Ex Parte Torrens et alDownload PDFPatent Trial and Appeal BoardJul 15, 201311457720 (P.T.A.B. Jul. 15, 2013) Copy Citation 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. 11/457,720 07/14/2006 Antoni TORRENS 006444.00047 (ET0043) 7610 22907 7590 07/15/2013 BANNER & WITCOFF, LTD. 1100 13th STREET, N.W. SUITE 1200 WASHINGTON, DC 20005-4051 EXAMINER HAVLIN, ROBERT H ART UNIT PAPER NUMBER 1626 MAIL DATE DELIVERY MODE 07/15/2013 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte ANTONI TORRENS, HELMUT BUSCHMANN, JORDI QUINTANA, SUSANA YENES, and JOSEP MAS __________ Appeal 2011-012659 Application 11/457,720 Technology Center 1600 __________ Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1 under 35 U.S.C. § 134 involving claims to a substituted pyrazoline compound. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We vacate and enter a New Grounds of Rejection. 1 Appellants have identified the Real Party in Interest as Laboratorios del Dr. Esteve S.A. (see App. Br. 4). Appeal 2011-012659 Application 11/457,720 2 Statement of the Case Background The Specification teaches compounds which “have a high affinity for cannabinoid receptors, particularly for the CB1-receptor, and that they act as modulators e.g. antagonists, inverse agonists or agonists on these receptors” (Spec. 2, ll. 25-27). The Claims Claims 1, 17, 21-27, and 42-44 are on appeal. Claim 1 is representative and is reproduced in the Appellants‟ Claims Appendix. The Issues A. The Examiner rejected claims 1, 17, 21-27, and 42-44 under 35 U.S.C. § 103(a) as obvious over Barth 2 and Lange „179 3 (Ans. 7-18). B. The Examiner rejected claims 1, 17, 21-27, and 42-44 under 35 U.S.C. § 103(a) as obvious over Lange „04 4 and Lange „05 5 (Ans. 22-30). We vacate the Examiner‟s rejections and enter the following new ground of rejection in order to combine all of the relevant teachings from the cited prior art into a single obviousness rejection. 2 Barth et al., US 5,624,941, issued Apr. 29, 1997. 3 Lange et al., US 2005/0171179 A1, published Aug. 4, 2005. 4 Lange et al., Synthesis, Biological Properties, and Molecular Modeling Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selective CB1 Cannabinoid Receptor Antagonists, 47 J. MED. CHEM. 627-643 (2004). 5 Lange et al., Bioisosteric Replacements of the Pyrazole Moiety of Rimonabant: Synthesis, Biological Properties, and Molecular Modeling Investigations of Thiazoles, Triazoles, and Imidazoles as Potent and Selective CB1 Cannabinoid Receptor Antagonists, 48 J. MED. CHEM. 1823- 1838 (2005). Appeal 2011-012659 Application 11/457,720 3 New Grounds of Rejection Under the provisions of 37 C.F.R. § 41.50(b), we enter the following new grounds of rejection. Claims 1, 17, 21-27, and 42-44 are rejected under 35 U.S.C. § 103(a) as obvious over Barth, Lange „179, and Lange ‟05. The issues are: (i) Does the evidence of record support a prima facie case of obviousness for the elected species? (ii) If so, have Appellants presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? Findings of Fact 1. Appellants elected cis-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid azepan-1-ylamide hydrochloride, with the structure reproduced below: (see Response to Election/Restriction, filed May 11, 2007; claim 17, compound 3). Appeal 2011-012659 Application 11/457,720 4 2. Barth teaches the following compound (Example #64): Barth teaches that this compound is “N-piperidino-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), or one of its pharmaceutically acceptable salts” (Barth, col. 26, ll. 42-44). 2. Barth teaches that: In particular, the compound of formula (I) in which g2,g3, g5, g6, w3, w5 and w6 are hydrogen, w2 and w4 are a chlorine atom, R4 is methyl, X is a direct bond and R is 1- piperidinylamino (namely N-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), or one of its pharmaceutically acceptable salts, exhibits a very good affinity for the central cannabinoid receptors. This compound is a potent and selective antagonist of the central cannabinoid receptors and has a Ki of about 2 nM. It is from 500 to 1000 times more active on the central receptor as on the peripheral receptor; it is also active upon oral administration and penetrates the blood-brain barrier. The good penetration of this compound in the central nervous system as well as its antagonist character are confirmed by the results obtained with the model of the antagonism of Appeal 2011-012659 Application 11/457,720 5 hypothermia induced by an agonist of cannabinoid receptors. Especially, this compound antagonizes the hypothermia induced by WIN 55 212-2 in mice with an ED50 of 0.3 mg/kg i.p. and 0.4 mg/kg per os. In this test . . . the above compound exerted its action for 8 to 10 hours after oral administration of a dose of 3 mg/kg. (Barth, col. 26, ll. 39-61.) 