Ex Parte Perc et alDownload PDFBoard of Patent Appeals and InterferencesJul 8, 201110531540 (B.P.A.I. Jul. 8, 2011) 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. 10/531,540 04/15/2005 Stanka Perc 4061-27PUS 1415 27799 7590 07/08/2011 Cozen O''Connor 277 Park Avenue, 20th floor NEW YORK, NY 10172 EXAMINER JEAN-LOUIS, SAMIRA JM ART UNIT PAPER NUMBER 1627 MAIL DATE DELIVERY MODE 07/08/2011 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 BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte STANKA PERC, IVANKA BANKO, and IVANKA KOLENC __________ Appeal 2011-003119 Application 10/531,540 Technology Center 1600 __________ Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and STEPHEN WALSH, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to an olanzapine pharmaceutical composition. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appeal 2011-003119 Application 10/531,540 2 Statement of the Case The Claims Claims 34-51 are on appeal. Claim 34 is representative and reads as follows: 1. A pharmaceutical formulation comprising a homogeneous mixture of: (a) uncoated olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient; (b) a monosaccharide and/or oligosaccharide and/or a reduced or oxidized form thereof; (c) a polysaccharide and optionally; d) one or more additional excipients. The issues A. The Examiner rejected claims 34-51 under 35 U.S.C. § 103(a) as obvious over Morris 1 and Nakajima 2 (Ans. 5-8). B. The Examiner rejected claims 34-51 under 35 U.S.C. § 103(a) as obvious over Chakrabarti 3 and Rubinstein 4 (Ans. 8-12). A. 35 U.S.C. § 103(a) over Morris and Nakajima The Examiner finds that Morris teaches “an oral formulation where the active ingredient olanzapine is subcoated and mixed with acceptable excipients” (Ans. 5). The Examiner finds that Morris teaches “that the oral formulation can contain diluents such as lactose, binders such as crospovidone and microcrystalline cellulose, disintegrants such as crospovidone, and lubricants and glidants such as magnesium stearate” (Ans. 1 Morris et al., EP 0830858 A1, published Mar. 25, 1998. 2 Nakajima et al., US 3,926,817, issued Dec. 16, 1975. 3 Chakrabarti et al., US 5,229,382, issued Jul. 20, 1993. 4 Rubinstein, M. H., Pharmaceutics: The Science of Dosage Form Design, 304-321 (2002). Appeal 2011-003119 Application 10/531,540 3 5). The Examiner finds that Morris teaches that “uncoated olanzapine stored in polyethylene bottles do not show discoloration until exposed to air thus suggesting that non-coated olanzapine can be envisioned in oral formulations” (Ans. 6). The Examiner “contends that it would be within the skilled artisan to formulate the tablets as uncoated tablets if the intended use is for rapid usage of the formulation before the discoloration period and/or for rapid dissolution” (Ans. 7). Appellants contend that “Morris does not disclose a formulation comprising uncoated olanzapine. Morris in fact contains many statements that would discourage or teach away a person of ordinary skill in the art from making an uncoated olanzapine formulation” (App. Br. 4). Appellants contend that “a person of ordinary skill in the art would not leave olanzapine uncoated, which would result in undesirable color change and appearance, in particular considering that the olanzapine formulation would be used for a patient suffering from hallucinations, delusions, and being out of touch with reality” (App. Br. 5). Appellants contend that “if one would use uncoated olanzapine for rapid consumption, as suggested by the Examiner, s/he should at least warn physicians and patients that the uncoated olanzapine product should be consumed as soon as possible after the package is opened. In case that the package is opened and the product is not used up immediately, the unused product will have to be abandoned due to the occurrence of discoloring” (App. Br. 8). Appellants contend that “it is Appellants, not others, who surprisingly discovered that a tablet formulation comprising a homogeneous mixture of Appeal 2011-003119 Application 10/531,540 4 uncoated olanzapine and other excipients in accordance with the present invention has good stability” (App. Br. 10). The issue with respect to this rejection is: Does the evidence of record support the Examiner‟s conclusion that Morris and Nakajima render obvious the uncoated formulation of claim 34? Findings of Fact 1. Morris teaches that “improved oral formulations were desired in light of the moisture sensitive, metastable nature of olanzapine, the tendency of olanzapine to undesirably discolor in the known tablet formulation” (Morris 2, ll. 8-9). 2. Morris teaches that the discoloration and mottled appearance does not produce an increase in the number of total related substances; however, the color change and appearance is not generally considered pharmaceutically desirable. The color change could be particularly undesirable for patients suffering from a psychotic conditions. Indeed, the patient most likely to receive olanzapine is a patient suffering from hallucinations, delusions, and loss of touch with reality. Thus, a formulation having consistent color and appearance is most desired. (Morris 2, ll. 14-18). 