Gruenenthal GmbH

Patent Trials and Appeals Board

Mar 24, 2022

2022000246 (P.T.A.B. Mar. 24, 2022)

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. 15/000,504 01/19/2016 Petra BLOMS-FUNKE 107101-245 KGB 2067 27384 7590 03/24/2022 Briscoe, Kurt G. Norris McLaughlin, PA 7 Times Square, 21st Floor New York, NY 10036-6524 EXAMINER BASQUILL, SEAN M ART UNIT PAPER NUMBER 1613 NOTIFICATION DATE DELIVERY MODE 03/24/2022 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): mgonzalez@norris-law.com nmanfredi@norris-law.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte PETRA BLOMS-FUNKE and KLAUS SCHIENE ____________ Appeal 2022-000246 Application 15/000,504 Technology Center 1600 ____________ Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and TAWEN CHANG, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 1-4, 7-9, and 13-17 (Final Act.2 2).3 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “Grünenthal GmbH” (Appellant’s May 10, 2021, Appeal Brief (Appeal Br.) 1). 2 Examiner’s July 24, 2020, Final Office Action. 3 Appellant’s claims 18-25 stand withdrawn from consideration (Final Act. 2). Appeal 2022-000246 Application 15/000,504 2 STATEMENT OF THE CASE Appellant’s disclosure: [R]elates to a combination comprising as components (a) the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- phenol, and (b) Paracetamol or a derivative thereof, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. chronic or acute pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration. (Spec.4 ¶ 2.) Appellant’s claim 1 is reproduced below: 1. A composition comprising a synergistic combination of (a) and (b): (a) at least one 3-(3-Dimethylamino-l-ethyl-2-methyl-propyl)- phenol compound corresponding to formula (I), or a hydrochloride addition salt thereof, and (b) Paracetamol. (Appeal Br. 26.) Grounds of rejection before this Panel for review: I. Claims 1-4, 7-9, and 13-17 stand rejected under the written description provision of 35 U.S.C. § 112, first paragraph. 4 Appellant’s January 19, 2016, Specification. Appeal 2022-000246 Application 15/000,504 3 II. Claims 1-4, 7-9, and 13-16 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Friderichs5 and Graham.6 III. Claims 1-4, 7-9, and 13-17 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Friderichs, Graham, and Migliardi.7 IV. Claims 1-4, 7-9, and 13-17 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Buschmann,8 Morton,9 and Migliardi. Written Description: ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention? 5 Friderichs et al., DE 102 54 785 A1, published June 3, 2004 (“’785”). Examiner relied upon Schiene et al., US 2005/0277687 A1, published Dec. 15, 2005 as an “English Language translation” of Friderichs (Final Act. 4), we do the same. 6 Garry G. Graham & Kieran F. Scott, Mechanism of Action of Paracetamol, 12 American Journal of Therapeutics 46-55 (2005). 7 JR Migliardi et al., Caffeine as an analgesic adjuvant in tension headache, 56 Clin. Pharmacol. Ther. 576-86 (1994). Examiner relied upon the PubMed abstract of this document. Therefore, we limit our review of this document to the PubMed abstract, available at http://www.ncbi.nlm.nih.gov/pubmed/7955822, last accessed Nov. 4, 2008. 8 Buschmann et al., US 6,344,558 B1, issued Feb. 5, 2002. 9 N. S. Morton & K. O’Brien, Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine, 82 Br. J Anaesth. 715-17 (1999). Appeal 2022-000246 Application 15/000,504 4 ANALYSIS10 “The ‘written description’ requirement serves a teaching function, . . . in which the public is given ‘meaningful disclosure in exchange for being excluded from practicing the invention for a limited period of time.”’ University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 922 (Fed. Cir. 2004) (citation omitted). Another “purpose of the ‘written description’ requirement is . . . [to] convey with reasonable clarity to those skilled in the art that, as of the filing date [], [the applicant] was in possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 10 Appellant’s contends that the rationale provided in Examiner’s Answer amounts to a new ground of rejection that should not be considered by this Panel (Reply Br. 2-3). “The line of demarcation between appealable matters for the Board and petitionable matters for the Director of the U.S. Patent and Trademark Office (Director) should be carefully observed.” MPEP § 1201 (9th ed. Rev. 10.2019, rev. June 2020). Therefore, we decline to review Appellant’s arguments regarding whether the Examiner’s Answer contained a new ground of rejection, which is a petitionable matter. See MPEP § 1002.02(c)(6)) (“Petitions under 37 CFR 41.40 to request review of the primary examiner’s failure to designate a rejection in the examiner’s answer as a new ground of rejection” (emphasis added)). We