Jose Maria. Cid-Nunez et al.

Patent Trials and Appeals BoardAug 12, 2019

14817676 - (D) (P.T.A.B. Aug. 12, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/817,676 08/04/2015 JOSE MARIA CID-NUNEZ 103693.000815/ PRD2855USD1 7816 45511 7590 08/12/2019 BakerHostetler Cira Centre, 12th Floor 2929 Arch Street Philadelphia, PA 19104-2891 EXAMINER O DELL, DAVID K ART UNIT PAPER NUMBER 1625 NOTIFICATION DATE DELIVERY MODE 08/12/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): eofficemonitor@bakerlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ________________ Ex parte JOSE MARIA CID-NUNEZ, ANDRES AVELINO TRABANCO-SUAREZ, GREGOR JAMES MACDONALD, GUILLAUME ALBERT JACQUES DUVEY, ROBERT JOHANNES LÜTJENS, and TERRY PATRICK FINN1 ________________ Appeal 2018-002613 Application 14/817,676 Technology Center 1600 ________________ Before FRANCISCO C. PRATS, JOHN G. NEW, and RACHEL H. TOWNSEND, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants identify Addex Pharmaceuticals, S.A. and Janssen Pharmaceuticals, Inc. as the real parties-in-interest. App. Br. 1. Appeal 2018-002613 Application 14/817,676 2 SUMMARY Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 1–8 as unpatentable under 35 U.S.C. § 103(a) as being obvious over the combination of Imogai et al. (US 2010/0166655 A1, July 1, 2010) (“Imogai ’655”) and Imogai et al. (US 2007/0213323A1, September 13, 2007) (“Imogai ’323”).2 Claims 1–8 also stand rejected as unpatentable under 35 U.S.C. § 103(a) as being obvious over the combination of Cid-Nunez et al. (US 2010/0063092 A1, March 11, 2010) (“Cid-Nunez ’092”) and Imogai ’323. Claims 1–8 stand further rejected as unpatentable under the nonstatutory doctrine of obviousness-type double patenting over the combination of claims 1–8 of US 9,114,138 B2, August 25, 2015 (the “’138 patent”), G.A. Patani et. al., Bioisosterism: A Rational Approach in Drug Design, 96 CHEM. REVS. 1996, 3147–176 (1996) (“Patani”), B. Wakefield, Fluorinated Pharmaceuticals, 74 INNOVS. PHARM. TECH. 76–78 (2003) (“Wakefield”), and Imogai ’655. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants’ claimed invention is directed to novel pyridinone- derivatives which are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”) and which are useful for the 2 Imogai ’655 is the US equivalent of WO 2007/104783 A2. Imogai ’323 is the US equivalent of WO 2006/030032 A1. Cid-Nunez ’092 is the US equivalent of WO 2008/107479 A1. Final Act. 6, 8. Appeal 2018-002613 Application 14/817,676 3 treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. Spec. 1. REPRESENTATIVE CLAIM Claim 1 is representative of the claims on appeal and recites: 1. A compound having the formula (I) or a stereochemically isomeric form thereof, wherein R1 is C1–6alkyl; or C1–3alkyl substituted with C3–7cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; R2 is halo, trifluoromethyl, C1–3alkyl or cyclopropyl; R3 is hydrogen, fluoro, hydroxyl, hydroxyC1–3alkyl, hydroxyC1–3alkyloxy, fluoroC1–3alkyl, fluoroC1–3alkyloxy or cyano; and Ar is phenyl substituted with n radicals R4, wherein n is 1, 2 or 3; R4 is selected from the group consisting of halo, C1–3alkyl, hydroxyC1–3alkyl, polyhaloC1–3alkyl, cyano, hydroxyl, amino, carboxyl, C1–3alkyloxyC1–3alkyl, C1–3alkyloxy, polyhaloC1–3alkyloxy, C1–3alkylcarbonyl, mono and di(C1–3alkyl)amino, and morpholinyl; or two vicinal R4 radicals taken together form a bivalent radical of formula Appeal 2018-002613 Application 14/817,676 4 -N=CH-NH- (a), -CH=CH-NH- (b), or -O-CH2-CH2-NH- (c); or R3 and a R4 radical in ortho position taken together form a bivalent radical of formula -CH2-O- (d), or -O-CH2- (e); or a pharmaceutically acceptable salt or a solvate thereof. App. Br. 15. ISSUES AND ANALYSES We are not persuaded by the Examiner’s findings, reasoning, and conclusion that the claims on appeal are prima facie obvious under 35 U.S.C. § 103(a) over the cited prior art. But we adopt the Examiner’s findings, reasoning, and conclusion that the claims on appeal are prima