Ex Parte Kandhagatla et alDownload PDFPatent Trial and Appeal BoardDec 20, 201812863317 (P.T.A.B. Dec. 20, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/863,317 07/16/2010 27557 7590 12/25/2018 BLANK ROME LLP 1825 Eye Street NW WASHINGTON, DC 20006-5403 UNITED ST A TES OF AMERICA FIRST NAMED INVENTOR Rajnarayana Kandhagatla 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. 135042.00101 5351 EXAMINER MCMILLIAN, KARA RENITA ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 12/25/2018 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): W ashingtonDocketing@blankrome.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte RAJNARA YANA KANDHAGATLA and SRIHARI RAJU KALIDINDI Appeal2017-003353 Application 12/863 ,31 71 Technology Center 1600 Before DEBORAH KATZ, MICHAEL J. FITZPATRICK, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to an aqueous, stable parenteral formulation of paracetamol, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b ). We affirm. STATEMENT OF THE CASE Paracetamol is a known analgesic. (Spec. 1-2.) In aqueous solution, paracetamol may undergo hydrolysis to p-aminophenol, which degrades to 1 Appellants identify the real party in interest as Pharmis Biofarmaceutica Lda. (Appeal Br. 2.) Appeal2017-003353 Application 12/863,317 quinoneimine, which may be potentially toxic. (Id.) The stability of paracetamol in an aqueous formulation is desirable. (Id. at 2.) Parenteral formulations of paracetamol are known. (Id.) "However, the prior art stabilized liquid formulation[ s] of paracetamol have the drawback of causing a potential irritant and/or allergic effect in certain patients, because of the toxicity of either the antioxidant or the organic solvent present in the formulation." (Id.) The present invention is directed to a stable aqueous paracetamol formulation that does not contain a buffer or an organic solvent. Claims 1, 7, 8, 12, and 14--19 are on appeal. 2 Claim 1 is representative and reads as follows: 1. An aqueous, stable parenteral formulation comprising: (i) hydroxypropyl-B-cyclodextrin; (ii) sodium metabisulfite as an antioxidant; and (iii) paracetamol; wherein the formulation (a) contains no buffering agent; (b) contains no organic solvent; and ( c) exhibits an oxygen content of not more than 2 ppm, and wherein (i) the formulation is prepared from hydroxypropyl-B- cyclodextrin, sodium metabisulfate and paracetamol without the use of organic solvents; and (ii) the pH of the formulation is from about 4.5 to about 7.5. (Appeal Br. 14.) 2 Claims 4, 5, and 9 are also pending but stand withdrawn from consideration. (Appeal Br. 14--15.) 2 Appeal2017-003353 Application 12/863,317 The following grounds of rejection by the Examiner are before us on review: Claims 1, 7, 8, 12, and 14--19 under 35 U.S.C. § 103 as unpatentable over Pitha, 3 Tseti, 4 and Nguyen-Xuan. 5 Claims 1, 7, 8, and 18 under 35 U.S.C. § 103 as unpatentable over Liu, 6 Tseti, and Nguyen-Xuan. DISCUSSION I. Claim Construction "[A] preamble limits the invention if it recites essential structure or steps, or if it is 'necessary to give life, meaning, and vitality' to the claim." Catalina Mktg. Int'!, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 808 (Fed. Cir. 2002) (quoting Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999)). Appellants argue that the phrase "aqueous, stable parenteral formulation" provides the only antecedent basis for the three separate recitations of "the formulation" appearing in the body of the claim, and that each of the terms "aqueous" "stable" and "parenteral" all "breathe life" into the claim "by structurally differentiating" the formulation claimed from other formulas such as tablets or unstable liquid formulations. (Reply Br. 4.) While we do not agree entirely with Appellants' reasoning, we do determine that the phrase "aqueous, stable parenteral formulation" is limiting. In particular, the body of the claim requires that the composition 3 Pitha, US 4,727,064, issued Feb. 23, 1988. 4 Tseti, EP 0916347 Al, published May 19, 1999. 5 Nguyen-Xuan, US 2006/0084703 Al, published Apr. 20, 2006. 6 Liu et al., US 2005/0215520 Al, published Sept. 29, 2005. 