3. Morris teaches that “directly coating the olanzapine substance with one or more carefully selected polymers can provide drug material that is resistant to such discoloration when formulated as a granule” (Morris 2, ll. 19-20). 4. Morris teaches that “[u]ncoated tablets stored at ambient conditions (approximately 23°C and 40% relative humidity) in amber, high density polyethylene bottles do not show signs of discoloration after 24 Appeal 2011-003119 Application 10/531,540 5 months; however, if the bottle is opened such that the tablets are exposed to open air ambient conditions then discoloration occurs within 5 days” (Morris 4, ll. 46-48). Principles of Law “A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant. The degree of teaching away will of course depend on the particular facts; in general, a reference will teach away if it suggests that the line of development flowing from the reference‟s disclosure is unlikely to be productive of the result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Analysis While Morris teaches an example of an uncoated tablet with olanzapine (FF 4), Morris also teaches that such uncoated tablets will discolor, and that this discoloration may be particularly damaging to the psychotic patient population for whom olanzapine is appropriate (FF 1-3). Thus, Morris discourages the use of uncoated tablets and is reasonably understood to teach way from the use of such uncoated olanzapine tablets. See Gurley, 27 F.3d at 553. The Examiner “maintains that obviousness does not hinge on whether better choices existed but rather whether such formulation can be reasonably made and be made successfully” (Ans. 13). The Examiner also argues that “if the desire is to provide a formulation of olanzapine that is rapidly consumed or consumed within 5 days, then one of ordinary skill in the art Appeal 2011-003119 Application 10/531,540 6 would have indeed found it obvious to formulate an uncoated olanzapine formulation” (Ans. 13). We are not persuaded. While we agree with the Examiner that the prior art does not need to show that the particular embodiment is the most preferred or desirable (see In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004)), when evaluating claims for obviousness, “the prior art as a whole must be considered. The teachings are to be viewed as they would have been viewed by one of ordinary skill.” In re Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986). Here, Morris strongly teaches away from the use of uncoated olanzapine due to the discoloration (FF 1-3). Regarding the Examiner‟s asserted reason that a desire for a rapidly consumed formulation of olanzapine would have been obvious, the Examiner has not provided any evidence supporting this position. If, for example, the Examiner had provided evidence of a packaging mode for individual pills for olanzapine which would have avoided the discoloration, such evidence might have balanced the teaching away in Morris, but no evidence supporting the Examiner‟s reasoning was provided. Conclusions of Law The evidence of record does not support the Examiner‟s conclusion that Morris and Nakajima render obvious the uncoated formulation of claim 34. B. 35 U.S.C. § 103(a) over Chakrabarti and Rubinstein The Examiner finds that Chakrabarti teaches “the use of olanzapine of formula I in the treatment of disorders of the central nervous system” (Ans. 8). The Examiner finds that Chakrabarti teaches Appeal 2011-003119 Application 10/531,540 7 the uncoated olanzapine tablet formulation without any solvent in example 4 where the tablet is made by mixing appropriate diluents such as starches at 68%, lubricants and glidants such as magnesium stearate at 0.3%, disintegrants such as microcrystalline cellulose at 25%, and binders such as povidone at 5.0%, and wherein the tablet is then compressed. (Ans. 9). The Examiner finds that Rubinstein teaches “the monosaccharide, lactose, as the principal diluent used in the art for bulking the tablet” (Ans. 10). The Examiner finds that “it is well within the purview of the skill of the artisan at the time of the invention to adjust the concentration and percentage of the ingredients in the composition during the course of routine experimentation so as to obtain the desirable type of product” (Ans. 10). Appellants contend that “Chakrabarti fails to disclose a homogeneous mixture of: (a) uncoated olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient; (b) a monosaccharide and/or oligosaccharide and/or a reduced or oxidized form thereof; (c) a polysaccharide and optionally; and d) one or more additional excipients” (App. Br. 14). Appellants contend that “Chakrabarti‟s method of granulating does