facie obvious over the cited prior art under the nonstatutory doctrine of obviousness-type double patenting. We address the arguments raised by Appellants below. Appeal 2018-002613 Application 14/817,676 5 A. Rejection of claims 1–8 under 35 U.S.C. § 103(a) Issue Appellants argue that the Examiner erred in failing to establish equivalence between a –CN residue and a halogen or an alkyl at the R2 position of the claimed compound. App. Br. 3. Analysis With respect to the rejection of the claims over Imogai ’323 and Imogai ’655, the Examiner finds that, although the exchange of a –CN for a halogen or alkyl would not ordinarily be an obvious modification, Imogai ’323 teaches that these groups are equivalent in the claimed compositions. Final Act. 7. Specifically, the Examiner finds that Table 10 of Imogai ’323 teaches pyridinone mGluR2 receptor ligands with –CN groups at the R2 locus. The Examiner further finds that Table 9 of Imogai ’323 teaches that the carbon at the R2 position of the pyridinone ring is occupied by a halogen and alkyl (R5 group). Id. at 7–8. The Examiner therefore finds that the compounds of the claims on appeal are analogs of compositions described by the prior art. Id. at 8. The Examiner concludes that a person of ordinary skill in the art would have been motivated to make the compounds of the invention because such an artisan would have expected the compounds to have similar properties. Id. Indeed, the Examiner finds, the compounds recited in the claims on appeal have the same properties as those described by the cited prior art references. The Examiner further finds that the choice of the difluorophenyl group recited in claims 4–8 is pointed to by the teachings of Imogai ’655, which discloses difluorophenyl compounds in a number of substituted derivatives in compounds having similar properties as a glutamate mGluR2 Appeal 2018-002613 Application 14/817,676 6 receptor agonist. Id. at 8 (citing Imogai ’655 Table 2, Exs. 2-045, 2-052, 2- 051). Similarly, the Examiner finds that, with respect to the rejection of the claims over Cid-Nunez ’092 and Imogai ’323, Table 10 of Imogai ’323 teaches pyridinone mGluR2 receptor ligands with –CN groups at the R2 position of the pyridinone ring. Final Act. 9. The Examiner also finds that Table 9 of Imogai ’323 teaches a halogen or an alkyl (R5 group) occupying the R2 position. Id. at 9–10. Arguing both art rejections together, Appellants contend that both Imogai ’655 and the Cid-Nunez ’092 differ, in part, from the claims of the instant application in that, whereas both describe compounds having a –CN group in the R2 position of the pyridinone moiety, the compositions recited in the claims on appeal have either a halo, trifluoromethyl, a C1–3alkyl or a cyclopropyl in the R2 position. App. Br. 3–4. Appellants assert that the Examiner has failed to establish that Imogai ’323 alters what would be the customary finding that the proposed change is not a change of equivalents and, hence, not an obvious substitution. Id. at 4. Specifically, Appellants argue, the Examiner points to Table 10 of Imogai ’323 as teaching exemplary pyridinone compounds containing -CN groups in the R2-position of the ring, and to and Table 9 as teaching of exemplary compounds in which the R2-position is occupied by a halogen or alkyl (as R5). App. Br. 4 (citing Final Act. 7–8). However, Appellants argue, the compounds of Tables 9 and 10, although sharing a pyridinone moiety, are significantly different, and do not support the equivalence of –CN and halo/alkyl as substituents. Id. Appellants point to Table 9 of Imogai ’323 as teaching a set of compounds having the general formula: Appeal 2018-002613 Application 14/817,676 7 In which R3 is a range of substituted phenyl groups; R4 (corresponding to piperidine in the instant claims) is H, -CH3, -CH2CH2OH, -CH2-O-CH3, - CH2-CH2-O-CH3, or -OCH3; and R5 is H, -F, -Cl, -NO2, -CH3, -CH2OH, - C(O)-O-CH3, or -OCH3.3 App. Br. 4–5. Appellants assert that comparison of the two sets of the