3 Appeal2017-003353 Application 12/863,317 include 1) hydroxypropyl-B-cyclodextrin, 2) sodium metabisulfite, and 3) paracetamol and excludes buffering agents and organic solvents. Nothing in these requirements about what is included and what is excluded explains how the formulation is able to have a pH between 4.5 to about 7.5 as required. Thus, the preamble requirement that the formulation be aqueous is necessary to breathe life and meaning into the claim. Furthermore, we determine that stability is a fundamental characteristic of the claimed invention. In the Specification it is stated: Formulating liquid compositions of paracetamol has critical considerations. The paracetamol in aqueous solution is liable to undergo hydrolysis to form p-aminophenol, which itself degrades to quinoneimine. Also, the stability of aqueous formulations is dependent on variables such as removal of dissolved oxygen from carrier, optional further presence of antioxidant in the formulation and adjustment to suitable pH. Hence a composition comprising an aqueous formulation of paracetamol wherein the stability of the formulation is achieved is highly desirable. (Spec. 2.) In providing a stable formulation, the pH of the formulation is important, as is the level of dissolved oxygen. (See, e.g., Nguyen-Xuan ,r 3 (noting the rate of degradation of paracetamol in an aqueous solution "is minimal at a pH in the region of 6"), ,r 4 ("It is known practice to add a buffer and an antioxidant or free-radical scavenger to stabilize paracetamol in solution."), ,r 7 (noting that the stability of injectable paracetamol solutions "requires the removal of the oxygen and other oxidizing agents from the aqueous medium").) Both of these elements are limitations of the claimed composition. Thus, the "stable" language of the preamble "describes a 'fundamental characteristic of the claimed invention' that 4 Appeal2017-003353 Application 12/863,317 informs one of skill in the art as to the structure required by the claim." Deere & Co. v. Bush Hog, LLC, 703 F.3d 1349, 1358 (Fed. Cir. 2012). Finally, as to the preamble requirement that the aqueous, stable formulation is a "parenteral" one, we note that Appellants contend that this language and the remaining body of the claim requires "ready for use" or "final formulation." (Appeal Br. 6, Reply Br. 5.) We agree, but only to the extent that the formulation be in a state that it can be administered parenterally without further manipulation, other than to place the formulation into a syringe for injection. II. Obviousness of Claims 1, 7, 8, 12, and 14-19 over Pitha, Tseti, and Nguyen-Xuan The Examiner finds that Pitha teaches "dissolution properties of drugs may be improved ... by complexation with cyclodextrins." (Final Action 8.) The Examiner explains that Pitha teaches "cyclodextrin mixtures that effectively solubilize lipophilic drugs into aqueous media." (Id.) The Examiner notes that "Pitha specifically teaches an aqueous composition comprising acetaminophen (paracetamol) and hydroxypropyl-B- cyclodextrin" and that the cyclodextrin "increases the solubility of paracetamol in water and thus is a suitable solubilizer of paracetamol." (Id. at 8-9.) The Examiner further finds that Pitha teaches "that the solutions of cyclodextrin mixtures are non-irritating topically and do not support microbial growth" and "have very low toxicity, both systemic and local when applied parenterally." (Id. at 8.) The Examiner explains that "Pitha specifically teaches that the lack of parenteral toxicity of the cyclodextrin derivatives was tested by intraperitoneal injection into mice with 5 Appeal2017-003353 Application 12/863,317 hydroxypropyl-B-cyclodextrin with a lower degree of substitution (i.e. 6) being nontoxic." (Id.) The Examiner also notes that Pitha "teaches that the cyclodextrin derivative, hydroxypropyl-B-cyclodextrin with medium degrees of substitution (5-7) is a more effective solubilizer than those of higher degrees of substitution." (Id.) The Examiner also finds that "Pitha further teaches that the solutions of drugs in cyclodextrin derivatives were stable when kept at room temperature for several months and no microbial growth on the solutions was observed." (Id. at 9.) Thus, the Examiner states that "Pitha teaches a stable aqueous solution comprising paracetamol and hydroxypropyl-B- cyclodextrin suitable for parenteral administration which does not contain a buffering agent or an organic solvent and moreover that is prepared without the use of organic solvents." (Id.) The Examiner notes that Pitha does not teach inclusion of sodium metabisulfite or what the pH of the formulation is. (Id.) The Examiner, finds, however, that maintaining the pH of the Pitha composition at around pH 6 and adding sodium metabisulfite would have been obvious to one of ordinary skill in the art in light of the teachings of Tseti and Nguyen-Xuan. (Id.) In particular, the Examiner notes that Tseti teaches injectable solutions of paracetamol require the composition to be chemically stable and not be influenced by pH declines. (Id.) The Examiner finds that Tseti teaches in that regard that it was known to include an antioxidant agent, such as sodium metabisulfite, in injectable solutions of paracetamol to assure solution stability. (Id.) In addition, the Examiner explains that Nguyen-Xuan teaches that metabisulfite is an antioxidant that is known for use in creating a stable 6 