3. Barth teaches that the “compounds of formula (I) can be isolated in the form of one of their salts, where appropriate, for example the hydrochloride or the oxalate” (Barth, col. 20, ll. 19-21). 4. Lange „179 teaches compounds, identified as compounds 2 and 3 in the text (and compound 2 was erroneously listed as compound 1 in the figure legend) which are reproduced below: “Compound 2: N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4- dichloropheny1)-4,5 -dihydro-( lH)-pyrazole-3-carboxamide” (Lange 7 ¶ 0071). Appeal 2011-012659 Application 11/457,720 6 “Compound 3: N-(Piperidin-1-yl)-1-(2,4-dichloropheny 1)-5 -phenyl-4,5 - dihydro-( 1H)-pyrazole-3-carboxamide” (Lange 7 ¶ 0072). 5. Lange „179 teaches “that potent and selective antagonism or inverse agonism of cannabinoid CB1 receptors is present in the novel 1,3,5- trisubstituted 4,5-dihydro-1H-pyrazole derivatives of the formula (I)” (Lange ‟179 1 ¶ 0003). 6. Table I of Lange „179 is reproduced below: Table I shows “Cannabinoid receptor affinity and functional in vitro data data” (Lange „179 10 ¶ 0094). Appeal 2011-012659 Application 11/457,720 7 7. Lange ‟05 teaches that: Bioisosteric replacement forms a rational medicinal chemistry approach for the discovery of new leads or series, based on existing key ligands. The three-dimensional structures of thiazoles, triazoles, and imidazoles maintain a high similarity to that of the pyrazole. As a consequence they can be regarded as isosteres thereof and have been applied in order to discover pyrazole bioisosteres. (Lange ‟05 1823, col. 2.) 8. Lange ‟05 teaches the structure of compound 62, reproduced below: (Lange ‟05 1830, col. 2). 9. Lange ‟05 teaches a compound 69R as reproduced below: Appeal 2011-012659 Application 11/457,720 8 10. Lange ‟05 teaches that “[s]ubstitution of the piperidinyl group in 62 by . . . the corresponding seven-membered azepanyl group containing 69 . . . elicited clearly decreased affinit[y]” (Lange ‟05 1826, col. 2). 11. Lange ‟05 teaches that “[f]ive- to seven-membered cycloalkyl groups (72-74) were also good receptor binders” (Lange ‟05 1827, col. 1). 12. Lange ‟05 teaches that “[m]olecular modeling studies revealed a close three-dimensional structural overlap between the key compound 62 and the known CB1 receptor antagonist rimonabant” (Lange ‟05 1830, col. 1). 13. Table 1 of Lange ‟05 is reproduced below: “Table 1. In Vitro Results of Compounds 13, 14, 27, 28, 60-80, 82, 87, 91- 93, 97, and 103” (Lange ‟05 1827). 14. Lange ‟05 teaches that the “5-methylated imidazole 62 was found very potent in both assays, indicating that a methyl group constitutes the optimal substituent in this series. Its potent in vivo activity is in line with that of 1 thereby again corroborating the bioisosteric concept” (Lange ‟05, 1828, col. 1). Appeal 2011-012659 Application 11/457,720 9 15. Lange ‟05 teaches that the “presence of more bulky bicyclic moieties such as in 71, 77, and 78 was well tolerated.” (Lange ‟05 1826, col. 2.) Principles of Law The analysis for obviousness of chemical variations is based on a long line of Federal Circuit and CCPA decisions. In In re Dillon, the Federal Circuit noted: In brief, the cases establish that if an examiner considers that he has found prior art close enough to the claimed invention to give one skilled in the relevant chemical art the motivation to make close relatives (homologs, analogs, isomers, etc.) of the prior art compound(s), then there arises what has been called a presumption of obviousness or a prima facie case of obviousness. In re Henze, 181 F.2d 196, 37 CCPA 1009, 85 USPQ 261 (CCPA 1950); In re Hass, 141 F.2d 122, 127, 130, 31 CCPA 895, 60 USPQ 544, 548, 552 (CCPA 1944). The burden then shifts to the applicant, who then can present arguments and/or data to show that what appears to be obvious, is not in fact that, when the invention is looked at as a whole. In re Papesch, 315 F.2d 381, 50 CCPA 1084, 137 USPQ 43 (CCPA 1963). The cases of Hass and Henze established the rule that, unless an applicant showed that the prior art compound lacked the property or advantage asserted for the claimed compound, the presumption of unpatentability was not overcome. In re Dillon, 919 F.2d 688, 696 (Fed. Cir. 1990). Analysis Prima facie case The current facts fall squarely within the ambit of Dillon, Henze and Hass. The elected species of claim 1 differs from compound 69 of Appeal 2011-012659 Application 11/457,720 10 Lange ‟05 in two ways. Lange ‟05 has an imidazole ring in the place of the pyrazoline ring and the location of the methyl group on the