structures of Tables 9 and 10 of Imogai ’323 demonstrates significant differences at all three of the 3-, 4-, and 5- positions, making a comparison of the effects of changes at the 3-position speculative at best. Id. at 5. According to Appellants, each of the three points of substitution contains substituent options which are mutually exclusive of one another. Id. On this basis, argue Appellants, the –CN group is no more equivalent to a halo or an alkyl residue at the R5 position than hydrogen would be to thiophenyl in the R4-position, or than hydrogen would be to a substituted phenyl in the R3-position, as taught, respectively, by Tables 9 and 10 of Imogai ’323. Id. Appellants next point to Table 19 of Imogai ’323, which, they argue, provides activity data for a selected set of compounds, including some of the compounds provided in Tables 9 and 10. App. Br. 6. Appellants assert that, again, there is no basis for the Examiner’s finding that Imogai ’323 teaches the equivalence of –CN and halo/alkyl in these pyridin-2(1H)-one core structures, much less when the 4-position is substituted with a functionalized 3 We note here that the R5 position of Imogai ’323 corresponds to the R2 position of Appellants’ claims on appeal Appeal 2018-002613 Application 14/817,676 8 piperidinyl moiety. Id. Appellants note that, of the three pyridin-2(1H)-one derivatives showing the highest activity, only two compounds (compounds 10-28 and 10-30) have a substituent at the R4-position of the pyridin-2(1H)- one core. Id. (citing, e.g., compounds 9-06, 10-28, and 10-30 of Table 19). Appellants assert that compound 9-06 does not share any structural features in common with compounds 10-28 or 10-30 other than the pyridinone core. Id. at 7. Rather, Appellants argue, compound 9-06 bears different substituents at the V1, R3, R4, and R5 positions of the pyridinone ring, compared with those locations at compounds 10-28 and 10-30. Id. Appellants argue that these data render suspect any structural comparison between these compounds. Id. Appellants also take issue with the Examiner’s finding that: “these groups would seem to be considered equivalent if the inventors drafted a Markush group to include them.” App. Br. 7 (quoting Final Act. 3). Appellants assert that the Examiner’s position is inconsistent with the law, citing In re Ruff, 256 F.2d 590, 599 (C.C.P.A. 1958), which held that the mere fact that components are claimed as members of a Markush group cannot be relied upon to establish the equivalency of the components. Id. We are not persuaded by the Examiner’s reasoning. As an initial matter, we do not find persuasive Appellants’ argument that the exemplary formulations of Tables 9 and 10 of Imogai ’323 “contain[ ] substituent options which are mutually exclusive of one another.” See App. Br. 5. Imogai teaches a vast array of compounds, a large number of which are based upon the pyridinone ring depicted supra, and all of which are claimed to have activity as mGluR2 receptor agonists. See Imogai ’323 Abstr., ¶¶ 35–42. We can discern no teaching or suggestion of Imogai ’323, nor do Appellants point us to any, that the various substituents of the exemplary Appeal 2018-002613 Application 14/817,676 9 compounds of Tables 9 and 10 are mutually exclusive of additional substitutions, as Appellants argue. To the contrary, the large number of possible substituents recited in Imogai ’323 encompass a much larger genus of pyridinone-based compositions than are provided for in the examples of Tables 9 and 10. See Medichem, S.A. v. Rolabo, S.L. Eyeglasses, 437 F.3d 1157, 1166 (Fed. Cir. 2006) (holding that: “the prior art must be considered as a whole for what it teaches”). Nevertheless, we conclude that the Examiner has failed to establish a prima facie case that the presence of a halogen or a nitrile (i.e., –CN) moiety at the R2 position of the claimed compounds would be equivalent or that the substitution of one for the other would have been obvious to a person of ordinary skill in the art. Our