not lead to a homogenous mixture of olanzapine with other excipients . . . Therefore, the tablets made by granulation are not a homogenous mixture, because the ingredients are not evenly distributed at different position or depth of the tablets” (App. Br. 14). The issues with respect to this rejection are: (i) Does the evidence of record support the Examiner‟s conclusion that Chakrabarti and Rubenstein render obvious the uncoated formulation of claim 34? Appeal 2011-003119 Application 10/531,540 8 (ii) and if so, have Appellants provided evidence of secondary considerations that outweighs the evidence supporting a conclusion of obviousness? Findings of Fact 5. Chakrabarti teaches olanzapine (the compound of Formula I) which “is useful in treating psychotic conditions such as schizophrenia, schizophreniform diseases and acute mania. At lower doses the compound is indicated for use in the treatment of mild anxiety states” (Chakrabarti, col. 2, ll. 25-57). 6. Chakrabarti teaches that the “active ingredient will usually be mixed with a carrier” (Chakrabarti, col. 8, ll. 23-24). 7. Chakrabarti teaches that “[w]hen the carrier serves as a diluent, it may be solid . . . examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose” (Chakrabarti, col. 8, ll. 26-34). 8. Chakrabarti teaches that a “tablet formulation is made by granulating the active with appropriate diluent, lubricant, disintegrant and binder and compressing” (Chakrabarti, col. 11, ll. 28-30, Example 4). 9. Chakrabarti teaches in Example 4, the following components Example 4 shows the use of an (a) component which may include uncoated olanzapine; a (c) component which is the polysaccharide, starch; and Appeal 2011-003119 Application 10/531,540 9 additional excipient such as magnesium stearate and povidone (Chakrabarti, col. 9). 10. Rubinstein teaches that “[d]iluents or „bulking agents‟ are „inert‟ substances which are added to the active ingredient in sufficient quantity to make a reasonably sized tablet. . . . The principal substance employed as a diluent is lactose” (Rubinstein 309, col. 2). 11. Rubinstein teaches that “[d]ry methods and in particular direct compression are superior to those methods employing liquids, since dry processes do not require the equipment and handling expenses required in wetting and drying procedures and can avoid hydrolysis of water-sensitive drugs” (Rubinstein 307, col. 1). 12. Rubinstein teaches that “[t]ablets are produced by mixing the drug with the compression vehicle in a blender. The powder mix is then compressed directly on a tableting machine” (Rubinstein 307, col. 1). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417. Analysis Claim 34 Chakrabarti teaches a pharmaceutical formulation comprising uncoated olanzapine (FF 5) mixed with diluents such as lactose (FF 7), a polysaccharide and additional excipients (FF 6, 8-9). Rubenstein teaches the Appeal 2011-003119 Application 10/531,540 10 use of lactose as a diluent (FF 10) and teaches formation of tablets by mixing the components in a blender and then directly compressing the blended material to form tablets (FF 11-12). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary creativity would have predictably followed the teachings of Chakrabarti and Rubenstein to form homogenous (FF 11) mixtures of uncoated olanzapine with the monosaccharide lactose (FF 5, 7, 10), the polysaccharide starch (FF 9) and additional excipients (FF 6-10). Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Appellants contend that “Chakrabarti fails to disclose a homogeneous mixture of: (a) uncoated olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient; (b) a monosaccharide and/or oligosaccharide and/or a reduced or oxidized form thereof; (c) a polysaccharide and optionally; and d) one or more additional excipients” (App. Br. 14). Appellants contend that “Chakrabarti‟s method of granulating does not lead to a homogenous mixture of olanzapine with other excipients . . . Therefore, the tablets made by granulation are not a homogenous mixture, because the ingredients are not evenly distributed at different position or depth of the tablets” (App. Br. 14). We are not persuaded. Chakrabarti teaches granulating all of the components together prior to compressing (FF 8). Appellants argue that Chakrabarti‟s granulation does not result in a homogenous mixture, but this argument lacks any basis in evidence or fact, and simply represents attorney argument. See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) Appeal 2011-003119 Application 10/531,540 11 (“Attorney‟s argument in a brief cannot take the place of evidence.”). Additionally, given Rubenstein‟s teaching to combine all of the ingredients into a blender, prior to compression (FF 12), the ordinary artisan following the combined teachings of Chakrabarti and Rubenstein would reasonably have blended the components together, prior to compression to form the tablet, so the resulting