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 .
Claim Objections
Claims 22-24, and 39 objected to because of the following informalities:
Claim 22 states “; Cyc is indolyl”, should state “; and Cyc is indolyl”
Claim 23 states “wherein R2 and R3 are each independent …”, should state “wherein R2 and R3 are each independently…”
Claim 24 states “wherein R2 is hydrogen and R3 is methoxy or methoxy-d3,”, should state “wherein R2 is hydrogen and R3 is methoxy or methoxy-d3;”
Claim 39 states “administering a subject”, should state “administering to a subject”
Claim 39 states “a compound of claim 22”, should state “the compound of claim 22”
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.
Claim 40 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. Claim 40 recites “The method of claim 22” but Claim 22 is a compound of Formula (II), and not a method claim. It is unclear what method Claim 40 is dependent from, rendering the claim indefinite.
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.
Claim 41 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.
Claim 41 states “The compound of claim 22, wherein Ra is fluoro, bromo, chloro, methyl, methyl-d3, ethyl, propyl, isopropyl, butyl, isobutyl, or tertbutyl”, but Claim 22 defines variable Ra as “wherein each of Ra, Rb, and Re is hydrogen, deuterium, C1-4alkyl, phenyl, heteroaryl, or heterocyclyl”. Claim 22 does not define variable Ra as a halogen, so Claim 41 defining variable Ra as a halogen, introduces new limitations, and fails to further narrow the independent claim.
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
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 22-25, 27-30, 32, 33, 36, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Murai (Murai et al., Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents, Neuropharmacology,126:97-197, November 2017, as cited on the IDS dated 12/10/2024), in view of Uto (Yoshikazu Uto, “1,2-Benzisoxazole compounds: a patent review (2009 -- 2014)”, Expert Opinion on Therapeutic Patents, Volume 2, Issue 6, Pub. Date: March 23, 2015).
Murai discloses lysophosphatidic acid (LPA) as a bioactive lipid that acts with protein-coupled receptors, LPA receptors 1-6. Murai discloses LPA5 antagonists are administered to treat allodynia, and neuropathic and inflammatory pain in rodents (Abstract).
Murai discloses AS2717638, as an LPA5 antagonist, bottom left, that overlaps with instant Formula (II), bottom right. To map AS2717638, with instant Formula II, R2 and R3 are C1 alkoxy substituents (Claims 22-24), X4 is CR4 where R4 is hydrogen (Claim 25), R5 is -C(O)NR5aR5b, wherein R5a and R5b form a 6 membered heterocycle ring with 1 heteroatom selected from nitrogen and the ring is unsubstituted (Claims 27-30).
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Murai teaches a benzisoxazole group, where instant Formula (II) teaches substituent Cyc. The closest Cyc substituent in the instant claims to the benzisoxazole group disclosed in Murai, is indol-3-yl substituted with one methyl group (Claims 22, 31-33, and 36), see below.
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Uto teaches benzisoxazole as an isostere of indole derivatives and discloses that benzisoxazoles and indole derivatives bind to important biological proteins in a similar manner (Pg. 644).
Regarding Claims 22-25, 27-30, 32, 33, 36, and 38-40, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date, to take the method disclosed in Murai for administering LPAR5 antagonist compounds, such as AS2717638, to patients with inflammatory pain, and substitute the benzisoxazole group, for an indolyl, to arrive at a compound of instant Formula (II), because Uto teaches that benzisoxazole and indole derivatives are functionally equivalent bioisosteres, and are therefore interchangeable. One of ordinary skill would be motivated to substitute benzisoxazole for indolyl because they have similar pharmacological activity.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Murai (Murai et al., Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents, Neuropharmacology,126:97-197, November 2017, as cited on the IDS dated 12/10/2024), and further in view of Barillari (Caterina Barillari et al., “Classical Bioisosteres”, Bioisosteres in Medicinal Chemistry, First Edition, Pgs. 15-29, Pub. Date: 2012).
The teachings of Murai discussed above, with respect to claim 22 are incorporated into this rejection.
Murai discloses compound AS2717638, bottom left, that overlaps with compound 5 in instant Claim 37, bottom right. The compounds share the same base structure, except compound AS2717638 disclosed in Murai has a methyl substitutent, and instant compound 5 has a chlorine substituent at the same position.
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Barillari discloses that -CH3 and -Cl are classical isosteres, because they both are monovalent groups (Pg. 17). Monovalent atoms/groups are chemical species that have a valency of one.