note, however, that, even if Examiner’s Answer contained a new ground of rejection, “[i]n response to an examiner’s answer that contains a new ground of rejection, appellant must either file: (A) a reply in compliance with 37 CFR 1.111 to request that prosecution be reopened; or (B) a reply brief that addresses each new ground of rejection in compliance with 37 CFR 41.37(c)(1)(iv) to maintain the appeal” (MPEP § 1207.03(I)). On this record, Appellant filed a Reply Brief, wherein “Appellant offers a response to these points[, presented in Examiner’s Answer,] out of an abundance of caution” (see Reply Br. 3, n.3). Therefore, we move forward with our deliberations on the record presented for our review. Appeal 2022-000246 Application 15/000,504 5 1563-64 (Fed. Cir. 1991) (emphasis omitted); see also Enzo Biochem Inc. v. Gen-Probe Inc., 323 F.3d 956, 969 (Fed. Cir. 2002). The written description requirement is satisfied when the specification “set[s] forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed.” University of Rochester, 358 F.3d at 928. “[A]pplicants have some flexibility in the ‘mode selected for compliance’ with the written description requirement” (id.), and it is well settled that actual reduction to practice is not necessary to satisfy the requirement (id. at 926). Whether or not a specification satisfies the requirement is a question of fact, which must be resolved on a case-by-case basis (Vas-Cath, 935 F.2d at 1562-63), and it is Examiner’s “initial burden [to] present[] evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims” (In re Wertheim, 541 F.2d 257, 263 (CCPA 1976)). “The written description requirement is not met if the specification merely describes a ‘desired result.’” Vasudevan Software, Inc. v. MicroStrategy, Inc., 782 F.3d 671, 682 (Fed. Cir. 2015) (citing Ariad Pharm. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349 (Fed. Cir. 2010)). In addition, “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (quoting Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69 (Fed. Cir. 1997) (alteration Appeal 2022-000246 Application 15/000,504 6 original)). “One shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious.” Lockwood v. Am. Airlines Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). On this record, Examiner finds that Appellant’s “claims encompass[] a ‘synergistic’ composition of [(b)] paracetamol and the [3-(3- Dimethylamino-l-ethyl-2-methyl-propyl)-phenol] compound [(a), corresponding to formula (I), which is] referred to as ‘tapentadol’” (Final Act. 3; see also Ans. 4 (Examiner finds that Appellant’s “claims are directed to a composition which combines the analgesic known as tapentadol with the analgesic paracetamol in sufficient quantities to provide a synergistic analgesic effect when the composition claimed is administered”)). Appellant discloses: The weight ratios of the components (a) and (b) that will lead to a supra-additive effect (synergistic effect) of the inventive pharmaceutical composition may be determined via the test of Randall and Selitto as described in Arch. Int. Pharmacodyn., 1957, 111: 409 to 419, which is a model for inflammatory pain. (Spec. ¶ 52.) Appellant further discloses: The analysis of the results with respect to a supra- additive effect of the inventive pharmaceutical composition comprising the components (a) and (b) is carried out via statistical comparison of the theoretical additive ED50-value with the experimentally determined ED50-value of a so-called fixed ratio combination (isobolographic analysis according to Tallarida JT, Porreca F, and Cowan A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989; 45: 947 - 961 [“Tallarida”]). The interactions studies presented herein were performed using equieffective doses of the two components, calculated Appeal 2022-000246 Application 15/000,504 7 from the ratio of the respective ED50 values of the components if administered alone. The application route was intravenous (i.v.) for (1R,2R)- 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol (A) and intraperitoneal (i.p.) for Paracetamol. When A was applied alone, the peak effect was reached 15 min p. appl. (timepoint of first measurement) and an ED50-value of 1.878 (1.694-2.065) mg/kg i.v. was calculated. Paracetamol induced a dose- dependent analgesic effect with an ED50-value of 189,9 (181,3 - 198,4) mg/kg i. p. respectively, reaching the peak effect 120 min p. appl. According to their respective timepoint of peak effect, (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- phenol was applied 15 min and Paracetamol 120 min before timepoint of measurement of the interaction-experiments (i. e. Paracetamol was applied 105 min before (1R,2R)-3-(3- Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, respectively). Thus, the