Appeal2017-003353 Application 12/863,317 paracetamol injectable solution. (Id. at 10.) And the Examiner further finds that Nguyen-Xuan teaches that it was known that to minimize the degradation of paracetamol in aqueous solution, one should keep the pH in the region of 6. (Id.) The Examiner also notes that Tseti teaches the pH of stable injectable solutions of paracetamol should be between 5.0 and 6.5. (Id. at 9.) The Examiner concludes that one of ordinary skill in the art would have been motivated to include an antioxidant such as sodium metabisulfite in the Pitha composition and keep that composition at pH 6 to improve the stability of the Pitha composition "since it is known that paracetamol is liable in water and undergoes hydrolysis and degradation" and since it was known that pH 6 keeps degradation of paracetamol in aqueous solution to a minimum. (Id. at 10-11.) The Examiner recognizes that Pitha does not discuss oxygen concentration, but notes that Pitha does not teach that the composition comprises any oxygen. (Id. at 9, 11.) The Examiner concludes that it would have been obvious "to remove oxygen and other oxidizing agents from the composition to further improve the stability of the composition and reduce degradation of paracetamol" in light of the teachings of Nguyen-Xuan. (Id. at 11.) In particular, the Examiner explains that "Nguyen-Xuan teaches that the use of antioxidants for stability of aqueous solutions require the removal of the oxygen and other oxidizing agents from the medium and also requires storage in containers that are not permeable to oxygen or that comprise traces of oxidizing residues." (Id.) We agree with the Examiner's findings and conclusion that claim 1 would have been obvious to one of ordinary skill in the art from the teachings of Pitha, Tseti, and Nguyen-Xuan. 7 Appeal2017-003353 Application 12/863,317 Appellants argue that the Examiner's rejection is in error because "Pitha is not focused on a formulation that is used directly, in a parenteral administration," "is silent on the need for a buffering agent in a ready-to-use parenteral formulation," and the two references that do teach parenteral formulations of paracetamol, Tseti and Nguyen-Xuan, use a buffering agent. (Appeal Br. 8; see also Reply Br. 6-7.) Thus, argue Appellants, "the Tseti and Nguyen-Xuan references teach away from the" claimed invention. (Appeal Br. at 8-9.) Appellants rely on the Declaration of Walter Chambliss 7 in support of the argument that the invention in Pitha is only directed to improved oral formulations, not parenteral formulations, of a drug. (Appeal Br. 6-7 .) According to Appellants, even though Pitha discusses testing parenteral toxicity of cyclodextrin derivatives, and describes that cyclodextrin complexes of the drug and cyclodextrin derivatives can be a liquid, the reference is directed to formulations for improved absorption of the drug, which "is not a relevant concern in the context of a parenteral formulation because a parenterally-administered drug is injected directly into the blood stream and, therefore, there is no absorption occurring." (Id.) According to Appellants, the disclosed paracetamol formulation "is not a ready-to-use pharmaceutical formulation for parenteral administration ... it is a complex of the API with a cyclodextrin." (Id.) Appellants assert: There can be no doubt that if a person skilled in the art were to start with the teachings [ of] Pitha, as the Examiner suggests, 7 Appellants note that the Declaration of Walter Chambliss was submitted with the response filed September 4, 2015. (Appeal Br. 6.) 8 Appeal2017-003353 Application 12/863,317 which is silent as to the need for a buffering agent, and then modify the formulations taught in th[ at] reference by incorporating the teaching of Tseti and Nguyen-Xuan, the skilled artisan would have incorporated all of the disclosed ready-to-use, paracetamol formulation features from those two references, including the buffering agent. (Id. at 9.) And Appellants further argue that "[i]t makes no sense to assume one skilled in the art would ignore the buffering agent ingredient when Pitha is silent on the need for a buffer." (Id.) The Appellants assert: Indeed, if the goal of the skilled artisan is to make a paracetamol formulation without a buffering agent, like the presently rejected claims, one skilled in the art would not have been motivated to start with Pitha and then modify the disclosed paracetamol formulation with the teaching of Tseti and Nguyen-Xuan. (Id. at 10.)8 We do not find these arguments persuasive. 8 In their Reply Brief, Appellants argue that "[b ]oth of the Tseti and Nguyen-Xuan references disclose parenteral formulations of paracetamol and thus would make a better starting point for the § 103 inquiry." (Reply Br. 6.) This is a new argument. First, "the reply brief [is not] an opportunity to make arguments that could have been made in the principal brief on appeal to rebut the Examiner's rejections, but were not." Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative). As stated inExparte Borden, consideration by the Board of new arguments presented for the first time in the Reply Brief that could have been presented earlier would "vitiate the force of the requirement in Board Rule 37(c)(l)(vii) that '[a]ny arguments or authorities not included in the brief ... will be refused consideration by the Board, unless good cause is shown."' Id. Appellants have not demonstrated any specific Examiner findings presented for the first time in the Answer necessitating this specific new argument in rebuttal in the Reply Brief. Nor do we find any substantial differences in the Examiner's initial findings and the Examiner's findings stated in the Answer that would warrant the new arguments presented in the Reply Brief for the first time. Second, Appellants' argument as to the better starting reference is not a persuasive argument. As discussed herein, we find that Pitha teaches a 9 Appeal2017-003353 Application 12/863,317 We disagree with Appellants that Pitha does not teach a parenteral formulation of the cyclodextrin with paracetamol that would be ready-to- use, even considering the testimony of Mr. Chambliss. We note that Mr. Chambliss agrees that Pitha teaches parenteral testing of cyclodextrin derivatives (Chambliss Declaration ,r 9), he just notes that Pitha's parenteral toxicity testing was by intraperitoneal injection, and, thus, the injections were not made intravenously. Of course, as the Examiner noted (Ans. 14), parenteral administration, which simply means administration other than orally, encompasses such injection. While Pitha does describe solid formulations and the suitability of cylcodextrin drug complexes for tableting, as Mr. Chambliss explains (Chambliss Declaration ,r,r 9-10), and may not be "focused on a preparation that can be used directly, in a parenteral administration," as Chambliss contends (Id. ,r 10), Pitha does describe liquid formulations, which Mr. Chambliss acknowledges,9 as Appellants note. (Appeal Br. 6 ("The cyclodextrin complexes can be a solid (powder) or a liquid.").) Moreover, Pitha teaches that a liquid formulation of paracetamol and hydroxypropyl-B- cyclodextrin without buffering agents and organic solvents is stable and that it would have very low toxicity upon parenteral administration. parenteral formulation. Moreover, the test of obviousness is what the combined references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413,425 (CCPA 1981). And, as explained herein, we conclude that the combined teachings of the three references relied upon by the Examiner render obvious Appellants' claimed invention. 9 See Chambliss Declaration ,r 9 ("[T]he cyclodextrin complexes taught in Pitha can be a solid powder or a liquid, Pitha teaches compressing the complexes that are solid powders into a tablet, and freeze drying complexes that are liquids"). 10 Appeal2017-003353 Application 12/863,317 In particular, Pitha explains that the cyclodextrins disclosed solubilize lipophilic drugs into aqueous media and that the cyclodextrins have "very low toxicity ... when applied parenterally." (Pitha 2:44--54; 4:64--5: 13.) Pitha also teaches that solutions of paracetamol and hydroxypropyl-B- cyclodextrin without buffering agents and organic solvents were stable when kept at room temperature for several months. (Pitha 7:33-36.) Furthermore, "no microbial growth" was observed. (Id.) Such attributes would have indicated to one of ordinary skill in the art that the aqueous solution that was tested parenterally in Pitha, would be ready-for-use and would be obvious to use as such. (Ans. 14--15.) And as already discussed above, Appellants' declarant, Mr. Chambliss, agrees that Pitha teaches parenteral testing of cyclodextrin derivatives. Thus, we agree with the Examiner that "based on the teachings of Pitha," it would have been obvious to a person of ordinary skill in the art that the stable liquid formulation taught which does not include organic solvents or even buffering agents, which Pitha also indicates would have very low toxicity when administered parenterally, would be able to be used as a ready-to-use parenteral formulation. (Ans. 15.) Appellants contend that the Examiner has "admitted" that "Pitha does not teach ready-to-use, parenterally-administered, paracetamol formulations." (Reply Br. 7.) We do not find any such admission by the Examiner. The Examiner contends that the preamble is not given weight as it merely states an intended use of the invention (Ans. 13.) For the reasons discussed above, we disagree with the Examiner's claim construction. However, we note the Examiner's incorrect construction is harmless error, as the Examiner finds Pitha specifically discloses an aqueous, stable parenteral formulation as claimed minus sodium metabisulfite. (Ans. 14.) 