Regarding Claim 37, it would have been prima facie obvious for one of ordinary skill before the effective filing date to take compound AS2717638 disclosed in Murai and substitute the methyl substituent for a chlorine as seen in instant compound 5, because Barrillari teaches that chlorine and methyl are classical monovalent biosteres. One of ordinary skill could substitute chlorine for methyl and get similar chemical activity from the resulting compound because both atoms/groups have a valency of one and are well known in the arts for their similar bonding activity.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Murai (Murai et al., Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents, Neuropharmacology,126:97-197, November 2017, as cited on the IDS dated 12/10/2024), in view of Uto (Yoshikazu Uto, “1,2-Benzisoxazole compounds: a patent review (2009 -- 2014)”, Expert Opinion on Therapeutic Patents, Volume 2, Issue 6, Pub. Date: March 23, 2015) as applied to claim 22 above, and further in view of Barillari (Caterina Barillari et al., “Classical Bioisosteres”, Bioisosteres in Medicinal Chemistry, First Edition, Pgs. 15-29, Pub. Date: 2012).
The teachings of Murai, Uto, and Barillari discussed above, with respect to claim 22 and 37 are incorporated into this rejection.
Substituent R5 in instant Formula (II), maps to the piperidine-1-carbonyl group in compound AS2717638 disclosed in Murai.
Murai does not disclose an additional Fluorine on the piperodine-1-carbonyl group in compound AS2717638, as in instant claim 42 wherein R5 is 4-fluoropiperidine-1-carbonyl.
Barillari discloses that replacing hydrogen with fluorine is the most common monovalent isosteric replacements, because both hydrogen and fluorine have similar van der Waals radii, but fluorine is more electronegative. Due to fluorine’s high bonding strength with carbon, it is often substituted with hydrogen to achieve greater metabolic stability (Pg. 17).
It would have been prima facie obvious for one of ordinary skill before the effective filing date, to take compound AS2717638 disclosed in Murai and add a fluorine atom to the piperidine-1-carbonyl group, to arrive at a compound of Formula (II) wherein R5 is 4-fluoropiperidine, because Barillari teaches that hydrogen and fluorine are monovalent isosteres. One of ordinary skill would be motivated to replace hydrogen with fluorine because of fluorine’s high bonding strength with carbon, and larger electronegativity when compared to hydrogen.
Allowable Subject Matter
Claims 34-35 are objected to as being dependent upon a rejected base claim 22 but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Closest Prior Art
The closest prior art is Murai (Murai et al., Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents, Neuropharmacology,126:97-197, November 2017, as cited on the IDS dated 12/10/2024), in view of Uto (Yoshikazu Uto, “1,2-Benzisoxazole compounds: a patent review (2009 -- 2014)”, Expert Opinion on Therapeutic Patents, Volume 2, Issue 6, Pub. Date: March 23, 2015).
Murai discloses AS2717638, as an LPA5 antagonist, bottom left, that overlaps with instant Formula (II), bottom right. To map AS2717638, with instant Formula II, R2 and R3 are C1 alkoxy substituents, X4 is CR4 where R4 is hydrogen, R5 is -C(O)NR5aR5b, wherein R5a and R5b form a 6 membered heterocycle ring with 1 heteroatom selected from nitrogen and the ring is unsubstituted.
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Murai teaches a benzisoxazole group, where instant Formula (II) teaches substituent Cyc. The closest Cyc substituent in the instant claims to the benzisoxazole group disclosed in Murai, is indol-3-yl substituted with one methyl group, see below.
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Uto teaches benzisoxazole as an isostere of indole derivatives and discloses that benzisoxazoles and indole derivatives bind to important biological proteins in a similar manner (Pg. 644).
Compound AS2717638 disclosed in Murai does not teach Cyc as indol-4-yl substituted with a halogen at position 6, or Cyc as indol-4-yl, unsubstituted at position 6, and position 1 substituted with a C3-8 cycloalkyl.
It would not be obvious for one of ordinary skill, before the effective filing date to modify compound AS2717638 disclosed in Murai by substituting the benzisoxazole group, for a indol-3-yl, and then further modify the compound by switching the position of the nitrogen atom in the indole, and then further substitute the compound by adding a halogen specifically at position 6. There is no motivation known in the art to make change the position of the nitrogen in the indole, and further substitute with a halogen atom, therefore Claims 34 and 35 are not obvious over the prior art.
Conclusion
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/C.M.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
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