reasoning, however, differs somewhat from that of Appellants. Although Imogai ’323 teaches, inter alia, compositions based upon a pyridinone ring (as depicted supra), it does not teach the piperidine- substituted phenyl claimed at the 3-carbon position of the compounds recited in Appellants’ claims. However, Imogai ’655 teaches compounds that are most closely related to the claimed composition, based upon structural Formula (I): Appeal 2018-002613 Application 14/817,676 10 See Imogai ’655 ¶ 17. Imogai ’655 teaches embodiments of this formula in which: “A is Het2 or phenyl, wherein each radical is optionally substituted with n radicals R4, wherein n is an integer equal to zero, 1, 2 or 3.” Id. at ¶ 22. Imogai ’655 further teaches that L can be a covalent bond, that Het2 is selected from selected from the group comprising, inter alia, piperazinyl and piperidinyl, and that R4 can constitute aryl, which the references teaches is: “naphthyl, phenyl, or biphenyl; wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other selected from the group of halo….” Imogai ’655 ¶¶ 20, 23, 27, 28. In short, Imogai ’655 teaches, among its embodiments, the claimed compositions with the single exception that the claimed compounds possess a “halo, trifluoromethyl, C1–3 alkyl or cyclopropyl” moiety at the R2 position, whereas Imogai ’655 teaches a nitrile moiety at the same locus4: Imogai ’655 Claim 1 Imogai ’323 teaches, inter alia, pyridinone ring-based compounds, but does not teach a piperidine ring, or a substituted phenyl at either R4 or Ar: 4 Appellants mention Cid-Nunez ’092 only briefly in their Appeal Brief, focusing principally upon the alleged deficiencies of Imogai ’323. However, Cid-Nunez ’092 also teaches compositions with a strong similarity to the claimed composition, but possess a nitrile group at the claimed R2 position, similar to that of Imogai ’655. We therefore include Cid-Nunez ’092 in this analysis. Appeal 2018-002613 Application 14/817,676 11 Imogai ’323 Imogai ’323 ¶ 40. Imogai ’323 further teaches that: R2, R3, R4 and R5 are each independently selected from the group of hydrogen, halogen, –CN, –NO2 , -C(=O)OR10, -OR10, and an optionally substituted radical, preferably substituted with hydroxy, selected from the group of –(C1-C6)alkyl and a radical –V2–T2–M2 ; and that: T2 , V2 are each independently a covalent bond or a radical selected from the group of –O-; –C(=O)–; –NR10– and an optionally substituted radical, preferably substituted with hydroxy, selected from the group of –(C1-C6)alkyl–; –(C2- C6)alkenyl-; –(C2-C6)alkynyl–; –(C0-C6)alkyl–O–(C1-C6)alkyl–; and –(C0-C6)alkyl-NR10–(C1-C6)alkyl- wherein R10 is preferably hydrogen or (C1-C6)alkyl. Imogai ’323 ¶¶ 40–41. Imogai ’323 thus teaches that in these compositions, and among many other possibilities, that a nitrile or a halogen may be substituted at any of the R2, R3, R4, or R5 locations. It is upon this teaching that the Examiner finds that, in the teachings of Imogai ’323, nitrile and halogen are equivalents at the R2 position, and concludes that it would therefore have been obvious to a person of ordinary skill in the art to have substituted the allegedly equivalent halogen atom for the nitrile group at the R2 position in the compounds of Formula (I) of Imogai ’655 to arrive at the claimed compounds. Appeal 2018-002613 Application 14/817,676 12 We are not persuaded. The Examiner acknowledges that: “[o]rdinarily the change of a –CN to a halogen or alkyl would not be an obvious modification, however the secondary reference teaches the equivalence of these groups.” See Final Act. 7. However, given the very large number of possible compounds taught by Imogai ’323 (a great many of which are not based upon a pyridinone ring), the dissimilarities between the compounds of Imogai ’665 and ’323 in substitutions at the R5 position of Imogai ’323, and the large number of possible locations for a halogen or nitrile moiety (among others) in the R2, R3, R4, or R5 positions taught by Imogai ’323, we