11 Appeal2017-003353 Application 12/863,317 We find that Mr. Chambliss's testimony that "Pitha's acetaminophen (paracetamol) preparation is not a pharmaceutical formulation ready to be used for parenteral administration" (Chambliss Declaration ,r 10) ignores the teachings in Pitha concerning ( 1) liquid formulations that are stable, (2) the fact of very low toxicity upon parenteral administration, and (3) that Pitha teaches parenteral testing of cyclodextrin derivatives. Therefore, we give his testimony little weight as to how one of ordinary skill in the art would view the scope of Pitha. In re American Acad. of Science Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004) ("The Board has broad discretion as to the weight to give to declarations offered in the course of prosecution ... [and is entitled to] conclude that the lack of factual corroboration warrants discounting the opinions expressed in the declarations."). It is certainly true that Pitha is silent on the use or need of buffer. (Appeal Br. 8.) However, when, as here, a reference is silent regarding the presence of a component excluded from a composition via a negative limitation, it is reasonable to interpret the reference's silence as to the excluded component as teaching that the reference does not include the component absent persuasive technical reasoning or evidentiary showing otherwise. Cf Upsher-Smith Labs., Inc. v. Pamlab, LLC, 412 F.3d 1319, 1322 (Fed. Cir. 2005) (concluding it was proper for the district court to place the burden on the patentee to present rebuttal evidence that the prior art required a particular ingredient that the claim explicitly recited was excluded where the evidence of record indicated that the prior art taught the ingredient was optional, and thus disclosed compositions with and without the ingredient). Appellants do not argue that there is a reason why it would be necessary for a buffer to be included in the modified Pitha. Instead, 12 Appeal2017-003353 Application 12/863,317 Appellants simply assert that it would not make any sense not to include a buffer when Tseti and Nguyen-Xuan use one. (Appeal Br. 9.) We do not find that argument to be well grounded. In particular, as the Examiner explains with reference to Nguyen-Xuan, it was known in the art that aqueous solutions of paracetamol undergo degradation, but that such degradation is minimal at a pH in the range of 6. (Ans. 15.) Pitha teaches, as discussed above, that the solution of paracetamol with hydroxypropyl-B- cyclodextrin is stable at room temperature. In light of the foregoing, we agree with the Examiner, that one of ordinary skill in the art would have presumed that the pH of Pitha was around 6 and thus was not in need of buffering (id.), and thus it would have made sense not to include a buffer such as is used in the Tseti and Nguyen-Xuan formulations. That is particularly true where Tseti teaches the need for an organic solvent to solubilize paracetamol in water (Tseti ,r,r 19--20) and Nguyen-Xuan similarly teaches the need for an organic solvent to solubilize paracetamol if the solution exceeds 1.0g/100 ml (Nguyen-Xuan ,r 18), whereas Pitha is specifically concerned with not using such a solvent. We also disagree with Appellants that Tseti and Nguyen-Xuan teach away from the present invention for these same reasons. In light of the foregoing, we are not persuaded that the Examiner erred in rejecting claim 1 as being obvious over Pitha, Tseti, and Nguyen-Xuan. Claims 7, 8, 12, and 14--19 have not been argued separately and therefore fall with claim 1. 3 7 C.F .R. § 41.3 7 ( c )(1 )(iv). 13 Appeal2017-003353 Application 12/863,317 III. Obviousness of Claims 1, 7, 8, and 14-19 over Liu, Tseti, and Nguyen- Xuan The Examiner finds that Liu teaches "a sterile water-soluble complex of water-insoluble or sparingly-soluble organic medicines and beta- cyclodextrin derivatives." (Final Action 13.) The Examiner explains that Liu teaches preparing the complex as a freeze-dried powder that can be further prepared into a solution for injection or other parenteral solutions. (Id.; Ans. 19.) The Examiner finds further that "Example 27 of Liu et al. specifically teaches the preparation of a complex of paracetamol and hydroxypropyl-B- cyclodextrin." (Final Action 13.) The Examiner finds that Liu further teaches that this composition is "extremely freely water-soluble or freely water-soluble as dissolved in water, and the dissolving speed is fast" and that "the complex is in possession of infinite dilution stability when its