA would not rely on Kikukawa to contradict or override the direct structure-activity (chain length-lipophilicity-stability) correlation disclosed in Luboch.
Applicant also argues that Luboch does not attribute increased stability to chain length, but instead to branching of the substituent chain and therefore, would not motivate a POSA to alter the number of -CH2- units are proposed in the rejection. However, while certain examples in Luboch involve branched substituents, the reference also includes n-alkyl and n-acyl differing in chain length. For example, Fig. 1 at p. 2462 discloses both n-alkyl and n-acyl compounds of varying lengths:
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. Compounds 5 and 6 (the main homologs to the instant compounds used in the rejection) are n-alkyl and n-acyl derivatives – not branched – and are still described as “highly lipophilic compounds” that give the best selectivity. See Luboch, pp. 2461 and 2468.Taken together with the related text at pp. 2467-2468, Luboch does not limit lipophilicity to substituent branching as alleged by Applicant.
C. Rejection maintained - Claims 23, 24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over by Luboch et al., as applied to claims 3, 5, and 7 above, in further view of Frensdorff et al. (“Stability Constants of Cyclic Polyether Complexes with Univalent Cations.” Journal of the American Chemical Society (1971); 93(3): 600-606.)
Claimed invention
Claim 23 further defines the compounds of Claim 3 wherein m = 3 and Claim 24 further defines the compounds of Claim 23 wherein n = 9. Claims 26 further defines the compounds of Claim 7 and wherein m = 3 and wherein n = 9.
Prior art
As outlined above, Luboch teaches the compounds
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(compound 5) and
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(compound 6) and suggests their homolog compounds of formula IB and formula IIB, respectively, including wherein n = 9.
While Luboch suggests compounds of instant formulae IB and IIB where m = 2 and n = 9, Luboch does not teach the compounds where m = 3, i.e., wherein the crown is
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.
However, Luboch teaches highly lipophilic crown ether compounds including compounds 5 and 6 are ion carriers that exhibit the best selectivity towards potassium with log kK,Na values of approximately -3.3 to -3.5. Luboch teaches a rise in lipophilicity is also advantageous as it causes an increase stability. See Luboch, pp. 2461 and 2468.
Frensdorff reported the stability constants for the 1:1 complexes of 22 cyclic polyethers (12- to 60-membered rings of C-C-O units with various substituents including nitrogen and sulfur) with several cations (Li+, Na+, K+, Cs+, NH4+, Ag+) in water and in methanol have been determined by potentiometry with cation-selective electrodes. Selectivity toward the different cations varies with polyether ring size, the optimum ring size being such that the cation just fits into the hole, i.e., 15-18 for Na+, 18 for K+, and 18-21 for Cs+. See abstract. Frensdorff teaches that the hole size in the 18-Crown-6 polyether ring
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corresponds with the size of the potassium ion diameter. See Table III at p. 603. Frensdorff further teaches that the stability constant (k) for 18-Crown-6 (Type 1 = A(CH2CH2OCH2CH2OCH2CH2)2B where A = B = O) was highest with potassium. See Table VII at p. 605.
Therefore, one of ordinary skill in the art (POSA) would have found it obvious to alter the size of the “crown” of two of the compounds that provided the best selectivity for potassium according to Luboch such as the compounds
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(compound 5) and
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(compound 6) to arrive at the compounds
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and
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because both Luboch and Frensdorff teach the use of crown ethers to form complexes with metal ions including potassium. Because Frensdorff teaches the 18-Crown-6 polyether ring
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corresponds with the diameter of potassium and possesses the highest stability constant (k) for potassium, the POSA would have used the 18-Crown-6 polyether ring
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in place of the 15-Crown-5 polyether ring
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in either compound 5 or compound 6 of Luboch in order to optimize the compounds affinity or compatibility for potassium ion. Further given that a rise in lipophilicity is also advantageous as it causes an increase stability, the artisan would have found it obvious to further change the carbon chain length of Compounds 5 and 6 as outlined above to adjust the lipophilicity in order to optimize stability.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Response to arguments
Applicant relies on the same arguments above that Luboch does not suggest varying chain length because Luboch attributes lipophilicity and consequently stability to branching side substituent. This is not deemed to be persuasive as indicated above because Compounds 5 and 6 were both described as “highly lipophilic compounds” that give the best selectivity.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1629
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622