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 Amendments
2. The rejection of claim(s) 14 under 35 U.S.C. 103 as being unpatentable over Garafolo US20230148214 in view of Okamoto is maintained. Applicants representatives arguments submitted April 20, 2026 have been fully considered but are unpersuasive. According to the arguments the examiner is engaging in improper hindsight by considering all the intermediates in a synthetic scheme. There is no conflation. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Conducting chiral resolution early in a synthesis is highly advantageous because it eliminates the unwanted enantiomer before building the more complex, expensive portions of the molecule and avoids the compounding of multiple stereoisomers during subsequent synthetic steps. This translates to material savings, reduced solvent usage, and improved overall scalability of the synthetic route. This is a fundamental precept of synthetic chemistry sometimes called early stereocenter control which advocates for building and controlling stereocenters as early as possible in a multi-step synthesis.
With regard to an argument of teaching away at 2., Garofalo does not disparage or otherwise suggest not pursuing the path of early resolution. Applicant merely argues that because it wasn't actually done it’s taught away from, this is unpersuasive. MPEP 2123 “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure….”. "[T]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Unless there is a criticism, discrediting, or discouragement of the early resolution there is no teaching away.
According to the arguments at 3., While applicant argues that Okamoto does teach chiral HPLC for separation and admits that it is routine, it is argued that there is no motivation to apply such techniques. The Examiner disagrees since as discussed above resolving intermediates further upstream offers a number of advantages, including material savings, reduced solvent usage, and improved overall scalability of the synthetic route.
According to the arguments at 4., Applicants solved a problem regarding the separation of an advanced intermediate, however this is exactly the motivation put forth in the rejection. This is a known advantage of conducting resolution of an upstream intermediate. While applicant may have an additional reasons for resolving the compound that does not take away from the obviousness of the resolution as set forth in the rejection. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The rejection of claim(s) 3 and 6 under 35 U.S.C. 103 as being unpatentable over Hahn US 20140031391 A1 is maintained. Applicants representatives arguments submitted April 20, 2026 have been fully considered but are unpersuasive. According to the arguments the examiner is engaging in improper hindsight. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant doesn’t dispute that the very small genus Of Hahn subsumes applicant’s compound but somehow considering the small genus is hindsight. Applicant then argues that a different intermediate was not rejected. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., The compounds of claims 8 and 10) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding the lack of motivation argued on page 13 the rejection clearly explains that any of these esters are expected to work in the synthesis of Hahn. The examiner gave a further motivation regarding the fact that methanol MeOH would be avoided since it is a Class 2 solvent, however butanol is a class 3 solvent. According to the argument this is a “an improper, non-technical rationale”. Choosing the solvent based on the technical classification is a proper technical rationale. Regardless, 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. This is not an obvious to try argument this is a genus of only seven possible alkyls, with a motivation to use the claimed compound.
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. THIS ACTION IS MADE FINAL. 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
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