tablet is reasonably interpreted as a “homogenous” composition. Appellants contend that “the Examiner still fails to articulate a reason why a person of skilled in the art would disregard specific granulating technique disclosed in Chakrabarti and select the technique of „direct compression‟ from among many other conventional techniques disclosed in Rubinstein to arrive at the present invention” (Reply Br. 8-9). We are not persuaded. Rubenstein expressly teaches that “[d]ry methods and in particular direct compression are superior to those methods employing liquids, since dry processes do not require the equipment and handling expenses required in wetting and drying procedures and can avoid hydrolysis of water-sensitive drugs” (Rubinstein 307, col. 1; FF 11). This is a particular reason to select the technique of “direct compression”. Further, “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR at 417. Unexpected results Appellants contend that “[w]ithout knowing the surprising discovery by the present inventors, a person of ordinary skill in the art would not simply mix olanzapine with other excipients evenly to make a homogenous mixture by, e.g., direct compression” (App. Br. 15). Appeal 2011-003119 Application 10/531,540 12 We are not persuaded. Appellants have not demonstrated an unexpected result relative to the disclosure of Chakrabarti and Rubenstein. Appellants have not compared their asserted improved stability with the composition of Chakrabarti. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). Further, even if we would accept that the result shown in Example 3 of the Specification is unexpected, relative to Example 2 of the Specification, the claims are not commensurate in scope with the asserted unexpected result of improved stability, since the only difference between Examples 2 and 3 in the Specification is the use of 20 mg less of cellactose (see Spec 9-10). 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.”) Claim 35 Appellants contend that “[n]either Chakrabarti nor Rubinstein discloses, suggests, or teaches preparation of an olanzapine formulation by direct compression of a mixture into tablets in the absence of any solvent” (App. Br. 17). We are not persuaded. Rubenstein expressly teaches that “[t]ablets are produced by mixing the drug with the compression vehicle in a blender. The powder mix is then compressed directly on a tableting machine” (Rubinstein 307, col. 1; FF 12). This is a direct compression of the mixture into tablets without solvent. Appeal 2011-003119 Application 10/531,540 13 Claims 50-51 Appellants content that “[n]either Chakrabarti nor Rubinstein discloses, suggests, or teaches a matrix composition” (App. Br. 18). Appellants also contend that “[n]either Chakrabarti nor Rubinstein discloses, suggests, or teaches an olanzapine formulation that is in a tablet form and does not have a layered structure” (App. Br. 18). We are not persuaded. Appellants Specification defines “direct compression” as “a process, wherein the various components of a tablet are blended, optionally milled, sieved and then compressed into tablets” (Spec. 4). The Specification also teaches that the “active ingredient is evenly distributed in a matrix formed by the other ingredients of the formulation. The tablets do not have a layered structure” (Spec. 4). Thus, when Chakrabarti and Rubenstein combine the same components using the same “direct compression” process, the Examiner reasonably finds that “the matrix is formed by the components in the formulation” (Ans. 18). Further, since the same “direct compression” process of tablet formation is taught by Rubenstein as that claimed, the result must be identical and yield tablets which do not have layered structures. See In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product.… Whether the rejection is based on „inherency‟ under 35 U.S.C. § 102, on „prima facie obviousness' under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the Appeal 2011-003119 Application 10/531,540 14 same, and its fairness is evidenced by the PTO‟s inability to manufacture products or to obtain and compare prior art products.) Conclusions of Law (i) The evidence of record supports the Examiner‟s conclusion that Chakrabarti and Rubenstein render obvious the uncoated formulation of claims 34, 35, 50 and 51. (ii) Appellants have not provided evidence of secondary considerations that outweighs the evidence supporting a conclusion of obviousness. SUMMARY In summary, we reverse the rejection of claims 34-51 under 35 U.S.C. § 103(a) as obvious over Morris and Nakajima. We affirm the rejection of claims 34, 35, 50 and 51 under 35 U.S.C. § 103(a) as obvious over Chakrabarti and Rubinstein. Pursuant to 37 C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 36- 49, as these claims were not argued separately. 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 alw Copy with citationCopy as parenthetical citation