are not persuaded that a person of ordinary skill in the art would have found it obvious to make the proposed substitution of a halogen atom for a nitrile moiety at the claimed position. Nor are we persuaded that, given the very large number of possible permutations taught by the references, a person of ordinary skill would have been motivated to make the substitution proposed by the Examiner. Rather, what the Examiner has proposed is, at best, a conclusion that it would have been obvious to try the halogen-for-nitrile substitution at R2. That is insufficient to establish a prima facie case of obviousness. As our reviewing court has held: The … “obvious to try” [error typically occurs] … [when] it would have “obvious to try” … to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful…. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988); see also In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009) (holding that: “In such circumstances, where a defendant merely throws metaphorical darts at a board filled with Appeal 2018-002613 Application 14/817,676 13 combinatorial prior art possibilities, courts should not succumb to hindsight claims of obviousness”). We consequently reverse the Examiner’s rejection of claims 1–8 over Imogai ’323 and Imogai ’665, and over Imogai ’323 and Cid-Nunez ’092. Furthermore, because we reverse the claims on this ground, we do not reach Appellants’ additional arguments with respect to dependent claims 4–6 and 8. See App. Br. 8–9. B. Rejection of claims 1–8 under the nonstatutory doctrine of obviousness-type double patenting Issue Appellants argue the Examiner erred because a person of ordinary skill would not have had a reasonable expectation that substituting fluorine for hydrogen on the phenyl group (Ar), as claimed, would have led to predictable results. App. Br. 9–10. Analysis According to Appellants, the Examiner’s rejection is based on the conclusion that the substitution of hydrogen by fluorine is an obvious and patentably indistinct substitution. App. Br. 10 (citing Final Act. 11). Appellants contend that, in reaching this conclusion, the Examiner relies upon Wakefield as providing a general motivation for fluorinating pharmaceuticals. Id. (citing Final Act. 12–13 (citing Wakefield 76)). Appellants argue, however, that Wakefield seeks to rationalize retrospectively why certain substitutions by fluorine in three specific examples have been successful. Id. Appellants assert that Wakefield provides no guidance or suggestions as to which substitutions would have Appeal 2018-002613 Application 14/817,676 14 positive, negative, or neutral effects on drug performance. Id. Appellants contend further that Wakefield addresses specific fluorine substitutions in 5-fluorouracil, ciprofloxacin, and lansoprazole, none of which are chemically related to the compounds of the instant claims. Id. Appellants argue that the effect of fluorine on the biological activity of organic compounds is subtle and difficult to predict and that intensive structure-activity relationship studies are necessary to pinpoint the correct position of fluorine in the target molecule. App. Br. 11 (citing J. Wang et al., Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011), 114 CHEM. REVS. 114, 2434 (2014) (“Wang”)). Appellants assert that neither Wakefield nor Patani provide a sufficient level of predictability such that a person of ordinary skill would be motivated to exchange the hydrogen for a fluorine on the phenyl group Ar. Id. Appellants argue further that, contrary to Wakefield’s teachings that “fluorinated compounds ... tend to have similar inherent biological activity [as their non-fluorinated analogues],” each of Patani’s examples show that fluorine substitution can significantly alter binding or biological activity. App. Br. 11 (citing Final Act. 5). Appellants contend that, although the examples provided by Patani demonstrate enhanced activity due to the fluorine substitution, such enhancement (as opposed to a neutral or negative