Ex Parte Wilhelm et alDownload PDFPatent Trial and Appeal BoardSep 11, 201814061578 (P.T.A.B. Sep. 11, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 14/061,578 10/23/2013 Rudolf Wilhelm 31496 7590 09/13/2018 SMITH PA TENT 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 ATTORNEY DOCKET NO. CONFIRMATION NO. LNK-083Cl 6643 EXAMINER 2210 Mount Vernon Avenue, Suite 304 HIRT,ERINE ALEXANDRIA, VA 22301 ART UNIT PAPER NUMBER 1616 NOTIFICATION DATE DELIVERY MODE 09/13/2018 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): chalin@smithpatent.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte RUDOLF WILHELM and MARKUS PRO ELS 1 Appeal2017-008582 Application 14/061,578 Technology Center 1600 Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants state that the real party-in-interest is Dr. Falk Pharma GmbH. App. Br. 1. Appeal2017-008582 Application 14/061,578 SUMMARY Appellants file this appeal under 35 U.S.C. § I34(a) from the Examiner's Final Rejection of claims 1-33. Specifically, claims 1-18, 23, 24, 26, 31, and 32 stand rejected as unpatentable under 35 U.S.C. § I03(a) as being obvious over the combination of Rau (US 2007 /0071817 Al, March 29, 2007) ("Rau"), Yang et al. (US 2006/0013873 Al, January 19, 2006) ("Yang"), S. Elad et al., Budesonide: A novel treatment for oral chronic graft versus host disease, 95(3) ORAL SURGERY ORAL MED. ORAL PATROL. ORAL RADIOL. ENDOD. 308-11 (2003) ("Elad"), Hill et al. (US 2007/0191323 Al, August 16, 2007) ("Hill"), Ubeda Perez et al. (WO 2009/043844 A2, April 9, 2009) ("Ubeda Perez"), Appellants' admissions, and Magic Mouthwash 23(230703) Pharmacist's Letter/Prescriber's Letter 1-5 (2007) ("MM"). Claims 18-33 stand rejected as unpatentable under 35 U.S.C. § I03(a) as being obvious over the combination of Rau, Yang, Elad, Hill, Ubeda Perez, and Appellants' alleged admissions as applied to claims 1--4, 6-10, 12-16, 18, 23, 26, and 31, and MM. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants' invention is directed to an effervescent tablet for preparing a mouth-rinsing solution, wherein the effervescent tablet exhibits a high release rate ofbudesonide. Spec. Abstr. 2 Appeal2017-008582 Application 14/061,578 REPRESENTATIVE CLAIM Claim 1 is representative of the claims on appeal and recites: 1. A solid pharmaceutical composition comprising a therapeutically effective amount of budesonide in combination with an effervescent mixture of a pharmaceutically acceptable acid in solid form and a compound containing carbonate and/or hydrogen carbonate, wherein said composition is formulated to rapidly dissolve in a specific volume of liquid so as to generate an orally-administrable mouth rinsing solution comprising a therapeutically effective amount of dissolved budesonide suitable for the treatment of inflammatory changes in the upper digestive tract. App. Br. 29. ISSUES AND ANALYSES We are persuaded by, and expressly adopt, the Examiner's findings, reasoning, and conclusion that Appellants' claims are primafacie obvious over the combined cited prior art. We address the arguments raised by Appellants below. Issue 1 Appellants argue the Examiner erred because there is no guidance in the prior art that would motivate a person of ordinary skill in the art to combine the prior art teachings with a reasonable expectation of success. App. Br. 15. Analysis The Examiner finds that Rau teaches effervescent oral care compositions, such as mouthwashes, wherein solid compositions, i.e., tablets, comprising an edible acid and a carbonate for effervescence, which 3 Appeal2017-008582 Application 14/061,578 can be dissolved in a specific volume of water (15-25 ml) to form a mouth rinsing solution which is then contacted/orally administered to the oral tissues of a user, or the tablet itself can be placed directly into the oral cavity of a user and allowed to dissolve and effervesce in the oral cavity. Final Act. 4 (citing Rau, e.g., Abstr., ,r,r 9-10, 16, 18, 44). The Examiner finds that Rau also teaches these tablets can carry active agents, such as prescription medications (which broadly includes corticosteroids such as budesonide) and antimicrobial agents, as well as binders/fillers/etc., specifically polyvinylpyrrolidone, and anhydrous surfactants, specifically ducosate sodium ( dioctyl sodium sulfosuccinate ), and flavorants. Id. ( citing Rau, e.g., ,r,r 20, 21, 23, 26, 32, 34, 25, Examples, claim 10). The Examiner finds that Rau does not expressly teach a tablet comprising budesonide as an active agent which is present in the recited range. Final Act. 5. The Examiner finds that Rau also does not teach that the mouthwash solution formed from the effervescent tablet is used to treat inflammatory changes in the upper digestive tract. Id. The Examiner finds that Ubeda Perez teaches orodispersible formulations of corticosteroids (budesonide is a known corticosteroid), which can comprise effervescent agents, specifically edible acids and carbonates, e.g., sodium carbonate or potassium carbonate. Final Act. 5 (citing Ubeda Perez, e.g., 9, 6, 11, claims 11, 14). The Examiner finds that Elad teaches that budesonide is suggested as an alternative treatment for chronic oral graft versus host disease ("GVHD") and has a clinical advantage over other treatments for oral GVHD. Final Act. 6 (citing Elad, e.g., Abstr., 308, 309). The Examiner also finds that Elad teaches methods of administering the budesonide to the upper digestive 4 Appeal2017-008582 Application 14/061,578 tract in which budesonide tablets are crushed and dissolved in water to form a solution used as a mouthwash to treat the upper digestive tract. Id. The Examiner finds that Yang teaches bioadhesive steroid nanoparticle compositions in the form of a tablet that rapidly disintegrates in the oral cavity and adheres to the periodontal pocket and oral mucosa to deliver the steroid. Final Act. 6. The Examiner finds that the compositions of Yang comprise: (1) a bioadhesive polymer surrounding the steroid and having an average particle size of 1,000 nm or less, (2) a surfactant; (3) a disintegrant; and (4) an effervescent agent. Id. (citing Yang title; Abstr., ,r,r 2, 15-16). The Examiner finds that Yang teaches that many steroids are anti-inflammatory agents and have poor water solubility. Id. (citing Yang ,r,r 4, 15). The Examiner finds that Yang also teaches that suitable effervescent agents include citric acid/ sodium carbonate, tartaric acid/sodium carbonate or tartaric acid/sodium citrate. Id. ( citing Yang ,r 20). The Examiner finds that Yang's formulations result in enhanced dissolution of the steroid which include steroids suitable to remedy an oral disease, e.g., triamcinolone acetonide. Id. ( citing Yang ,r,r 2, 25, claims 2, 11 ). The Examiner concludes that it would have been prima facie obvious to a person of ordinary skill in the art to select budesonide as a steroid for use in the formulations of Rau because budesonide is well known in the art as being suitable for treating oral diseases, such as chronic oral GVHD, as taught by Elad. Final Act. 7. The Examiner further concludes that a person of ordinary skill in the art would have had a reasonable expectation of successfully including budesonide in Rau's formulations, because Yang teaches formulations which are designed to increase the dissolution of steroids with poor water solubility, such as budesonide. Id. at 7-8. The 5 Appeal2017-008582 Application 14/061,578 Examiner concludes that Yang teaches that its compositions comprise effervescent agents, and specifically the same effervescent agents taught by Rau, that these are readily taken up in the oral cavity for treatment of an oral disease. Id. at 8. Appellants argue that Rau teaches a large array of effervescent oral care compositions that constitutes a "laundry list" of functional ingredients that may be incorporated into the solid composition and thus carried to oral cavity. App. Br. 15-16. According to Appellants, a particular objective of Rau is to provide a solid effervescent oral care composition that is "pleasing to the user" and "substantially free of insoluble particulate material," particularly "material that can impart a gritty feeling to the composition." Id. at 16 (quoting Rau ,r,r 8, 15). In addition, assert Appellants, Rau expressly restricts the compositions to those having osmolality values of 310 mOsm/kg (millimoles per 5 kg water) or less, as osmolality values in excess of this threshold "can result in damage due to cell dehydration when contacted with the oral tissues." Id. (citing Rau ,r 38, claim 1). Appellants therefore contend that a person of ordinary skill in the art would expect the composition to be restricted to stable, water-soluble components. Id. However, Appellants argue, budesonide is not only difficult to dissolve in water, but tends to be highly unstable in its dissolved form, particularly in the absence of precise pH, preservatives, and further stabilizers, or in the absence of careful manufacture in a mixing vessel under oxygen-depleted conditions. App. Br. 16-17 (citing Declaration of Dr. Rudolf Wilhelm 11 (the "Wilhelm Declaration"), Declaration of Prof. Dr. Sharon Elad (the "Elad Declaration"), Hill ,r 5, Fig. 1 ). Appellants assert that, even assuming, arguendo, that a person of ordinary skill in the art were 6 Appeal2017-008582 Application 14/061,578 to contemplate the modification of Rau's compositions to include steroids, such a skilled artisan would not reasonably expect budesonide to be suitable. Id. at 17. Appellants point out that, none of the additional references cited by the Examiner teach or suggest a solid soluble formulation of budesonide. App. Br. 17. Furthermore, argue Appellants, only two of these references (Elad and Hill) mention budesonide per se and both references establish the difficulties associated with formulating budesonide. Id. Therefore, Appellants contend, none of the secondary references, alone or in combination, provide the requisite motivation and reasonable expectation of success necessary to support the Examiner's prima facie conclusion of obviousness. Id. With respect to Yang, Appellants argue that, whereas the Rau formulation is designed to wholly disintegrate and dissolve, thereby yielding a solution (acknowledged by Appellants as having an osmolality of 310 mOsm/kg), the solid matrix of the Yang formulations ( which "comprises a disintegrant, an effervescent agent and an excipient" are designed to disintegrate and thereby release a suspension of chitosan-coated steroid- surfactant micelles (i.e., the "steroid nanoparticles") so that they will adhere to the tissue of interest ( e.g., the periodontal pocket and oral mucosa). App. Br. 17 ( citing Yang claim 1 ,r,r 16, 22, 24 ). According to Appellants, because the bioadhesive dosage form taught by Yang, and the effervescent tablet taught by Rau are structurally divergent, arising from divergent manufacturing processes and having significantly different modes of action and administration, a person of ordinary skill in the art would not have looked to Yang for ways to modify and/or improve Rau so as to allow for 7 Appeal2017-008582 Application 14/061,578 the inclusion of the poorly soluble budesonide. Id. at 17-18. Nor, argue Appellants, would such an artisan have had any reasonable expectation that such a combination would lead to successful result. Id. at 18. Furthermore, assert Appellants, were an ordinary artisan to attempt to modify the Rau effervescent formulation to include Yang's bioadhesive steroid nanoparticle construction, such a tablet would not rapidly dissolve in a specific volume of water to generate an orally-administrable mouth rinsing solution comprising a therapeutically effective amount of dissolved budesonide as recited in the claims on appeal. Id. With respect to Ubeda Perez, Appellants assert that the object of the reference is to "provide an orodispersible [i.e., orally disintegrating] tablet which can be dissolved quickly in the oral cavity, which presents good palatability properties, and that can be obtained by conventional processes, such as direct compression." App. Br. 18 (quoting Ubeda Perez 4). Appellants contend that the orally disintegrating tablet taught by Ubeda Perez is preferably formed from direct compression of a homogeneous dry powdered mixture comprised of calcium silicate, a generic diluent, a generic disintegrant, and a generic active ingredient, and optionally a generic effervescent component. Id. ( citing Ubeda Perez 5---6, line 7). Appellants assert that Ubeda Perez, like Rau, teaches an extensive laundry lists of options for each component; as such, the disclosed genus necessarily gives rise to innumerable combinations. Id. Therefore, Appellants argue, one must look to the express guidance and illustrative examples of Ubeda Perez to determine whether one of ordinary in the art would have been motivated to select the claimed species or subgenus. Id. Appellants assert that whereas Ubeda Perez expresses a preference for crospovidone ( a polymer of 8 Appeal2017-008582 Application 14/061,578 vinylpyrrolidone) as a disintegrant, there is no mention of docusate sodium or budesonide. Id. Appellants acknowledge that, whereas corticosteroids as an active agent are generically referenced, amid a Markush group of more than 30 other categories of pharmaceutical, ranging from analgesics to antidepressants to antihistamines, none of the six formulations taught by the Examples of Ubeda Perez includes an anti-inflammatory, much less a corticosteroid. Id. ( citing Ubeda Perez 9). Therefore, argue Appellants, nothing in the teachings of Ubeda Perez may be fairly characterized as guiding one skilled in the art toward or rendering obvious the selection of the budesonide. Id. Furthermore, Appellants argue, Ubeda Perez expressly teaches that non-water soluble components be "considerably minimized," so as to ensure a positive organoleptic sensation. Id. ( citing Ubeda Perez 6). Appellants assert that these teachings "suggest away" from the inclusion of an only sparingly soluble active ingredient such a budesonide and would necessarily undermine any expectation for success. Id. With respect to Elad, Appellants argue that reference does not teach a solution or a homogeneous mixture of budesonide fully dissolved in water, as recited in the claim. App. Br. 19. Appellants point to the Wilhelm Declaration, in which Dr. Wilhelm states that when he attempted to replicate the Elad protocol, he found that: "[i]ndependent from the level of crushing reached, there is no development of a stable and homogenous suspension of active ingredient, let alone a solution," but rather, that most of the capsule components remained as "insoluble powder," a "solid fraction," or "sediment" in the sample. Id. ( quoting Wilhelm Deel. 9, ,r 2). Appellants contend that Dr. Wilhelm states that further testing revealed that the 9 Appeal2017-008582 Application 14/061,578 percentage of the 3 mg dosage of budesonide capsules dissolved in 10 ml sample of water provided a mean value range of from 0.15% to 1.9%. Id. ( citing Wilhelm Deel. Table 1 ). Therefore, Appellants argue, although the Elad reference may teach the utility of a budesonide mouthwash, the use of the budesonide capsules to form the mouthwash in Elad does not give rise to a solution as recited in the claims on appeal. Id. Appellants argue further that Elad is not enabling in that it does not teach how to make and use a solid composition or tablet using the budesonide capsules, which can subsequently be used to generate an orally- administrable mouth rinsing solution. App. Br. 19. Appellants point again to the Wilhelm Declaration, in which Dr. Wilhelm states, following the teachings of Elad, he was unable to formulate a solid composition or tablet using crushed budesonide capsules, which could be used to generate an orally-administrable mouth rinsing solution, as recited in the claims. Id. Appellants also argue that the claims require that the "composition is formulated to rapidly dissolve in a specific volume of liquid." App. Br. 19- 20. Appellants argue that this limitation requires the complete dissolution of the tablet within a period of time of less than two minutes. Id. at 20. Appellants assert that the Wilhelm Declaration states that the Elad crushed capsules do not result in either a rapid or complete dissolution of the budesonide in water, and that the Wilhelm Declaration further states that only O .15-1. 9% dissolution of budesonide. Id. Moreover, Appellants argue, the Wilhelm Declaration further states that the teachings of Elad are "wholly unsuitable to provide a sufficient dose of active ingredient when administering the mouth rinse solution." Id. 10 Appeal2017-008582 Application 14/061,578 With respect to Hill, Appellants argue that the reference is not directed to the formulation of a solid pharmaceutical composition or tablet comprising budesonide, as recited in the claims. App. Br. 20. According to Appellants, the "solubility enhancer" is intended to be mixed with the corticosteroid and water under oxygen-depleted conditions in order to increase the solubility of the aqueous solution and increase the stability of the corticosteroid in solution. Id. Therefore, argue Appellants, a person of ordinary skill in the art would not have been motivated to utilize the components intended for an aqueous solution to formulate a solid composition or tablet, nor would an artisan be motivated to combine the teachings of Hill with the effervescent solutions taught by Rau. Id. at 20-21. Appellants argue further that the teachings of Hill would not have motivated a skilled artisan to specifically select PVP or docusate sodium. App. Br. 21. According to Appellants, Hill sets forth large "laundry lists" of "optional additional ingredients" including at least 50 possible "solubility enhancers." Id. (citing Hill ,r 34). Appellants note that neither PVP nor docusate sodium comes within the first 40, nor is either highlighted or exemplified. Id. Instead, contend Appellants, Hill focuses on cyclodextrin solubility enhancers, such as sulfoalkyl ether cyclodextrin (SAE-CD) derivatives, especially SBE7-beta-CD. Id. Therefore, Appellants assert, a skilled artisan would have had to judiciously choose from among the wide array of possible combinations, selecting components that are neither extensively analyzed nor highlighted as particularly preferred. Id. ( citing Wilhelm Deel. ,r 5(c)). Appellants note that Dr. Wilhelm concludes that "one of skill in the art would not have looked to Hill for ways and means to modify and/or 11 Appeal2017-008582 Application 14/061,578 improve Rau so as to allow for the inclusion of the hardly soluble budesonide. Nor would the skilled artisan have had any reasonable expectation that such a combination would lead to successful results."2,3 Id. With respect to Magic Mouthwash, Appellants argue that the reference, like Rau, Yang, and Ubeda Perez, Pather provides no teaching of budesonide or docusate sodium, and provides only a passing reference to "crospovidone" ( a polymer of polyvinylpyrrolidone) in the context of optional "noneffervescent disintegration agents" that may be employed to aid in the dispersion of the drug in the gastrointestinal tract." App. Br. 21- 22. Appellants summarize their arguments, asserting that only Elad and Hill teach the use ofbudesonide. App. Br. 22. According to Appellants, although Elad teaches a mouthwash made from budesonide capsules, these 2 Dr. Rudolf Wilhelm, the declarant, received his Dr. rer. nat. (Ph.D.) in 1996 and is presently Head of the Pharmaceutical Development Department at Dr. Falk Pharma Gmbh, a position he has held since 2005. See Wilhelm Deel. ,r,r 2-3. He has extensive experience in the development of novel immediate-release, delayed-release, and modified- release oral solid dosage formulations of new and already existing drugs. Id. at ,r 3. We find that Dr. Falk is qualified to render an expert opinion, and we also note that he is one of the co-inventors of the claimed invention. 3 We note that the Wilhelm Declaration, while convincingly documenting Dr. Wilhelm's scientific expertise, provides no evidence or statement that Dr. Wilhelm has any training in the law or, specifically, that Dr. Wilhelm, a citizen of Germany, has any training in U.S. patent law, or is a member of the patent bar. We therefore do not recognize Dr. Wilhelm's qualification to express a legal conclusion in this regard and we disregard this conclusion. 12 Appeal2017-008582 Application 14/061,578 teachings would not motivate a skilled artisan to modify Rau to include anything other than crushed budesonide capsules in its formulations. Id. However, Appellants argue, Dr. Wilhelm, following the teachings of Elad, was unable to make a budesonide solid composition or tablet that would rapidly dissolve in a specific volume of liquid to generate an orally- administrable mouth rinsing solution comprising a therapeutically effective amount of dissolved budesonide to treat inflammatory changes in the upper digestive tract, as recited in the claims. Id. Furthermore, contend Appellants, the teachings of Hill are directed to improving the stability of budesonide in aqueous solutions, not in the formulation of solid compositions or tablets that can subsequently be used to generate mouth rinsing solutions. Id. at 22-23. Therefore, Appellants assert, none of the references that actually describe budesonide provide the requisite motivation for a person of ordinary skill in the art to modify Rau to formulate the composition recited in the claims on appeal. Id. at 23. Finally, Appellants argue, with respect to claims 2, 3, 8, 9, 14, and 15, that Rau neither highlights nor exemplifies the use of PVP or docusate sodium. App. Br. 23 ( citing Rau Table 1 ). Appellants point to Table 1 of Rau, which, Appellants assert, recommends PEG over PVP and sodium lauryl sulfate over docusate sodium. Id. Appellants further assert that none of the illustrative embodiments include any of the claimed components much less two or more in combination. Id. We are not persuaded by Appellants' arguments. As an initial matter, we remind Appellants that: "one cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of 13 Appeal2017-008582 Application 14/061,578 references," which is what Appellants have primarily done, as discussed above. In re Keller, 642 F.2d 413,426 (C.C.P.A. 1981). We agree with the Examiner's findings, reasoning, and conclusion. Specifically, we agree with the Examiner that Rau teaches, generally, a solid pharmaceutical composition, comprising an effervescent mixture of a pharmaceutically acceptable acid in solid form and a compound containing carbonate and/or hydrogen carbonate, in which "composition is formulated to rapidly dissolve in a specific volume of liquid." Furthermore, Yang and Ubeda Perez teach similar compositions, indicating that such compositions are well known in the art. The issue before us then, is whether a person of ordinary skill in the art would have been motivated to combine the teachings of the cited references with a reasonable expectation of success in arriving at Appellants' claimed invention. As we see it, the dispositive issues, according to Appellants' arguments, are twofold. The first is, given the generally poor solubility of budesonide, would the combination of references give a person of ordinary skill in the art a reasonable expectation of success in using budesonide in the dissolvable effervescent compositions taught by Rau? The second is whether Yang teaches a "solution" as recited in the claims using the construction of that term that Appellants urge us to adopt. We address the latter issue first. Appellants' Specification provides no express definition of the claim term "solution." Consequently, we adopt the broadest reasonable interpretation of the term consistent with Appellants' Specification as it would be interpreted by a person of ordinary skill in the art. Cuozzo Speed Tech., LLCv. Lee, 136 S. Ct. 2131, 2145 (2016); Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005). 14 Appeal2017-008582 Application 14/061,578 Appellants urge us to construe the claim term "solution" as meaning a homogeneous mixture of solvent and dissolved substance (solute) in which the solute does not exist as a solid. App. Br. 6. Appellants contend that the dictionary definition of solution is a type of homogeneous, mixture that is made up of two or more substances. Id. (citing Study.com, What is a Solution in Science? -Definition & Examples - Video & Lesson Transcript I (2016), available at: https://study.com/academy/lesson/what-is-a-solution- in-science-definition-examples.html, last visited August 13, 2018). Appellants assert that a homogeneous mixture is a type of mixture with a uniform composition, and that this means that the substances cannot be distinguished easily from one another. Id. at 6-7. Appellants' Specification provides no express definition of the claim term "solution." However, the Specification discloses an example of the size distribution of the particles of budesonide that are dispersed in the specific volume of liquid recited in the claims. According to Appellants' Specification: Micronised budesonide is preferably used. The size of the budesonide particles plays an essential part in the dissolution rate and the resorbability. Budesonide is preferably used in which the particle size distribution is adjusted such that at least 90% of the particles have a diameter of less than 20 µm, preferably less than 10 µm. In a particularly preferred embodiment, 100% of the particles have a diameter ofless than 10 µm, 95% of the particles have a diameter of less than 5 µm and 80% of the particles have a diameter ofless than 3 µm. The particle diameter is determined by conventional measuring methods. Spec. 3/3. Yang teaches that the bioadhesive steroid nanoparticles have a bioadhesive polymer surrounding the steroid nanoparticles and with an 15 Appeal2017-008582 Application 14/061,578 average diameter of less than 1000 nm. Yang Abstr. Yang further teaches that the steroid/polymer nanoparticles are added to an effervescent matrix that rapidly dissolves into a suspension of nanoparticles which can adhere to tissues of the upper digestive tract. Id. at ,r,r 24--25. We agree with the Examiner that a homogeneously dispersed suspension of particles of less than 1000 nm would be understood by a person of ordinary skill in the art, applying the broadest reasonable interpretation, to constitute: "an orally-administrable mouth rinsing solution," as recited in the claims. Although the claims do not recite bioadhesive polymers, the claims recite, "[a] solid pharmaceutical composition comprising ... ," meaning that the scope of the claims does not exclude additional components. See Crystal Semiconductor Corp. v. TriTech Microelectronics Int'!, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001) (Use of the transition "comprising" in the language of a claim "creates a presumption ... that the claim does not exclude additional, unrecited elements"). Rau and Hill similarly teach that sodium ducosate is known in the art as a component of effervescent solutions and can act as a solubility enhancer. Appellants' second issue is whether, given the poor solubility of budesonide, the combination of references cited by the Examiner give a person of ordinary skill in the art a reasonable expectation of success in using budesonide in the dissolvable effervescent compositions taught by Rau. Appellants' Specification discloses that: "Surprisingly, it was found that the solubility of budesonide effervescent tablets is significantly increased by the addition of polyvinylpyrrolidone (PVP) and ducosate 16 Appeal2017-008582 Application 14/061,578 sodium." Spec. 6. However, we agree with the Examiner that both Rau and, particularly Hill teach that, at the time of Appellants' claimed invention, it was well known in the art that polyvinylpyrrolidone can be used to enhance the solubility of corticosteroids, such as budesonide. See Rau ,r,r 7, 23; Hill ,r,r 34--36 (listing polyvinylpyrrolidone as a "solubility enhancer" and stating that: A "solubility enhancer," as used herein, includes one or more compounds which increase the solubility of corticosteroid in the aqueous phase of the corticosteroid mixture. In general the solubility enhancer increases the solubility of the corticosteroid in water without chemically changing the corticosteroid. In particular, the solubility enhancer increases the solubility of corticosteroid without substantially decreasing, and in some embodiments increasing, the activity of the corticosteroid. Hill ,r 36. Hill continues: "Solubility enhancers are known in the art and are described in, e.g., U.S. Pat. Nos. 5,134,127, 5,145,684, 5,376,645, 6,241,969 and U.S. Pub. Appl. Nos. 2005/0244339 and 2005/0008707, each of which is specifically incorporated by reference herein." Id. at ,r 37. Importantly, Hill does not teach that the solubility enhancers are useful for enhancing solubility only in the low-oxygen protocols taught by Hill for the synthesis of corticosteroid solutions with long-term stability. We therefore agree with the Examiner that the combined references teach that polyvinylpyrrolidone was well known in the art as an ingredient in effervescent solutions and could be used to increase the solubility of corticosteroids in aqueous solutions. Appellants contend that the "solubility enhancer" of Hill is intended to be mixed with the corticosteroid and water under oxygen-depleted conditions in order to increase the solubility of the aqueous solution and 17 Appeal2017-008582 Application 14/061,578 increase the stability of the corticosteroid in solution. See App. Br. 20. Therefore, argue Appellants, a person of ordinary skill in the art would not have been motivated to utilize the components intended for an aqueous solution to formulate a solid composition or tablet, nor would an artisan be motivated to combine the teachings of Hill with the effervescent solutions taught by Rau. Id. at 20-21. We are not persuaded. First, Rau expressly teaches that polyvinylpyrrolidone is well known as a component of effervescent solutions. See Rau ,r,r 7, 23. Although we acknowledge Appellants' point that the procedures taught by Hill are directed to the preservation of long- term solubility in solutions, we agree with the Examiner that the combination of the teachings of Yang, Rau, and Hill would give a person of ordinary skill in the art a reasonable expectation of success, for the reasons we have explained, in making an effervescent composition with a soluble budesonide component. Issue 2 Appellants argue that the Examiner erred because the combined cited references do not adequately render the presently claimed invention "obvious to try." App. Br. 23. Analysis Appellants argue that, because none of the references cited by the Examiner describe or suggest a solid soluble formulation ofbudesonide, the Examiner's position is that the formulation would have been "obvious to try" i.e., it would have been obvious to a person of ordinary skill to modify 18 Appeal2017-008582 Application 14/061,578 the Rau compositions to include solid budesonide. App. Br. 23. Appellants argue that, the Examiner's findings and conclusion notwithstanding, the potential pathways for modification are neither finite nor identified nor predictable and, therefore, for this additional reason, the invention of the pending claims may not be fairly characterized as obvious. Id. at 23-24. Appellants largely repeat their arguments from the previous section of this decision. Appellants assert that a person of ordinary skill could not have readily extracted or synthesized from these teachings the requisite small number of easily traversed options or identifiable predictable solutions required to support a conclusion of "obvious to try." Appellants point to our reviewing court's holding in Sanofi-Aventis Deutsch/and GmbH v. Glenmark Pharmaceuticals Inc., USA, 748 F.3d 1354 (Fed. Cir. 2014) that, when there are potentially hundreds of possible combinations and the prior art gives "either no indication of which parameters [are] critical or no direction as to which of many possible choices is likely to be successful," modification may not be fairly characterized as "obvious to try." Id. at 24 (citing Glenmark, 748 F.3d at 1360 (citing In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)). Appellants argue further that "impermissible hindsight must be avoided and the legal conclusion must be reached on the basis of the facts gleaned from the prior art," as opposed to the cited prior art. App. Br. 24 ( quoting MPEP § 2142). Appellants allege that the Examiner impermissibly employed hindsight reasoning, asserting that, in this appeal, the references that the Examiner concludes teaches the invention of the claims on appeal are even more tangential and farther removed than those applied in Glenmark, etc. 19 Appeal2017-008582 Application 14/061,578 We are not persuaded by Appellants' arguments. The test for obviousness is: "what the combined teachings of the references would have suggested to those of ordinary skill in the art." Keller, 642 F.2d at 425. We agree with the Examiner that the combined prior art teaches or suggests the combined invention. Specifically, Rau generally teaches effervescent compositions that can be used to deliver medicaments. Ubeda Perez similarly teaches effervescent compositions for drug delivery, including those containing corticosteroids. See Ubeda Perez claims 11 and 14. Yang and Hill teach that corticosteroids in general, and budesonide in particular, are poorly soluble, and Yang teaches methods by which corticosteroid solubility can be improved in an effervescent solution that is within the scope of the claims, and is combinable with the teachings of Ubeda Perez and Rau. See Yang ,r,r 7, 8, 15-16. Both Rau and Hill teach the use of polyvinylpyrrolidone in their compositions, with Hill teaching that polyvinylpyrrolidone is a solubility enhancing agent for corticosteroids, of which budesonide is one such. See Hill ,r,r 34--36; Rau ,r 23. The ... "obvious to try" [ error typically occurs in one of two contexts: (1) when it] would have been "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[; or (2)] to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it. In re O'Farrell, 853 F.2d at 903. We do not think either criterion applies to the references cited by the Examiner. Rau and Ubeda Perez teach general 20 Appeal2017-008582 Application 14/061,578 effervescent compositions, including polyvinylpyrrolidone, which Hill teaches enhances corticosteroid solubility. Yang and Hill both teach that cortical steroid solubility in solutions is known in the art to be a problem, and provide methods by which the solubility can be increased. Elad teaches that oral compositions containing budesonide, in particular, is helpful in treating "inflammatory changes in the upper digestive tract," as recited in the claims. We consequently agree with the Examiner that the teachings and suggestions of the combined cited prior art teach the limitations of the claims, and that a person of ordinary skill would have had a reasonable expectation of success in combining the references. With respect to Appellants' argument that the Examiner improperly applied hindsight reasoning: 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 (C.C.P.A. 1971). Appellants point to no evidence of record that the Examiner relies on information or knowledge that can be gleaned solely from Appellants' Specification and makes only the mere assertion that the Examiner relied on hindsight reasoning. Such attorney argument is not persuasive. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (holding that attorney arguments and conclusory statements that are unsupported by factual evidence are entitled to little probative value). 21 Appeal2017-008582 Application 14/061,578 Issue 3 Appellants argue the Examiner erred because the Examiner's conclusion that the claims are obvious is rebutted by the unexpected results of record. App. Br. 25. Analysis Appellants argue that they have developed a novel effervescent budesonide tablet configured for the creation of a single-dose, user-prepared mouth rinsing solution that affords significant advantages with regard to long-time stability of the drug, as well as delivering a simple and accurate dosage. App. Br. 25. Appellants assert that, in contrast to Yang's bioadhesive tablets that rely exclusively on saliva to disperse through the mouth, Appellant's effervescent tablet-generated mouth rinsing solution provides better dispersion, contacting more tissues (i.e., more volume= greater tissue contact). Id. Appellants claim that their effervescent tablets also avoid the need for precise pH adjustment, preservatives and stabilizers associated with liquid formulations of the prior art such as those disclosed by Hill and Elad. Id. Moreover, argue Appellants, the claimed composition demonstrates an unexpected superiority over the exemplary Elad formulations. Appellants point to the Elad Declaration which, contend Appellants, not only characterizes embodiments of the present invention as showing "superior results" and a "superior design" but further attests that "one of skill in the art would consider the present invention to constitute a significant improvement over the prior art alternatives including those described in [the Elad reference]." Id. at 25-26 (citing Elad Deel. ,r,r 8, 11, 12) ( emphasis omitted). 22 Appeal2017-008582 Application 14/061,578 Appellants point to the Wilhelm Declaration as similarly stating that the superior results achieved by the present invention as compared to the prior art "could not have been predicted a priori, are not disclosed or suggested in the prior art, and are, therefore, quite unexpected and surprising." App. Br. 26. We do not find Appellants' arguments to be persuasive. "[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art." In re Baxter Travenol Labs., 952 F.2d 388,392 (Fed. Cir. 1991). As evidence of the unexpected properties of their claimed composition, Appellants point to the Elad and Wilhelm Declarations. Both declarants point to the Elad references as closely-related prior art with which to compare the claimed composition. See Wilhelm Deel. ,r 7, App 'x A; Elad Deel. ,r 11. Elad teaches results of a clinical trial employing budesonide in the treatment of chronic oral graft versus host disease ("GVHD"). Elad teaches that the method employed consisted of having patients crush a budesonide capsule, dissolve it in 5 mls of water, and rinse for 15 minutes 2 or 3 times daily, then expectorate the solution. Elad 309. Elad teaches that an objective response to budesonide mouthwashes was observed in all patients and that all patients reported subjective improvement. Id. at 310. 23 Appeal2017-008582 Application 14/061,578 Dr. Elad4 attests that the Phase III clinical trial of Appellants' claimed composition disclosed in the Elad Declaration has a superior design compared to the initial study taught by the Elad reference. Elad Deel. ,r 11. Dr. Elad states that the reasons for the superiority of the design of the clinical trial are based upon the lack of a placebo in the Elad reference study, the larger sample size of the clinical trial, and the extent of data collection in the clinical trial. Id. Dr. Elad opines that, for these reasons, the Phase III clinical trial has a superior design as compared to the study in the Elad reference. Id. Dr. Elad further opines that one of skill in the art would consider the Appellants' invention to constitute a significant improvement over prior art alternatives including those described in the Elad reference. Id. at 12. Dr. Wilhelm identifies the Elad reference as the closest prior art. Wilhelm Deel. App 'x A at 8. Appendix A of the Wilhelm Declaration relates how Dr. Wilhelm attempted to replicate the study taught by Elad. Id. at 10. The Wilhelm Declaration then compares the results of the replicated Elad study to a similar study using Appellants' claimed composition. Id. at 15. Dr. Wilhelm opines that: "The effervescent tablet according to the present invention allows for the routine and reproducible production of an orally applicable mouth rinse solution that cannot be achieved using the 4 Dr. Sharon Elad is professor of dentistry and a professor of oncology at the University of Rochester where I am Chair of the Division of Oral Medicine at the Eastman Institute for Oral Health (EIOH). Elad Deel. ,r 3. Dr. Sharon is the first author of the Elad reference and has published extensively in the field of oral medicine. We find Dr. Elad qualified to render an expert opinion. 24 Appeal2017-008582 Application 14/061,578 product and techniques of the prior art. Moreover, the effervescent tablets show surprising, advantageous effects over the prior art." Id. at 16. As an initial matter, we are not persuaded that Elad is the closest prior art to Appellants' claimed invention. The composition of the budesonide administered in Elad is not directly comparable to that of Appellants' effervescent tablet and contains none of the other ingredients recited in Appellants' claims, e.g., an effervescent mixture of a pharmaceutically acceptable acid in solid form and a compound containing carbonate and/or hydrogen carbonate, polyvinylpyrrolidone. Rather, 3 mg budesonide capsules are simply crushed and mixed with water. Corticosteroids in effervescent compositions are cited in both Rau and Ubeda Perez, and methods of increasing the solubility of corticosteroids were also known in the art. See, e.g., Hill ,r 3. We also note that Dr. Elad's opinion that the superiority of the Phase III clinical trial disclosed in the Elad Declaration refers to the superiority of the design of the Phase III clinical trial to that of the Elad reference. Dr. Elad does not offer an opinion as to the superiority of the composition, other than to state that: "that one of skill in the art would consider the [Appellants'] invention to constitute a significant improvement over prior art alternatives including those described in [the Elad reference,]" although Dr. Elad does not offer a specific opinion as to the properties of other, corticosteroid effervescent compositions. See Elad Deel. ,r 12. With respect to the comparative study disclosed by the Wilhelm Declaration, we find the data persuasive of the superiority of Appellants' claimed composition, however, as we have explained supra, we are not persuaded that Elad represents close prior art due to the differences of the 25 Appeal2017-008582 Application 14/061,578 composition taught by Elad and that of Appellants' claims. On balance then, we do not find that Appellants' argument claiming unexpected results outweighs the other evidence of record that the claims are prima facie obvious over the combined cited prior art. See also Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) (unexpected results are not sufficient to outweigh a stronger showing of obviousness). Issue 4 Finally, Appellants dispute the Examiner's finding that Appellants' argument of unexpected results are "not necessarily unexpected." App. Br. 26 ( emphasis omitted). Analysis Appellants contend that the Examiner rejected their argument that the claimed compositions exhibit unexpected properties because: (1) Pather et al. (US 6,641,838 B2, November 4, 2003) ("Pather") teaches the inclusion of "effervescent agents into drugs to increase the dissolution of the drug and thereby increase its biovailability"; and (2) "[Ubeda Perez] and Hill already recognized that PVP and/or docusate sodium increased the dissolution of the steroid active agents (i.e., budesonide)." App. Br. 26 (quoting Non-Final Act., 15-16, August 13, 2015). Appellants assert that these findings by the Examiner have no support in law. Id. (citing In re Piasecki, 745 F.2d 1468 (Fed. Cir. 1984)). Appellants rely upon Piasecki 's holding that: "If rebuttal evidence of adequate weight is produced, the holding of prima facie obviousness, being but a legal inference from previously uncontradicted evidence, is dissipated. Regardless of whether the prima facie case could 26 Appeal2017-008582 Application 14/061,578 have been characterized as strong or weak, the examiner must consider all of the evidence anew." Id. at 26 (emphasis omitted) (citing Piasecki, 745 F.2d at 1472). According to Appellants, Piasecki stands for the proposition that it is wholly improper for an earlier decision to be considered as "set in concrete" with Appellants' rebuttal evidence evaluated only on its "knockdown ability," and therefore that "[f]acts established by rebuttal evidence must be evaluated along with the facts on which the earlier conclusion was reached, not against the conclusion itself." Id. at 26-27 (citing Piasecki, 745 F.2d at 1472). Appellants therefore allege that the Examiner has ignored the facts provided by both Dr. Wilhelm and Dr. Elad. App. Br. 27. Appellants point to the Wilhelm Declaration's statement that a person of ordinary skill in the art would not "reasonably expect the stability achieved by Hill under such high regulated conditions to extend and/or translate to the effervescent-based mouthwashes of Rau." Id. (quoting Wilhelm Deel. ,r 5). Appellants argue that Dr. Wilhelm does not consider Hill's recitation of a "vast laundry list of 'optional additional ingredients' including at least 50 possible 'solubility enhancers"' to give rise to the expectation found by the Examiner, viz., that "the addition of docusate sodium and PVP ... would increase the solubility and bioavailability of the drug in the mouth." Id. ( citing Final Act. 18). Appellants assert that the Examiner is not free to simply disregard this testimony in the Wilhelm Declaration. Id. Appellants therefore argue that, given that: nothing in the references of record may be fairly characterized as clearly teaching the use of PVP and/or docusate sodium to increase the dissolution of budesonide in the context of effervescent tablet formulations as presently claimed, it must 27 Appeal2017-008582 Application 14/061,578 Id. therefore be accepted as fact that the superior results achieved by the present invention could not have been predicted a priori, are not disclosed or suggested in the prior art, and are, therefore quite unexpected and surprising. We are not persuaded. As an initial matter, we do not agree that the Examiner simply ignored the disclosures and opinions of the Wilhelm and Elad Declarations. The Examiner discusses, in the Final Office Action, both Declarations at some length, but does not find the arguments raised in the Declarations sufficient to overcome the Examiner's conclusion that the claims are prima facie obvious over the prior art. See Final Act 18-20; see also Ans. 9-11. As we have explained in the previous section, we agree with the Examiner's reasoning that Appellants have not provided comparison data which shows that their solubility results are in fact unexpected as have been asserted. See Ans. 9-10. We have also explained why we find that Elad is not sufficiently close prior art to support an argument that the allegedly unexpected results are sufficient to overcome the Examiner's conclusion that the claims are prima facie obvious over the combined cited prior art. We consequently affirm the Examiner's rejection of the claims. DECISION The Examiner's rejection of claims 1-33 under 35 U.S.C. § 103(a) is affirmed. 28 Appeal2017-008582 Application 14/061,578 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv). AFFIRMED 29 Copy with citationCopy as parenthetical citation