Ex Parte Moolenaar et alDownload PDFPatent Trial and Appeal BoardJul 28, 201711547152 (P.T.A.B. Jul. 28, 2017) 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. 11/547,152 10/20/2006 Sytske Hyke Moolenaar 2004.837US 8600 210 7590 MERCK P O BOX 2000 RAHWAY, NJ 07065-0907 EXAMINER MCCORMICK, MELENIE LEE ART UNIT PAPER NUMBER 1621 NOTIFICATION DATE DELIVERY MODE 08/01/2017 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): US-DOCKET-PATENT@merck.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SYTSKE HYKE MOOLENAAR, GERARDUS JOHANNES KEMPERMAN, and KEES VAN DER VOORT MAARSCHALK1 Appeal 2015-003491 Application 11/547,152 Technology Center 1600 Before ULRIKE W. JENKS, RYAN H. FLAX, and RACHEL H. TOWNSEND, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a non sublimating solid salt of mirtazapine, and a method of producing the solid salt. The Examiner rejects the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 According to Appellants, the real party in interest is Merck, Sharp and Dohme Corp. MSD Oss B.V., a subsidiary of Merck, Sharp and Dohme Corp. Appeal Br. 2. Appeal 2015-003491 Application 11/547,152 STATEMENT OF THE CASE Claims 1—9 are on appeal, and can be found in the Claims Appendix of the Appeal Brief. Claims 1 and 5 are representative of the claims on appeal, and read as follows: 1. A pharmaceutical formulation comprising an enantiomerically purified form of mirtazapine, wherein the mirtazapine is present as a pharmaceutically suitable non sublimating and solid salt of mirtazapine. 5. A method to prevent sublimation of mirtazapine from a pharmaceutical formulation comprising an enantiomerically purified form of mirtazapine in solid form, characterized by selecting a pharmaceutically suitable non-sublimating salt of S- or R-mirtazapine during manufacturing the pharmaceutical formulation. Appellants seek review of the Examiner’s rejection of claims 1—9 under 35 U.S.C. § 103(a) as unpatentable over Burg2 and Watthey3 in view of Gould4 and Moody.5 The issue is: Does the preponderance of evidence of record support the Examiner’s conclusion that the combination of references renders the claims directed to a non-sublimating salt of S- or R-mirtazapine obvious? Findings of Fact FF1. Example 19 of Burg teaches the optical resolution of 2-methyl- 1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[ 1,2-a]pyrido[3,2- 2 William J. van der Burg, US 4,062,848, issued Dec. 13, 1977 (“Burg”). 3 Jeffrey W.H. Watthey, US 4,515,792, issued May 7, 1985 (“Watthey”). 4 Philip L. Gould, Salt selection for basic drugs, 33 Intem’l J. Pharmaceutics 201-217 (1986)(“Gould”). 5 Joanna Moody et al., Biotransformation of Mirtazapine by Cunninshamella Elesans. 30 Drug Metabolism and Disposition 1274—79 (2002) (“Moody”). 2 Appeal 2015-003491 Application 11/547,152 fjazepine, a.k.a. mirtazapine. Burg 20:5—35. The structure of the compound of example 19 is provided below: 2-methyl-1,23,4,10, 14b~hexahydro-benzo[c jpyrazmol 1,2-aJpyrido[3,24]azepine See Burg 20:5—35. FF2. Burg teaches the acid addition of salts of compounds. See Burg 20, By salts of the compounds according to the invention are understood: the pharmaceutically acceptable acid addition salts and quaternary ammonium compounds I. The acid addition salts are obtained by reaction of the free base I with a suitable inorganic or organic acid, such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, ascorbic acid etc. Burg 6:60-68. FF3. Burg teaches acid addition salts of mirtazapine. Treatment of the “free base with an alcoholic HC1 [(hydrochloric acid)]solution gives the HC1 salt of 2-methyl l,2,3,4,10,14b-hexahydro-benzo[c] pyrazino-[l,2-a]-pyrido[3,2-f]azepine.” Burg 11:28—31. claim 1. 3 Appeal 2015-003491 Application 11/547,152 FF4. Example 17 of Burg teaches the acid addition of maleic acid to a structurally related compound to mirtazapine. Burg 19:44-47. The structure of the compound in Example 17 is as follows: 1,2 <3,4? 