solution is diluted with water again." (Id. at 14.) The Examiner notes that in the preparation of the complex an organic solvent is used, but that such solvent is removed prior to the formation of the stable aqueous solution. (Id.) The Examiner concludes: (Id.) Thus since Liu et al. teaches that the dried complex of paracetamol and hydroxypropyl-B-cyclodextrin can be prepared into a solution for injection and that the dried complex is freely water-soluble as dissolved in water, an aqueous solution comprising paracetamol and hydroxypropyl-B-cyclodextrin is rendered obvious as it would have been obvious to a person of ordinary skill in the art to dissolve the dried paracetamol and hydroxypropyl-B-cyclodextrin complex of Liu et al. with water for injection to prepare a solution for injection. 14 Appeal2017-003353 Application 12/863,317 Similar to the rejection involving Pitha, the Examiner notes that Liu does not teach the use of an antioxidant such as sodium metabisulfite in the composition, or the pH of the composition, or the oxygen content of the composition. (Id.) However, the Examiner contends that these requirements of the claimed invention would have been obvious in light of the teachings of Tseti and Nguyen-Xuan for the same reasons as discussed above regarding the Pitha based rejection. (Id. at 15-17.) Appellants' arguments that the rejection is in error are similar to those made regarding the Pitha based rejection. In particular, Appellants argue, again relying on the Chambliss Declaration, that Liu does not teach ready- to-use parenteral formulation. (Appeal Br. 11.) Appellants also argue that Liu does not teach whether buffering is needed or not. (Id.) We do not find Appellants' arguments persuasive. In particular, we agree with the Examiner that Liu reasonably teaches one of ordinary skill in the art that the formulation of the dried paracetamol and hydroxypropyl-B- cyclodextrin complex described in Example 27 is extremely freely soluble in water (Liu ,r 9) and that it can be prepared as a solution for injection (Id. ,r,r 27, 46). Indeed, Liu indicates that a different drug and hydroxypropyl-B- cyclodextrin complex that is prepared similarly to paracetamol and hydroxypropyl-B-cyclodextrin is prepared "for injection." (Id. ,r,r 75-79.) Mr. Chambliss's conclusion to the contrary rests on the fact that Liu only specifically describes preparing a tablet of hydrochloric Sibutramine-HP-B- CD complex (Liu ,r 154), and by ignoring Liu's discussion concerning the fact that the complexes can be freely dissolved in water and prepared for injection (Liu ,r,r 27, 46). (Chambliss Declaration ,r 11 ( citing only Liu ,r 154.)) Thus, as was the case with Chambliss's testimony as to how one of 15 Appeal2017-003353 Application 12/863,317 ordinary skill in the art would view the scope of Pitha, we give his testimony little weight as to how one of ordinary skill in the art would view the scope of Liu. In reAmericanAcad. of Science Tech Ctr., 367 F.3d at 1368. Moreover we agree with Appellants and the Examiner that Liu, similar to Pitha, is silent regarding the use of a buffer in the dissolution of the paracetamol and hydroxypropyl-B-cyclodextrin complex. However, here again, we conclude that it is reasonable to interpret the reference's silence as to the excluded component as teaching that the reference does not include the component absent persuasive technical reasoning or evidentiary showing otherwise. Appellants do not provide any reason why it would be necessary for a buffer to be included in the modified Liu, i.e., a solution for injection. As with Pitha, Liu teaches the combination of paracetamol and hydroxypropyl-B-cyclodextrin results in a complex that is soluble in aqueous solution with the use of an organic solvent. Thus, we disagree with Appellants, that one of ordinary skill in the art would have looked to Tseti Nguyen-Xuan, both of which require an organic solvent to solubilize paracetamol, and determine it would be necessary to add a buffer to the Liu composition. We also disagree with Appellants that Tseti and Nguyen-Xuan teach away from the present invention for these same reasons. In light of the foregoing, we are not persuaded the Examiner erred in rejecting claim 1 for obvious over Liu, Tseti, and Nguyen-Xuan. Claims 7, 8, and 18 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 4I.37(c)(l)(iv). SUMMARY We affirm the rejection of claims 1, 7, 8, 12, and 14--19 under 3 5 U.S.C. § 103 as unpatentable over Pitha, Tseti, and Nguyen-Xuan. 16 Appeal2017-003353 Application 12/863,317 We affirm the rejection of claims 1, 7, 8, and 18 under 35 U.S.C. § 103 as unpatentable over Liu, Tseti, and Nguyen-Xuan. 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). AFFIRMED 17 Copy with citationCopy as parenthetical citation