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/EP2021/062837 05/14/2021; FOREIGN APPLICATIONS: EP 20175721.8 05/20/2020.
Claims 1-15 are pending.
Response to Restriction Election
2. Applicant’s election of group II and the species, the compound in claim of Formula XII, in the reply filed on October 28, 2025 is acknowledged. According to applicants’ representative claim 3 reads on the elected species. The election was made with traverse on the grounds that there is no search burden, however lack of search burden is not a grounds for traversal for applications filed under 35 U.S.C. 371, but rather it is the presence of a special technical feature that is grounds for traversal. Since the arguments are not directed towards arguing the presence of a special technical feature, they are not persuasive.
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.
3. Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garafolo US20230148214 in view of Okamoto “Chiral HPLC for efficient resolution of enantiomers” Chem. Soc. Rev., 2008, 37, 2593–2608. 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:
Determining the scope and contents of the prior art
Garofalo teaches the compound of claim 14 on page 155:
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The compound was an essential intermediate in the synthesis of a number of drug compounds including Example 133 5-((3-Cyclopropyl-lH-indazol-5-yl)oxy)-5,6, 7,8-tetrahydroquinoline-2-carbonitrile, enantiomer 1 and 2 on pages 155-156.
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The racemic compound was ”subjected to chiral separation using Method D” to give the enantiomers. Additional resolved isomers of the drug compounds with this 5-((2-cyano-5,6,7,8-tetrahydroquinolin-5-yl)oxy unit include Example 135 on page 157. Example 137 was in the most potent class of compounds according to Table A-1 on page 254 enantiomer 1 was a + at LRRK2 WT and a + LRRK2 G2019S; IC50 <=100nM.
The ability to separate enantiomers has evolved to the point that it is a routine operation by HPLC in 2008, 12 years before the invention was made “Among several resolution techniques in the past few decades, direct enantioseparation by high performance liquid chromatography (HPLC) has significantly advanced, and a large number of chiral stationary phases (CSPs) for HPLC have been developed using both chiral small molecules and polymers with chiral recognition abilities.” [Introduction]. “Today, more than one hundred types of commercially available CSPs have been used for analytical and preparative resolutions around the world. Among them, the polysaccharide-based CSPs have been recognized as the most powerful due to their wide applicability to racemates and high loading capacity.” [Conclusion]. Garafolo shows the level of skill in the art on pages 21-30 where around 200 chiral separations using various Chiralpak columns were used.
Ascertaining the differences between the prior art and the claims at issue
The prior art compound was racemic while the compound of claim 14 is drawn to the 5-R isomer.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
As discussed above, Garofalo resolved the penultimate drug compounds. As an alternative, the intermediate upstream could be resolved on columns or reducing the 5-Oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile by using any number of known chiral reducing agents instead of sodium borohydride. Garofolo shows that compound Example 133 enantiomer 1, which is the 5 (R) compound, was the most potent, which is good reason to pursue this process. Upon scale up a more convergent route to make the compound would be chosen which would involve conducting operations upstream. In view of the ability of the chemist at the time the invention was made, to separate the racemic mixture of Garofolo into the individual enantiomers and a clear motivation to do so, to make the potent compound on scale, the instant invention is obvious.
4. Claim(s) 3 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hahn US 20140031391 A1. 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:
Determining the scope and contents of the prior art.
Hanh teaches the compounds of a genus of Formula II on page 6 paragraph [0136]:
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L' represents 1,4-phenylene, as disclosed on page 4 [0066] and on page 2 under formula (I) [0017]. A similar genus of formula (VI) is shown on page 7:
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The diester intermediate compound Example 92A on page 101 is a mixed alkyl ester where one group is methyl and the other is ethyl, A is the CF3,Cl-biphenyl group. This is the closest compound of Formula VI and is an alkyl homolog of the compound of claim 3.
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Ascertaining the differences between the prior art and the claims at issue
The prior art compound 92A has methyl and ethyl esters, while the compound of claim 3, is drawn to a dibutyl compound. It does not appear that compounds of Formula (II) where L1 is phenylene were disclosed at least according to the sequence on col 2 on page 11, which has a Boc projected compound that is deprotected, isolated as a HCl salt then coupled.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
One would prepare the compound of claim 3 and hydrolyze the n-butyl esters since they would work the same. MeOH would be avoided since it is a Class 2 solvent, however butanol is a class 3 solvent. Hahn discloses a small genus for the T1 and T2 groups, C1-C4 alkyl, which is only 7 possible alkyls. Since the prior art genus is very small all the species subsumed by this narrow genus are described, they could be said to anticipate the instant claims, See In re Schaumann (CCPA 1978) 572 F2d 312, 197 USPQ 5; In re Petering (CCPA 1962) 301 F2d 676, 133 USPQ 275; Ex parte Broadbent (POBA 1965) 150 USPQ 468; Ex parte Schaefer (POBA 1964) 148 USPQ 160. However this is not necessary since choosing an alternative alkyl group from such a small list is obvious. The same can be said for the compound in claim 6 which is just a species of the small genus of Formula (II).
Allowable Subject Matter
5. Claims 8, 10 are allowed. The following is a statement of reasons for the indication of allowable subject matter: The closest prior art is Hanh WO 2014012934 A1 (cited on the IDS) also published as US 20140031391. The sequence in US ‘391 col 2 on page 11 has a Boc projected compound that is deprotected, isolated as a HCl salt then coupled. The compounds of claims 8 and 10 have no natural analogs in Hahn as the free acids are not revealed until the end and no bisnitrile is ever suggested.
Conclusion
6. 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