time point of ED50 calculation of the combination corresponds to the timepoint of the peak effect of the respective compound. The isobolographic analysis revealed that the experimental ED50-values of the combinations were significantly lower than the respective theoretical ED50-values. Thus, the combination studies demonstrate significant synergistic interaction of (1R,2R)-3-(3-Dimethylamino-1-ethyl- 2-methyl-propyl)-phenol with Paracetamol. (Spec. ¶¶ 54-56 (emphasis added).) In sum, Appellant discloses a single synergistic combination of (a) tapentadol and (b) paracetamol that was obtained when paracetamol was administered i.p. 105 minutes prior to an i.v. dosage of tapentadol (Spec. ¶ 56; see also Final Act. 3-4 (Examiner finds that Appellant discloses “a single ‘synergistic’ combination of paracetamol and tapentadol”); Ans. 5 (citing Spec. ¶ 56) (Examiner finds that Appellant’s Specification “makes clear that two distinct compositions are administered at vastly different time points through two distinct routes of administration to optimize the synchronization of bioavailability of each”)). Examiner finds that this Appeal 2022-000246 Application 15/000,504 8 disclosure of a single synergistic combination fails to provide written descriptive support for the full scope of Appellant’s claimed invention (see Ans. 7-8 (Examiner finds that Appellant “offer[s] neither data nor justification to extrapolate their showing beyond the single combination of staggered i.v. and i.[p.] administration of the two components of the composition claimed”)). Examiner recognizes that Appellant discloses that “the determination of alternative synergistic [combinations] ‘can be determined by methods well known to those skilled in the art,’” but finds that this additional disclosure is not sufficient to bridge the distance between Appellant’s single disclosed synergistic combination and Appellant’s claimed invention (Final Act. 4 (quoting Spec. ¶ 28); see also Lockwood, 107 F.3d at 1572 (“One shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious.”). Examiner further finds that Appellant’s disclosure “represents not a description of an invention, but a mere indication of a result one might achieve if one made that invention” (Ans. 5 (quoting Spec. ¶ 28).) We agree. See Vasudevan, 782 F.3d at 682 (“The written description requirement is not met if the specification merely describes a ‘desired result.’”). For the foregoing reasons, we agree with Examiner’s finding that Appellant’s Specification fails to provide adequate written descriptive support for the full scope of Appellant’s claimed invention. Appeal 2022-000246 Application 15/000,504 9 For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner fails to appreciate the significance of Appellant’s specification data and improperly treats it as proving the synergy of a single weight ratio of components (a)+ (b), when persons skilled in the art, being familiar with the experimental method employed, would have viewed this weight ratio as indicative and representative of other synergistic weight ratios. (Appeal Br. 3.) Synergistic weight ratios is merely one of numerous undisclosed variables associated with the combination required by Appellant’s claimed invention, which, to name a few, include the route of administration, timing of administration, i.e., whether concurrent or sequential, which may vary dependent upon administration route and dosage (see, e.g., Spec. ¶ 2 (Appellant’s disclosure contemplates simultaneous or sequential administration and administration “either via the same or a different pathway,” all of which is encompassed by the scope of Appellant’s claimed invention)). As Examiner explains, Appellant’s disclosure “establishes that it may be possible to formulate a composition whereby a combination of paracetamol and tapentadol provides synergistic analgesic effect, but which would require additional formulation steps and knowledge in order to provide such a composition” (Ans. 6). In this regard, we recognize Appellant’s reliance on Tallarida to describe “isobolographic analysis,” but find that Appellant failed to adequately explain how Tallarida accounts for the undisclosed variables discussed above, as opposed to the concurrent administration of two drugs (see Appeal Br. 4-7; cf. Tallarida 947 (Tallarida discloses “[w]hen two drugs are administered concurrently there is a need to characterize the effect of the combination in relation to the effect of each drug individually” (emphasis added); cf. Reply Br. 3 Appeal 2022-000246 Application 15/000,504 10 (Appellant contends that “[p]roper and complete responses to [the merits of the written description rejection presented for review on this Appeal] . . . are calculated by Appellant to require further expert review and testimony”)). Examiner further finds that Tallarida’s “review article, while potentially a basic primer on interpreting isobolographic analysis, cannot serve to overcome the fundamental shortcomings of the data in the context of the written description analysis” on this record (Ans. 7). Tallarida also recognizes the limits of isobolographic analysis: Since the points of an isobole are pairs of numbers (doses or concentrations) that are obtained from experimental testing they are subject to both random as well as systematic errors. In other words, these concentrations represent random variables whose values are estimated by experimental samples. Thus, the line of additivity, drawn from sample values . . . must be subjected to statistical analysis in order to distinguish sub- and super-additivity from simple additivity. . . . The isobologram is, however, useful for display . . . and, to the extent that regression analysis may be desirable on points of the mixture, it is important to point out that both x and y have errors. (Tallarida 950; see id. at 947 (Tallarida discloses that “[t]he isobologram . . . provides a convenient graphical display of the respective doses by using rectangular coordinates (x,y) to represent equieffective pairs of [concurrent] doses of drugs X and Y, respectively”); see also Ans. 7. For the foregoing reasons, we are not persuaded by Appellant’s contention that “the original specification does, in fact, support a single composition comprising ingredients (a) and (b) in a synergistic weight ratio,” which Appellant alleges satisfies the written description requirement on this record because Appellant’s “claims are limited to only synergistic Appeal 2022-000246 Application 15/000,504 11 combinations, for which Appellant has demonstrated possession” (Appeal Br. 8; Reply Br. 4-5 (citing Spec. ¶¶ 6, 32)). For the foregoing reasons, we are not persuaded by Appellant’s contention that “[t]he experimental data[, presented in its Specification,] are supportive of expected synergy for such a combination despite the fact that tapentadol has been administered in a first formulation and paracetamol has been administered separately in a second formulation” (Reply Br. 5). We are not persuaded by Counsel’s contention, which Counsel concedes is “without benefit of expert input,” that A person skilled in this art would understand that the demonstrated synergy, while achieved using different administration routes, occurs in vivo because the two active ingredients (a) and (b) simultaneously come to be present in the blood in a quantity that brings about a synergistic interaction between them. Thus, it should not matter how active ingredients (a) and (b) were introduced to the body, whether separately by different administration routes or, alternatively, together in a single composition, as long as the proper blood concentrations of both active ingredients are simultaneously achieved. (Reply Br. 5-6) (emphasis omitted.) Argument by counsel cannot take the place of evidence. In re Cole, 326 F.2d 769, 773 (CCPA 1964); In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997); see also In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). As discussed above, Appellant’s claimed invention comprises a synergistic combination of tapentadol and paracetamol. According to Appellant, “[t]he technical hurdle that needed to be cleared here was the finding that tapentadol and paracetamol synergized in the first place,” when administered in a manner consistent with the full scope of Appellant’s Appeal 2022-000246 Application 15/000,504 12 claimed invention (Reply Br. 6). Thus, for the reasons discussed above, we are not persuaded by Appellant’s contention that “we are here dealing with active ingredients that have been used widely clinically, namely tapentadol and paracetamol,” that “[p]ersons skilled in the art are familiar with their formulation for clinical purposes,” and that “such persons have a working knowledge of pharmaceutical formulation principles” (id.). See Lockwood, 107 F.3d at 1572 (“One shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious.”). For the foregoing reasons, we are not persuaded by Appellant’s contention that “Examiner nowhere explains why a single showing of synergy [(]assuming, for the sake of argument, that is all Appellant has demonstrated[)] is insufficient to support a claim expressly requiring ‘synergy’” (Reply Br. 10). For the foregoing reasons, we are not persuaded by Appellant’s contention that the “isobolographic specification data are such that ‘persons skilled in the art would have expected that many other ratios falling below the line of additivity would also have been synergistic’ (emphasis added)” (Reply Br. 11 (footnote omitted; quoting Appeal Br. 6)). CONCLUSION The preponderance of evidence on this record supports Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention. Rejection I: The rejection of claim 1 under the written description provision of 35 U.S.C. § 112, first paragraph is affirmed. Claims 2-4, 7-9, and 13-17 are not separately argued and fall with claim 1. Appeal 2022-000246 Application 15/000,504 13 Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Friderichs discloses “compound A, which is selected from the . . . group[, which includes,] (-)-(1R,2R)-3-(3-dimethylamino-2-ethyl-2- methyl-propyl)-phenol” (Friderichs ¶¶ 90, 101 (emphasis added); see Final Act. 6 (citing ’785 ¶ 23; Friderichs ¶ 88) (Examiner makes clear that although “the original German publication recites (1R,2R)-3-(3- dimethylamino-1-ethyl-2-methyl-propyl)-phenol . . . , during translation the US document appears to have transposed the ethyl substituent from the 1 to the 2 carbon, a configuration clearly prohibited by the generic structure [of Friderichs’ formula] ‘Ia’”) (emphasis added)). FF 2. Friderichs discloses group B COX-II inhibitors, wherein “[t]he term ‘COX-II inhibitors’ refers to selective inhibitors of COX II, the inducible isoform of cyclooxygenase” (Friderichs ¶¶ 2, 62; see Final Act. 6.) FF 3. Friderichs “relates to the combination of analgesics of group A with COX-II inhibitors of group B, pharmaceutical compositions, including advantageous galenical forms containing this combination, and to the use thereof, in particular for the treatment of pain” (Friderichs ¶ 2). FF 4. Friderichs discloses that “it has been found that a combination of selected analgesics of group A with COX-II inhibitors exhibit an outstanding analgesic effect” (Friderichs ¶ 6; see Final Act. 5). Appeal 2022-000246 Application 15/000,504 14 FF 5. Friderichs “provide[s] substances or substance combinations that are suitable for the treatment of pain . . . and, in particular, in the combinations which exhibit a synergistic effect for the treatment of pain” (Friderichs ¶ 5 (emphasis added); see Final Act. 5). FF 6. Examiner finds that “Friderichs indicates that the combinations according to the instant claims are suitably combined with additives and/or auxiliaries suitable for providing galenic dosage forms suitable for, among others, oral delivery, and may be formulated to provide for delayed release” (Final Act. 6 (citing Friderichs ¶ 171)). FF 7. Examiner finds that “Friderichs does not teach that paracetamol may be employed as the COX-II inhibiting agent” and relies on Graham to make up for this deficiency (Final Act. 6). FF 8. Graham discloses that although “[p]aracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs) . . . the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors” (Graham Abstr.; see also id. at 52 (Graham discloses that “[f]unctionally, paracetamol . . . act[s] as a selective COX-2 inhibitor”)). FF 9. Examiner finds that the combination of Friderichs and Graham does not disclose a composition comprising caffeine, and relies on Migliardi to make up for this deficiency (Final Act. 7). FF 10. Migliardi discloses a “caffeine-containing analgesic consist[ing] of combination of 1000 mg acetaminophen and 130 mg caffeine,” and found that “the caffeine-containing analgesics were significantly superior both to placebo and to 1000 mg acetaminophen” (Migliardi, Abstr.; see Final Act. 7 (citing Migliardi, Abstr. (Examiner finds that “Migliardi indicates that Appeal 2022-000246 Application 15/000,504 15 caffeine is a known analgesic adjuvant which improves the efficacy of analgesics when administered to patients”)). ANALYSIS Rejection II: Friderichs discloses that the combination of Appellant’s 3-(3- Dimethylamino-l-ethyl-2-methyl-propyl)-phenol compound with a selective inhibitor of COX II exhibit outstanding analgesic effect, are suitable for the treatment of pain, and exhibit a synergistic effect for the treatment of pain (FF 1-6). Further, although Friderichs does not explicitly disclose paracetamol, Graham makes clear that “the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors” and “[f]unctionally, paracetamol . . . act[s] as a selective COX-2 inhibitor” (FF 7-8). Thus, based on the combination of Friderichs and Graham, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to have utilized paracetamol as the COX-II selective inhibitor to be combined with either of a diastereomeric mixture or single diastereomer of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- phenol such as the instantly claimed (1R,2R)-3-(3- dimethylamino-1-ethyl-2-methyl-propyl)-phenol to provide oral dosage forms with the expectation that such an arrangement would provide supraadditive analgesic effect. This is because just such a synergistic effect is taught by Friderichs to be expected by combinations of l-phenyl-3-dimethylaminopropane analgesics including 3-(3-dimethylamino-1-ethyl-2-methyl- propyl)-phenol and COX-II inhibitors in a variety of orally Appeal 2022-000246 Application 15/000,504 16 deliverable dosage forms, and Graham establishes that paracetamol indeed functions as a selective COX-II inhibitor. (Final Act. 6; see also FF 1-6.) We agree. As Appellant explains, “[t]he technical hurdle that needed to be cleared here was the finding that tapentadol and [a selective COX-II inhibitor] . . . synergized in the first place,” as was disclosed by Friderichs, and “[o]nce [Friderichs cleared] that hurdle . . . it is merely a routine matter to formulate [tapentadol with a selective COX-II inhibitor, such as paracetamol,] . . . into a single composition to reproduce the synergy demonstrated” (Reply Br. 6). Claim 1: For the foregoing reasons, we are not persuaded by Appellant’s contention that “Examiner has not shown how the cited combination reveals a reasonable expectation that a combination of (a) tapentadol . . . and (b) paracetamol would have been [reasonably] expected to be synergistic” (Appeal Br. 11). Appellant directs attention to the Declaration of Thomas M. Tzschentke, signed July 11, 2013, (“First Tzschentke Decl.”) and Declaration of Thomas M. Tzschentke, signed May 27, 2019, (“Second Tzschentke Decl.”) (see Appeal Br. 11). The First Tzschentke Declaration addresses a rejection of claims under 35 U.S.C. § 103(a) over the combination of Buschmann, Mimoz,11 and Varrassi,12 which is not before this Panel for review (see First 11 O. Mimoz et al., Analgesic Efficacy and Safety of Nefopam vs. Propacetamol Following Hepatic Resection, 56 Anaesthesia 520 (2001). 12 Giustino Varrassi et al., A Double-Blind Evaluation of Propacetamol Versus Ketorolac in Combination with Patient-Controlled Analgesia Appeal 2022-000246 Application 15/000,504 17 Tzschentke Decl. ¶¶ 5-22, 26-29). Therefore, we are not persuaded by the First Tzschentke Declaration’s discussion of “the behavior of morphine in combination with propacetamol as disclosed in Mimoz and Varrassi,” which is not before this Panel for review (see id. ¶ 19; see also id. ¶¶ 20-21, 26- 29). As discussed above, the evidence on this record, supports a conclusion that those of ordinary skill in this art would have reasonably expected that the combination of Appellant’s 3-(3-Dimethylamino-l-ethyl-2-methyl- propyl)-phenol compound with a selective inhibitor of COX II, such as paracetamol, will exhibit outstanding analgesic effect, is suitable for the treatment of pain, and will exhibit a synergistic effect for the treatment of pain (FF 1-8). See In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success. . . . For obviousness under § 103, all that is required is a reasonable expectation of success.”). Therefore, we are not persuaded by Tzschentke’s statement that “a synergistic analgesic effect is unexpected because, generally, the behavior of a combination of two or more drugs administered together cannot be reliably predicted from the behavior of the drugs when administered alone,” “[t]wo or more drugs may or may not interact with one another upon administration,” “[e]ven if interaction occurs, the interaction may be negative,” and “most analgesic combinations result in purely additive analgesic effect” (First Tzschentke Decl. ¶¶ 24-25; see generally Reply Br. 13). Morphine: Analgesic Efficacy and Tolerability After Gynecologic Surgery, 88 Anesth. Alalg. 611 (1999). Appeal 2022-000246 Application 15/000,504 18 The evidence on this record establishes that a combination of Appellant’s 3-(3-Dimethylamino-l-ethyl-2-methyl-propyl)-phenol compound with compounds that exhibit the same mode of action, specifically, selective inhibitors of COX II, such as paracetamol, will exhibit outstanding analgesic effect, is suitable for the treatment of pain, and will exhibit a synergistic effect for the treatment of pain (FF 1-8). As Tzschentke makes clear, “synergy might well be reasonably extrapolated from one combination to another where the structural differences and/or differences in the modes of action between the drugs being exchanged are minor” (Second Tzschentke Decl. ¶ 9 (emphasis added)).13 O’Farrell, 853 F.2d at 903-04 (“Obviousness does not require absolute predictability of success. . . . For obviousness under § 103, all that is required is a reasonable expectation of success.”). For the same reasons, discussed above with respect to the First Tzschentke Declaration, we are not persuaded by Tzschentke’s statements regarding drug combinations comprising morphine (see, e.g., Second Tzschentke Decl. ¶¶ 9, 22). A reference disclosure is not limited only to its preferred embodiments, but is available for all that it discloses and suggests to one of ordinary skill in the art. In re Lamberti, 545 F.2d 747, 750 (CCPA 1976). Therefore, we are not persuaded by Tzschentke’s testimony that attempts to limit Friderichs’ disclosure to its specifically exemplified compounds, 13 Absent evidence to the contrary, given Tzschentke’s express statements regarding “structural differences and/or differences in the modes of action,” we find Tzschentke’s statements relating to “structural differences and differences in the modes of actions” to represent a typographical error (see Second Tzschentke Decl. ¶¶ 9, 10; cf. id. ¶¶ 8, 11, 18, 21). Appeal 2022-000246 Application 15/000,504 19 celecoxib and rofecoxib (see Second Tzschentke Decl. ¶¶ 11-14; see also Appeal Br. 11). Prior art is presumed to be enabled. See In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012) (“[A] prior art printed publication cited by an examiner is presumptively enabling barring any showing to the contrary by a patent applicant or patentee.”). Therefore, we are not persuaded by Tzschentke’s statement: Had Friderichs provided further experimental data showing COX-II inhibitors structurally remote from celecoxib and rofecoxib also synergized with tapentadol, one could possibly start to imagine that the synergy could, in this particular instance, be based in mechanism alone and that other untested COX-II inhibitors might show synergy as well. However, Friderichs did not provide such additional data and so it seems impossible reasonably to conclude that COX-II inhibitors structurally remote from celecoxib and rofecoxib would be expected to synergize with tapentadol as well. (Second Tzschentke Decl. ¶ 14); see also Appeal Br. 14 (Appellant contends that “the limited data Friderichs has provided are insufficient to permit a person having ordinary skill in this art to conclude that tapentadol would have been expected to synergize with all COX-II inhibitors irrespective of their structural remoteness to celecoxib and rofecoxib”); cf. FF 1-8.) This statement fails to appreciate that once Examiner establishes a prima facie case of obviousness, as was done on this record, the evidentiary burden shifts to Appellant. See In re Huang, 100 F.3d 135, 139 (Fed. Cir. 1996) (“Once a prima facie case of obviousness has been established, the burden shifts to the applicant to come forward with evidence of nonobviousness to overcome the prima facie case”) (emphasis omitted). Appeal 2022-000246 Application 15/000,504 20 For the foregoing reasons, we are not persuaded by Tzschentke’s statements regarding the structural differences between paracetamol and Friderichs’ exemplified compounds, i.e., celecoxib and rofecoxib (see Second Tzschentke Decl. ¶¶ 12-17; see also Appeal Br. 12-13; Appeal Br. 17 (Appellant contends that although “celecoxib and rofecoxib bear close structural similarity to one another . . . paracetamol does not bear close structural similarity to celecoxib and rofecoxib”); Reply Br. 13-14). For the same reasons, we are not persuaded by Tzschentke’s statement that “[d]ata that might permit a conclusion that the synergy is independent of structure and depends on mechanism alone is missing from Friderichs” (Second Tzschentke Decl. ¶ 21; see also Appeal Br. 15-16). For the foregoing reasons, we are not persuaded by Appellant’s contention: Appellant justifiably questions the ability of persons skilled in the art to extrapolate from Friderichs’ showing that celecoxib and rofecoxib synergize with tapentadol to an expectation that all other COX-II inhibitors, irrespective of structural differences to celecoxib and rofecoxib, would likewise have also been expected to synergize with tapentadol. The Examiner does not make that case and, moreover, the weight of entirety of the evidence is against such extrapolation. (Appeal Br. 12.) Notwithstanding Appellant’s contention to the contrary, for the reasons discussed above, the preponderance of the evidence on this record falls in favor of Examiner’s prima facie case of obviousness. Friderichs defined the term COX-II inhibitors and provides examples of compounds that fall within the scope of that definition. Appellant failed to identify any precedent that supports its intimation that Friderichs’ failure to specifically include paracetamol among its exemplified list of COX-II inhibitors is somehow significant on this record (see Appeal Br. 15 Appeal 2022-000246 Application 15/000,504 21 (Appellant contends “[t]he Board is . . . asked to consider despite the fact that paracetamol was first synthesized in 1877, and it is the most commonly used medication for pain and fever in both the United States and Europe, it is conspicuously absent from the list of COX-II inhibitors in Friderichs” and “[t]he exclusion of paracetamol from the list of COX-II inhibitors in Friderichs is more likely intentional than not.”)). In order to be persuasive of non-obviousness, “[e]vidence of secondary considerations must be reasonably commensurate with the scope of the claims.” In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). For the reasons discussed above, including the discussion of the written description rejection, we find that Appellant’s evidence of unexpected results is not commensurate in scope with Appellant’s claimed invention. Therefore, we are not persuaded by Appellant’s contention “that combinations of the instant active ingredients (a) and (b) are, in fact, synergistic must be regarded and surprising and unexpected and, therefore, as objective evidence of nonobviousness” (Appeal Br. 22; see also Reply Br. 15). For the reasons discussed above, including the discussion of the written description rejection, we are not persuaded by Appellant’s contention that it “has demonstrated both the unexpected synergistic result; and the adequate basis to support the conclusion that other embodiments falling within the claims will behave in the same manner” (Reply Br. 12 (citing Kao, 639 F.39 at 1068)). Appeal 2022-000246 Application 15/000,504 22 Claim 9: Appellant’s claim 9 depends from and further limits the compound corresponding to formula (i) to a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2- methyl-propyl)-phenol compound corresponding to formula (I’), or a hydrochloride addition salt thereof (see Appeal Br. 27). “Appellant respectfully requests separat[e] consideration of claim 9 since this claims . . . specific component (a) compound tested in the experiments reported in Table 1” (Appeal Br. 22). Having separately considered Appellant’s claim 9 together with Appellant’s disclosure, including the experiments reported in Appellant’s Table 1, and Appellant’s contentions, we find that Appellant failed to establish error in Examiner’s prima facie case of obviousness. Further, Appellant failed to establish that this compound taken with the limited exemplification of Appellant’s Specification is representative of the full scope of Appellant’s claimed invention. As explained above, in order to be persuasive of non-obviousness, “[e]vidence of secondary considerations must be reasonably commensurate with the scope of the claims.” See Kao, 639 F.3d at 1068. Appeal 2022-000246 Application 15/000,504 23 Rejection III: Based on the combination of Friderichs, Graham, and Migliardi, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to combine the modified analgesic of Friderichs and Graham with the caffeine analgesic adjuvant described by Migliardi to yield the analgesic combination of the instant invention. One having ordinary skill in the art would have combined the analgesic compounds both because of Friderichs’ and Graham’s teaching that paracetamol can be used to in combination with 3- (3-dimethylamino-1-ethyl-2-methylpropyl)-phenol to provide for a synergistic analgesic effect, but also because each of 3-(3- dimethylamino-1-ethyl-2-methylpropyl)-pheno[l], paracetamol, and caffeine were known as analgesics or adjuvants effective in improving analgesia at the time of the instant invention. (Final Act. 7.) Having found no deficiency in the combination of Friderichs and Graham, with respect to Appellant’s claims 1 and 9, we are not persuaded by Appellant’s contention that Migliardi fails to make up for Appellant’s alleged deficiency in Friderichs and Graham (Appeal Br. 22-23). Rejection IV: We vacate Rejection IV as cumulative to Rejections II and III. CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. Rejection II: The rejection of claims 1 and 9 under 35 U.S.C. § 103(a) as unpatentable over the combination of Friderichs and Graham is Appeal 2022-000246 Application 15/000,504 24 affirmed. Claims 2-4, 7, 8, and 13-16 are not separately argued and fall with claim 1. Rejection III: The rejection of claims 1 and 9 under 35 U.S.C. § 103(a) as unpatentable over the combination of Friderichs, Graham, and Migliardi is affirmed. Claims 2-4, 7, 8, and 13-17 are not separately argued and fall with claim 1. Rejection IV: We vacate, as cumulative, the rejection of claims 1-4, 7-9, and 13-17 under 35 U.S.C. § 103(a) as unpatentable over the combination of Buschmann, Morton, and Migliardi. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-4, 7-9, 13-17 112, first paragraph Written Description 1-4, 7-9, 13-17 1-4, 7-9, 13-17 103(a) Friderichs, Graham 1-4, 7-9, 13-17 1-4, 7-9, 13-17 103(a) Friderichs, Graham, Migliardi 1-4, 7-9, 13-17 1-4, 7-9, 13-17 103(a) Buschmann, Morton, Migliardi14 Overall Outcome 1-4, 7-9, 13-17 14 For the reasons discussed above this rejection is vacated. Appeal 2022-000246 Application 15/000,504 25 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv) (2019). AFFIRMED