10* 1,4b-hexahydro-benzo[e]pyrazmo[ 1,2-a]pyrido-[3,2-f]azepme “The purified oil [containing 1,2,3,4, 10, 14b-hexahydro- benzo[c]pyrazino[l,2- a]pyrido-[3,2-f]azepine] is then treated with a solution of 1.78 g maleic acid in 100 ml acetone, resulting in crystallization of the maleate-salt of the title compound. After recrystallization from ethanol, 3.6 g of the maleate salt is obtained.” Burg 19:44-47. FF5. Gould teaches: Salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug without modifying its chemical structure. The importance of choosing the ‘correct’ salt form of a drug is well outlined in a published review (Berge et al., 1977) but, although salt form can have a dramatic influence on the overall properties of a drug, the selection of the salt form that exhibits the desired combination of properties remains a difficult semi-empirical choice. Gould 201. 4 Appeal 2015-003491 Application 11/547,152 FF6. Gould teaches that “[s]alt formation is frequently employed to raise the melting point (and crystallinity) of the drug species being processed.” Gould 206. “In general, an increase in melting point, usually by maximizing or encouraging crystal symmetry, leads to reduced solubility in all solvents but generally improved stability, particularly if salt formation results in a crystalline solid, and easier formulation processing.” Gould 207. FF7. Moody teaches Cunninghamella elegans is a suitable microbial model of mammalian metabolism. Incubation of C. elegans with optically pure R(-) and lS,(+)-mirtazapine showed that all seven metabolites were formed from the lS'(+)-enantiomer, with mirtazapine N- oxide as the major metabolite .... The R(-) enantiomer formed N-desmethyl-8- hydroxymirtazapine, mirtazapine A-oxide, A-desmethylmirtazapine, and 8- hydroxymirtazapine. 8-Hydroxymirtazapine was the major metabolite. Moody 8. “The lS,(+)-enantiomer was converted to the same metabolites as the racemic mixture, whereas the /?(-)-enantiomer formed neither 12- nor 13-substituted metabolites.” Moody 9. FF8. The Specification defines non-subliming as: a salt of S- or R-mirtazapine, from which less than 1 % of the mirtazapine is sublimating from the sample, calculated on the basis of the amount of the base, when a sample of approximately 10 mg (for example an amount between 8-12 mg) is placed for the duration of 72 hours under standard conditions of 150 mBar pressure and 60°C temperature. 5 Appeal 2015-003491 Application 11/547,152 Spec. 2. Examples of non-subliming salts of mirtazapine, include salts of: maleic acid, hydrochloric acid, hydrobromic acid, fumaric acid, and methanesulfonic acid. Spec. 1. Principle of Law “If the claim extends to what is obvious, it is invalid under § 103.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007). Analysis The Examiner finds that Burg teaches the method of producing mirtazapine, as well as optical resolution of mirtazapine, as well as producing acid addition salts of mirtazapine. Final Act. 4—5; Ans. 3^4. The Examiner, however, finds that “Burg does not teach a solid-salt form” of a maleic acid addition salt of mirtazapine. Final Act. 6; Ans. 4. The Examiner looks to Watthey for the production of “therapeutically acceptable salts.” Final Act. 6; Ans. 4. The Examiner looks to Gould for an explanation “why a salt such as maleic acid inter alia (claim 5) would be most preferred.” Final Act. 8. The Examiner relies on Moody to establish a “reason[] as to why the S-enantiomer may be preferred over its counter enantiomer.” Final Act. 8; Ans. 5. The Examiner relies on the combination of references to provide a “motivation to prepare a maleate salt form of S-mirtazapine. This salt would be non-sublimating, as instantly claimed. Whether recognized as non sublimating or not, this is a property of the maleate salt of mirtazapine, which is suggested by the instantly cited prior art.” Ans. 8. 6 Appeal 2015-003491 Application 11/547,152 Claim 1 Appellants contend that there is no motivation to combine the references. Appeal Br. 5—9, 14. Appellants also contend that Gould teaches that the preparation of salt forms of a compound are unpredictable. Appeal Br. 15—17. Appellants also contend that the rejection relies on hindsight. Appeal Br. 17—18. We are not persuaded by Appellants’ contentions. Based on the combination of Burg, Gould, and Moody, we agree with the Examiner’s conclusion that it would have been obvious to formulate an enantiomerically pure form of mirtazapine as a salt form, as suggested by Burg. FF1—FF2. To summarize, Burg teaches the optical resolution of mirtazapine. FF1. Burg teaches the production of pharmaceutically acceptable acid addition salts of mirtazapine, as well as related compounds. FF1—FF3. The pharmaceutical formulation teaching of Burg implies that the salts are intended for use in patients. As recognized by the Examiner, “Burg does not teach a solid-salt form” of a maleic acid addition salt of mirtazapine. Ans. 4. However, Burg does teach the production of a maleic acid addition salt with a structurally related compound of mirtazapine. FF4. Gould teaches that the benefits of creating a salt form of drugs is to alter the “physicochemical and resultant biological characteristics of a drug without modifying its chemical structure.” FF5. Gould teaches that the salt form of a pharmaceutical is easier to process into formulations for administration to patients. FF6; see Gould 204 (“high melting point crystalline salts are potentially easier to process”), 205 (“small highly hydrogen bonding acids such as malonic and maleic gave higher melting salts”). Moody teaches pure enantiomer forms of mirtazapine and that the 7 Appeal 2015-003491 Application 11/547,152 S-enantiomer of mirtazapine results in the same metabolites as the racemic mixture, suggesting that the use of the S-enantiomer will have the same beneficial properties as the racemic mixture. FF7. Claim 1 is directed to a product, wherein the product is an enantiomerically purified solid salt of mirtazapine. The claims further describe the salt as having the property of being a non-sublimating solid salt of mirtazapine. We understand that sublimation is the transformation of a solid to a gaseous phase without forming a liquid state in between. The Specification defines “non-sublimating salt” as a salt of S- or R-mirtazapine, from which less than 1 % of the mirtazapine is sublimating from the sample in the specific parameters recited. FF8. The Specification provides examples of non-sublimating and solid salts of S-mirtazapine as well as R- mirtazapine. See Spec. 1. The Specification further indicates that suitable salts that meet the non-sublimating requirements include salts of mirtazapine that are made using the following acids: maleic acid, hydrochloric acid, hydrobromic acid, fumaric acid, and methanesulfonic. See Spec. 1. Thus, a mirtazapine salt form made with any of the listed acids is expected to have the non-sublimating property because a chemical and its properties inseparable. “From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing.” In re Papesch, 315 F.2d 381, 391 (CCPA 1963). “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d705, 709 (Fed. Cir. 1990). Burg teaches the production of an HCl-mirtazapine salt. FF3. Burg also suggests using optically pure forms of mirtazapine, as well as making a salt of the optically pure form. See FF1, FF2. Both Burg and Moody teach 8 Appeal 2015-003491 Application 11/547,152 that mirtazapine has two enantiomeric forms. See FF1, FF7. Moody teaches that the S(+) form of mirtazapine produces the same metabolites as the racemic mixture, therefore, suggesting that the use of the S(+) form of mirtazapine would have the same beneficial effects. FF7. Based on these combined teachings in Burg and Moody, we agree with the Examiner’s conclusion that the combination of references would have rendered obvious a solid salt form of mirtazapine, including using an optically pure form of mirtazapine for the production of salts with acids that include acids such as hydrochloric acid and maleic acid. FF2. Here, the totality of the evidence provided suggests the production of the claimed salts, which are expected to have the requisite non-subliming properties because those are properties associated with the structure of the compound. We are not persuaded by Appellants’ contention that there is no motivation to combine the references. Appeal Br. 4. Here, Burg specifically suggests the production of pharmaceutical salts made with hydrochloric and maleic acid compounds that include mirtazapine. FF1—FF4. Acid addition salts are recognized as beneficial for the production and formulation of pharmaceuticals, especially if they result in crystalline solids because that eases formulation processing. FF6. Burg teaches that a closely related compound to mirtazapine is able to form a crystalline salt with the use of maleic acid. FF4. Based on the close structural similarity between this compound combined with the suggestion in Burg to make salts of mirtazapine, as well as optically purified mirtazapine, we find there is ample motivation to combine the references. See FF1-FF3. Burg suggest making acid addition of salt of compounds including mirtazapine and the other 9 Appeal 2015-003491 Application 11/547,152 references relied on by the Examiner support the position that there is a reasonable expectation of success when making the claimed products. Appellants contend that “[t]he specification and Gould teach that preparation of a salt form of a compound is unpredictable.” Appeal Br. 4. Appellants contend that “there is an assumption by the Examiner that there is a relationship between melting point of a compound or salt thereof and sublimation of the compound and salt thereof. . . . However, there is no teaching anywhere in Gould that sublimation is related to melting point.” Appeal Br. 8. We are not persuaded. Even though Gould teaches that the selection of the salt form that exhibits the desired combination of properties” requires experimental verification (FF5), the rejection is not solely based on the teachings of Gould but is combined with the teachings of Burg that teaches a crystalline salt of a structurally related compound to mirtazapine, differing only by the presence of a single methyl substituent on the piperazine ring (FF4). “Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success.” In re Droge, 695 F.3d 1334, 1338 (Fed. Cir. 2012) (quoting In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citingIn re O’Farrell, 853 F.2d 894, 903-04 (Fed.Cir.1988)). Here, Burg produces a maleic acid addition salt of a closely related compound to mirtazapine. Compare FF1 and FF4. This salt forms a crystal structure. See FF4 (“The purified oil [containing 1,2,3,4, 10, 14b-hexahydro-benzo[c]pyrazino[l,2- a]pyrido-[3,2-f]azepine] is then treated with a solution of 1.78 g maleic acid in 100 ml acetone, resulting in crystallization of the maleate-salt of the title compound”). Burg suggests making acid addition salts of compounds including mirtazapine. FF1—FF3. 10 Appeal 2015-003491 Application 11/547,152 Burg also suggests optically purified forms of mirtazapine. FF1. Gould is relied on for teaching that salt forms are beneficial for the ease of making pharmaceutical formulations. See FF6. Based on the combined teachings we find no error with the Examiner’s conclusion that the solid salt form of an enantiomeric mirtazapine compound is obvious. Appellants contend that there is no “relation between melting point and sublimation.” Appeal Br. 14. The Examiner is not relying on the relationship between melting point and sublimation in arriving at the conclusion that the product is obvious. Appellants argue that Examiner had made an inadvertent relationship between sublimation and melting point and hereby withdraw any explanation drawn to same. This inadvertent disclosure will no longer be submitted as objective evidence. The Moores references Appellant refers to is not relied upon in the pending rejection. Ans. 8. As discussed above, the combination of Burg, Gould, and Moody renders obvious the production acid addition salts of compounds including optically purified structures that include mirtazapine. We note that we may affirm a multiple reference rejection under 35 U.S.C. § 103 relying on fewer than all of the references relied on by the Examiner and without designating it as a new ground of rejection. In re Bush, 296 F.2d 491, 496 (CCPA 1961). “From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing.” In re Papesch, 315 F.2d at 391. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d at 708. In other words, the combination of references suggests the production of acid 11 Appeal 2015-003491 Application 11/547,152 addition of salts of an enantiomerically pure mirtazapine, even though the references do not recognize that sublimation is an issue with these solid forms of mirtazapine. FF6. Because there is another reason for making the claimed salts, namely for the ease of making pharmaceutical formulations, we find no error with the Examiner’s conclusion that production of an enantiomerically pure mirtazapine salt is obvious. Appellants contend the rejection is based on hindsight. Appeal Br. 4, 17-18. While we are fully aware that hindsight bias often plagues determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly stated that the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, 550 U.S. at 416. 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 applicant’s disclosure, such a reconstruction is proper. In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Here, the Examiner is relying on Burg to teach the production of pharmaceutical acid addition salt of compounds including mirtazapine. See FF1—FF4. Acid addition of salts are recognized as beneficial for the production and formulation of pharmaceuticals. FF6. Burg teaches that a closely related compound to mirtazapine, is able to form a crystalline salt with the use of maleic acid. FF4. The Examiner explains that “Burg adequately addresses the limitations of claim 1. Burg does teach maleic acid 12 Appeal 2015-003491 Application 11/547,152 which is a salt formulation which would make the mirtazapine species of claim 5 obvious because of the further teachings of. . . Gould.” Ans. 7. We agree with the Examiner’s position that Burg teaches optically pure forms of mirtazapine, and suggests the formulation of compounds encompassing mirtazapine as acid addition of salt for the purpose of formulating pharmaceuticals, and Burg even discloses a list of acids that are suitable for the purpose of making such salts. See FF1—FF4. Based on these teachings in Burg alone, one or ordinary skill in the art would have found an acid addition salt of mirtazapine obvious, because Burg already teaches an HC1- mirtazapine salt. FF2. We agree with the Examiner’s conclusion that the teachings of Burg combined with the additional teachings in Gould, and Moody render an enantiomerically purified salt of mirtazapine obvious. Accordingly, we affirm the obviousness rejection of claim 1. Appellants do not separately argue dependent claims 2-4. Therefore, these claims fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). Claim 5 Appellants contend that the cited references “failed to recognize that there was a sublimation problem with enantiomers of mirtazapine in base form and with enantiomers of mirtazapine HC1.” Appeal Br. 4. We recognize, but are not persuaded by, Appellants’ contention that none of the references recognize that sublimation is a problem. We note that this argument contradicts the teaching in the Specification that “non subliming salts of mirtazapine, include salts of: maleic acid, hydrochloric acid, hydrobromic acid, fumaric acid, and methanesulfonic acid.” FF8. The references also do not have to recognize the problem of sublimation with 13 Appeal 2015-003491 Application 11/547,152 mirtazapine salts because they provide a different reason to make salt forms of mirtazapine to ease pharmaceutical formulation processing. The law does not require that the teachings of the reference be combined for the reason or advantage contemplated by the inventor, as long as some suggestion to combine the elements is provided by the prior art as a whole. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). As explained above, Burg already suggests the production of acid addition salts of compounds that include mirtazapine. See FF1—FF4. Gould teaches that acid addition of salts are beneficial for the production and formulation of pharmaceuticals, especially if they result in crystalline solids because this eases formulation processing. FF6. Burg teaches that a closely related compound to mirtazapine, is able to form crystalline salt with the use of maleic acid. FF4. The Examiner recognizes that “Burg does teach maleic acid which is a salt formulation which would make the mirtazapine species of claim 5 obvious because of the further teachings of. . . Gould.” Ans. 7. Here, the Examiner relies on the teachings of Burg that acid addition salts are useful for the formulation of pharmaceutical compositions and Gould supports this position that such salts are useful for formulating pharmaceuticals. See FF2, FF6. We find no error with the Examiner rationale for combining the teachings of the references to arrive at the conclusion that the claims are obvious. Accordingly, we affirm the rejection of claim 5 under 35 U.S.C. § 103(a). Appellants do not separately argue dependent claims 6—9. Therefore, these claims fall with claim 5. 37 C.F.R. § 41.37(c)(l)(iv). 14 Appeal 2015-003491 Application 11/547,152 SUMMARY We affirm the rejection of claims 1 and 5 under 35 U.S.C. § 103(a) over Burg in view of Gould and Moody. Claims 2-4 and 6—9 were not separately argued and fall with claims 1 and 5. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 15 Copy with citationCopy as parenthetical citation