central ring differs (FF 1, 10). Both compounds bind to the cannabinoid receptor (FF 13; Spec. 2, ll. 4-6). The elected species of claim 1 (FF 1) also differs from compound 64 of Barth (FF 2) in two ways. The elected species has a pyrazoline ring in the place of the pyrazole ring of Barth, representing a single bond, and the elected species has the seven membered azepan ring in the place of a six membered piperidino ring in Barth (FF 2). Both compounds bind to the cannabinoid receptor (FF 2; Spec. 2, ll. 4-6). Lange „179 teaches a compound 3 (FF 4) which has cannabinoid receptor binding activity (FF 5) which also differs from the elected species in three ways. Compound 3 of Lange „179 lacks the 4-methyl group on the pyrazoline ring present in the elected species, and compound 3 of Lang „179 lacks the 4-chloro group on the 5-phenyl ring in the elected species, and and compound 3 of Lange „179 has a six membered piperidino ring in the place of the seven membered azepan ring in the elected species (FF 1, 4). Compound 2, not tested by Lange „179, is actually more similar to the elected species, and differs in only two ways, lacking the 4-methyl group and the azepan group, but having the 4-chloro group. We note that Lange 179‟s compounds 2 and 3 would reasonably anticipate claim 1, though they do not anticipate the elected species. Appeal 2011-012659 Application 11/457,720 11 The ordinary artisan would have reasonably substituted the pyrazoline ring of Lange „179 for the pyrazole ring of Barth and the imidazole ring of Lange ‟05 since Lange ‟05 teaches that: Bioisosteric replacement forms a rational medicinal chemistry approach for the discovery of new leads or series, based on existing key ligands. The three-dimensional structures of thiazoles, triazoles, and imidazoles maintain a high similarity to that of the pyrazole. As a consequence they can be regarded as isosteres thereof and have been applied in order to discover pyrazole bioisosteres. (Lange ‟05 1823, col. 2; FF 7.) That is, Lange ‟05 teaches that in rational drug design, substituting groups such as imidazoles and pyrazoles with the structurally similar pyrazoline group would have been an obvious selection (FF 7). Further, the ordinary artisan would have been motivated to place the methyl group on the pyrazoline group of Lange „179 at the 4-position since Lange ‟05 teaches that “the “5-methylated imidazole 62 was found very potent in both assays, indicating that a methyl group constitutes the optimal substituent in this series. Its potent in vivo activity is in line with that of 1 thereby again corroborating the bioisosteric concept” (Lange ‟05 1828, col. 1; FF 14). Just like the 4-position on the pyrazoline group of Lange „179, the 5-methyl imidazole position in Lange ‟05 is placed on the only carbon of the 5 membered ring not linked to another substituent (see FF 2, 4, 8, 9). All of these compounds share the same activity, binding to the cannabinoid receptor (FF 2, 5, 13; Spec. 2, ll. 4-6). Activity of the claimed and prior art compound plays a role in the obviousness inquiry. See Dillon, 919 F.2d at 696 (“Some of the cited cases also contained language Appeal 2011-012659 Application 11/457,720 12 suggesting that the fact that the claimed and the prior art compounds possessed the same activity were added factors in the establishment of the prima facie case.”). Because the prior art compounds all share the cannabinoid receptor binding activity of the elected species, this common function serves to further support the prima facie obviousness determination (see FF 2, 5, 13). Appellants contend that “[o]ne skilled in the art would therefore not have reasonably expected that modifying (i) the degree of saturation of the core ring, in the compounds disclosed in Barth, or (ii) the substitution pattern about this ring, in the compounds disclosed in Lange „179, would conserve cannabinoid-CB1 receptor inhibition activity” (App. Br. 15). We are not persuaded. Lange „179 teaches that when the degree of saturation of the core ring is changed from pyrazole to pyrazoline, the reduction of a bond, the resulting compounds maintain cannabinoid-CB1 receptor inhibition activity (FF 4). In addition, Lange ‟05 teaches that inclusion of a methyl on the imidazole ring resulted in optimal activity (FF 14) while Barth showed that inclusion of a methyl on the pyrazole ring resulted in a “potent and selective antagonist of the central cannabinoid receptors” (Barth, col. 26, ll. 46-47; FF 2). Thus, the ordinary artisan would reasonably have expected the incorporation of a methyl group on the pyrazoline ring of Lange „179 to improve the properties consistent with the results shown by Lange ‟05 on the imidazole ring (FF 14). Appeal 2011-012659 Application 11/457,720 13 Secondary Considerations The CabanesDeclaration I 6 does not include an example of the elected species (see FF 1). In a supplemental Declaration, Cabanes Declaration II 7 , Table I shows the tested parent compounds, corrected to include a pyrazoline core ring (see Cabanes Dec. II ¶ 5), but none of these compounds represents the elected species. While each of the compounds in the “a” series comprises a 4-substituted pyrazoline core ring, even compound Va, which also comprises the azepan ring of the elected species, differs from the elected species in comprising a 4-oxygen in the place of the 4-chlorine on the phenyl group of the elected species. Thus, none of the results shown in the Cabanes Declaration I or II are commensurate in scope with the elected species. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (Unexpected results must also be “commensurate in scope with the degree of protection sought by the claimed subject matter.”) In addition, the Cabanes Declaration II lacks an explanation of the data for compounds Va and Vb, the closest structures in the Cabanes Declaration II, which data is shown in Appendix I, page 5. The table is not clear whether the n.d. simply means not detected, that is not assayed for, or undetectable as below the lowest limits of detection. We recognize that the data for compounds I-IV demonstrate some improvement, up to 62%, for the methyl substitution on the core ring (see, e.g., Cabanes Dec II ¶ 8, table B). However, Lange ‟05 teaches that the “5- methylated imidazole 62 was found very potent in both assays, indicating 6 Declaration of M a Teresa Serafini Cabanes, filed Jun. 26, 2008. 7 Declaration of M a Teresa Serafini Cabanes, filed Sep. 4, 2009. Appeal 2011-012659 Application 11/457,720 14 that a methyl group constitutes the optimal substituent in this series. Its potent in vivo activity is in line with that of 1 thereby again corroborating the bioisosteric concept” (Lange ‟05 1828, col. 1; FF 14). We therefore find that rather than being unexpected, inclusion of a methyl substituent on the core ring would have been expected by the ordinary artisan to improve activity. See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are evidence of obviousness of a claimed invention. Just as unexpected beneficial results are evidence of unobviousness.”) We also find that the amount of improvement, 62% at most, is substantially less than the variance shown by Lange ‟05 between the in vitro results of compounds 71, 77, and 78 where Lange ‟05 teaches that the equivalence of the results of these compounds, stating that the “presence of more bulky bicyclic moieties such as in 71, 77, and 78 was well tolerated.” (Lange ‟05 1826, col. 2; FF 15.) However, compound 71 shows a Ki of 40, compound 77 a Ki of 34 and compound 78 a Ki of 19, so that the Ki of compound 78 is twofold better than compound 71, but this difference is not interpreted by Lange ‟05 as substantial or unexpected in any way (FF 15). Consequently, the evidence of record does not clearly demonstrate that an improvement of 62% represents an unexpected result relative to the prior art. See In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (“[I]t is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference”). Conclusion of Law (i) The evidence of record supports a prima facie case of obviousness for the elected species. Appeal 2011-012659 Application 11/457,720 15 (ii) Appellants have not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. SUMMARY In summary, we vacate the rejection of claims 1, 17, 21-27, and 42-44 under 35 U.S.C. § 103(a) as obvious over Barth and Lange „179. We vacate the rejection of claims 1, 17, 21-27, and 42-44 under 35 U.S.C. § 103(a) as obvious over Lange „04 and Lange ‟05. This decision also contains new grounds of rejection pursuant to 37 C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” Claims 1, 17, 21-27, and 42-44 are rejected under 35 U.S.C. § 103(a) as obvious over Barth, Lange „179, and Lange ‟05 under the New Grounds of Rejection as discussed above. 37 C.F.R. § 41.50(b) also provides that the Appellants, WITHIN TWO MONTHS FROM THE DATE OF THE DECISION, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new evidence relating to the claims so rejected, or both, and have the matter reconsidered by the Examiner, in which event the proceeding will be remanded to the Examiner.… (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same record.… Appeal 2011-012659 Application 11/457,720 16 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). VACATED, §41.50(b) cdc Copy with citationCopy as parenthetical citation