effect) is not taught by Patani to necessarily be expected. Id. at 11–12. Appellants argue that, to the extent that Patani describes substitution of fluorine for hydrogen at all, it does so in the context of an “exploration,” and generally explains the results of such substitution in terms of after-the-fact rationale. Id. at 12. Therefore, Appellants argue, Patani supports the position that substitution with even one fluorine atom in any particular Appeal 2018-002613 Application 14/817,676 15 position on a molecule will not yield predictable results, since until tested, no particular results are expected. Id. We are not persuaded by Appellants’ arguments. Claim 1 of the ’138 patent recites a molecule that is substantially identical to the compositions of claim 1, with the exception that the ’138 patent recites: “Ar is unsubstituted phenyl.” Appellants’ claim 1, in contrast, recites: “Ar is phenyl substituted with n radicals R4, wherein n is 1, 2 or 3; [and] R4 is selected from the group consisting of halo[gen]….” The Examiner finds that the substitution of difluorophenyl group at Ar is suggested by Imogai, which teaches difluorophenyl compounds in a number of substituted derivatives at this position. Final Act. 13 (citing Imogai ’655 Table 2, examples 2-052, 2-051, 2-045). We agree. Specifically, Imogai ’655 teaches that, at this same locus, in a substantially similar compound (Formula (I))5, that: “aryl is naphthyl, phenyl, or biphenyl; wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other selected from the group of halo[gen]….” Imogai ’655 ¶ 28. Imogai ‘655 thus directly teaches the use of an unsubstituted phenyl or a phenyl substituted with 1, 2, or 3 fluorine atoms at this location. Furthermore, the references cited by the Examiner, and by Appellants, provide motivation to substitute fluorine for hydrogen on the phenyl at the Ar locus. Patani teaches: The substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements. Steric parameters for hydrogen and fluorine are similar, their van der 5 The principal difference being, as we explained supra, a nitrile group at the R2 position, rather than a fluorine atom. Appeal 2018-002613 Application 14/817,676 16 Waal’s radii being 1.2 and 1.35 Å, respectively. Due to its electronegativity, fluorine exerts strong field and inductive effects on the adjacent carbon atom. Fluorine substitution, in general, exerts a diminished electron-withdrawing effect at distal sites. Patani 3149 (internal reference omitted). Similarly, Wakefield teaches that: “[T]he fluoro-organic compound has inherent biological activity, [and] the introduction of fluorine into a biologically active compound improves its pharmacological properties.” Wakefield 74. Wakefield further teaches that “[O]rganofluorine compounds should be recognized as important mainstream pharmaceuticals and advances in synthetic methodology make them readily available.” Id. at 78. Finally, Wang, cited in rebuttal by Appellants, expressly teaches: While substitution of fluorine for hydrogen results in minor steric alterations, electrostatic repulsive interaction or attraction of fluorine23 or CF324 with other functional groups in a molecule can lead to significant conformational changes. Another rather established effect of fluorination is a modulation of metabolic stability. In particular, replacing hydrogen with fluorine on aromatic rings is a very effective strategy to slow down significantly the oxidative metabolic step of a given drug by Cytochrome P450 monooxygenases. Hydrolytic metabolism can also be noticeably influenced by fluorination. In this case the electron-withdrawing property of fluorine plays a key role in effecting reaction rates and the stability of the intermediates. One may agree that these general areas of the fluorine effect provide quite attractive opportunities in drug design. Wang 2434 (emphases added). We conclude that Imogai ’655’s teaching of multiple phenyl substitutions on the phenyl ring of a highly similar compound, combined with the teachings of Patani, Wakefield, and Wang encouraging substituting fluorine for hydrogen on a phenyl ring in bioactive compounds as a way of Appeal 2018-002613 Application 14/817,676 17 increasing their activity and preventing their degradation, would give a person of ordinary skill a reason to make the substitution and would give a skilled artisan a reasonable expectation of success. We consequently affirm the Examiner’s rejection. B. Rejection of claims 4–6 and 8 under the nonstatutory doctrine of obviousness-type double patenting Issue Appellants argue these claims separately. App. Br. 12. Claim 5 is exemplary, and recites: “The compound according to claim I wherein said compound is: or a pharmaceutically acceptable salt or a solvate thereof.” Id. at 16. Appellants argue that the Examiner erred by failing to show that a person of ordinary skill in the art would be motivated to provide multiple substitutions of H to F. Id. at 12. Analysis Appellants point to the Examiner’s finding that: “the choice of the difluorophenyl group is pointed to by the teachings of Imogai [’655],” and citing compounds 2-052, 2-045, and 2-051. App. Br. 13 (quoting Final Act. 13). Appellants contend that such a comparison is “suspect” because these compounds use difluorophenyl groups having different substitution patterns (i.e., 3,4-difluoro and 3,5-difluoro), attached to different pyridinone Appeal 2018-002613 Application 14/817,676 18 frameworks, i.e., the difluorophenyl moiety is attached to a piperazine in Imogai ’655, and not a piperidine, as in the instant claims. Id. Appellants argue further that the R1 substituents in at least claims 2–8 (1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2- (cyclopropyl)-1-ethyl) are very different from the V1-M1 substituents of Imogai ’655 (para-fluoro benzyl or para-trifluoromethoxy benzyl). Given the alleged uncertainty associated with the effect of fluorine substitution, argue Appellants, any particular level of performance would have been unpredictable. We are not persuaded by Appellants’ arguments. The exemplary embodiments in Table 2 of Imogai ’655 do not constitute all of the possible compounds asserted by the claims or by the Specification. Claim 1 of the ’138 patent teaches a piperidine linking the pyridinone group to the phenyl Ar, as is recited in Appellants’ claim 5. Imogai ’655 expressly teaches that the group linking the pyridinone and the phenyl can be, interchangeably, a piperidine or a piperazine. Imogai ’655 ¶ 27. Imogai ’655 also teaches substitution of fluorine for hydrogen at 1, 2, or 3 locations on the phenyl ring, and does not exclude the positions (2,4 difluoro) recited in claim 5. Id. at ¶ 28. Patani, Wakefield, and Wang all provide a motivation to make the fluorine substitutions and provide a reasonable expectation of success. Nor are we persuaded by Appellants’ argument that the difference between the V1-M1 substituents of Imogai ’655 and the substituents at the R1 position in Appellants’ claims inject so much uncertainty into the obviousness analysis that the fluorine substitution would not have been obvious. The R1 substituents of both claim 1 of the ’138 patent (the basis of the rejection) and Appellants’ claims are identical, i.e.: “C1-6alkyl; or Appeal 2018-002613 Application 14/817,676 19 C1-3alkyl substituted with C3-7cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy.” As we have explained supra, Imogai ’655, Patani, Wakefield, and Wang teach that a person of ordinary skill in the art would have been motivated to substitute fluorine for hydrogen at different positions on the phenyl ring Ar, and would have had a reasonable expectation of success in so doing. We consequently affirm the Examiner’s rejection of the claims. DECISION The Examiner’s rejection of claims 1–8 under 35 U.S.C. § 103(a) is reversed. The Examiner’s rejection of claims 1–8 under the nonstatutory doctrine of obviousness-type double patenting is affirmed. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED