Bo Liang et al.Download PDFPatent Trials and Appeals BoardJul 29, 201914127846 - (D) (P.T.A.B. Jul. 29, 2019) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/127,846 03/14/2014 Bo Liang 146660-010400 1726 160605 7590 07/29/2019 Venture Partner, LLC Weisun Rao 401 N. Michigan Ave. Suite 1200 Chicago, IL 60611 EXAMINER LIU, SUE XU ART UNIT PAPER NUMBER 1616 NOTIFICATION DATE DELIVERY MODE 07/29/2019 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): chen@venturepartnerllc.com ipmail@venturepartnerllc.com rao@venturepartnerllc.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte BO LIANG, BELACHEW TESSEMA, JOSEPH A. CAPRIOTTI, MICHAEL C. SAMSON, and WEI SONG1 __________ Appeal 2018-004521 Application 14/127,846 Technology Center 1600 __________ Before ERIC B. GRIMES, DEBORAH KATZ, and RYAN H. FLAX, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a pharmaceutical composition, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE The Specification states that “[i]odine and steroid[s] have both been used in treating nasal conditions or diseases.” Spec. ¶ 10. The Specification 1 Appellants identify the Real Party in Interest as IVEIW Therapeutics, Inc. Br. 2. Appeal 2018-004521 Application 14/127,846 2 also states that “[i]t has been widely known that iodine or iodine-releasing agents . . . are incompatible with most steroid preparations due to the high potential for chemical reactivity between molecular iodine and steroid moieties. As a result, these agents must be made from separate solutions, administered independently.” Id. The Specification discloses that, [t]hough the reactivity of iodine with steroids is well known, the pharmaceutical compositions of this invention are surprising[ly] stable, as the steroids contained therein (e.g., mometasone, fluticasone, budesonide, or a salt or adduct thereof) have been able to resist iodination, iodine oxidation and iodine-catalyzed addition reactions. Id. ¶ 13. Claims 1–5, 7–15, 19–21, and 23 are on appeal. Claim 1 is representative and reads as follows: 1. A pharmaceutical composition for treating a sinus disease or infection of a patient comprising an iodine-containing compound and a steroid, wherein the steroid comprises fluticasone or budesonide, or a salt or ester thereof. The claims stand rejected as follows: Claim 3 under 35 U.S.C. § 112, second paragraph, as indefinite (Final Action2 2); Claims 1–5, 7–14, and 23 under 35 U.S.C. § 103(a) as obvious based on Leshchiner3 and Cagle4 (Final Action 4); 2 Office Action mailed Dec. 9, 2016. 3 Leshchiner et al., US 2006/0280809 A1, published Dec. 14, 2006. 4 Cagle et al., WO 00/18404, published Apr. 6, 2000. Appeal 2018-004521 Application 14/127,846 3 Claim 15 under 35 U.S.C. § 103(a) as obvious based on Leshchiner, Cagle, and Haslwanter5 (Final Action 10); and Claims 19–21 under 35 U.S.C. § 103(a) as obvious based on Leshchiner, Cagle, and Lulla6 (Final Action 12). I The Examiner rejected claim 3 as indefinite, because it “recites the terms ‘organic polymer’, ‘polyol’, ‘surface active anion’, and ‘cation’, the scope of said terms is unclear. One of ordinary skill in the art would not have been readily aware of the scope of said terms or said claim.” Final Action 3. Appellants filed an amendment canceling claim 3,7 but the amendment was not entered.8 Appellants did not address this rejection in the Appeal Brief or Reply Brief. Because Appellants have waived their arguments with respect to this rejection, we affirm it. See 37 C.F.R. § 41.37(c)(1)(iv); Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008) (“When the appellant fails to contest a ground of rejection to the Board, . . . the PTO may affirm the rejection of the group of claims that the examiner rejected on that ground without considering the merits of those rejections.”). 5 Haslwanter et al., US 6,565,832 B1, issued May 20, 2003. 6 Lulla et al., US 8,163,723 B2, issued Apr. 24, 2012. 7 Response to Final Office Action, filed March 8, 2017. 8 Advisory Action mailed March 23, 2017 (indicating “rejected” for the status of claim 3). Appeal 2018-004521 Application 14/127,846 4 II The Examiner has rejected claims 1–5, 7–14, and 23 as obvious based on Leshchiner and Cagle. The Examiner finds that “Leshchiner et al. teach iodine based compositions for nasal use comprising an anti-inflammatory (abstract).” Final Action 5. The Examiner also finds that Leshchiner’s composition can comprise steroid anti-inflammatories, but Leshchiner does not disclose budesonide or fluticasone for use in its composition. Id. The Examiner finds, however, that “Cagle et al. teach nasal compositions comprising antibiotics in combination with anti-inflammatory agents (abstract), specific steroidal anti-inflammatory agents including budesonide and fluticasone (page 7).” Id. The Examiner concludes that it would have been obvious to produce the formulations of Leshchiner et al. with 0.01–1% budesonide or fluticasone as taught by Cagle et al. . . . because both references are drawn to pharmaceutical nasal formulations comprising an antibiotic in combination with a steroidal anti- inflammatory and Cagle et al. teach specific anti- inflammatory agents and percentages thereof that may be utilized. Id. at 6. We agree with the Examiner that the formulation of claim 1 would have been prima facie obvious based on Leshchiner and Cagle. Leshchiner states that “[o]tic and nasal infections are often accompanied by inflammation and pain in the infected otic and nasal tissues.” Leshchiner ¶ 11. Leshchiner states that “[t]here is a need for otic and nasal pharmaceutical compositions that combine the broad anti-infective activity of iodine-based compounds with the anti-inflammatory and analgesic Appeal 2018-004521 Application 14/127,846 5 activity of natural and synthetic oils and extracts as well as steroidal and non-steroidal anti-inflammatory agents.” Id. Leshchiner discloses “topical antimicrobial, non-antibiotic, pharmaceutical compositions for the treatment of otic and nasal infections. . . . The compositions are based on the use of polyvinlypyr[r]olidone-iodine (PVP-I).” Id. ¶ 30. “The compositions of the present invention may also contain one or more anti-inflammatory, analgesic and antiseptic agents.” Id. ¶ 31. In a specific embodiment, Leshchiner discloses a topical pharmaceutical composition comprising PVP-I, an excipient, and a vehicle (claim 1), and further comprising an anti-inflammatory agent (claim 9), wherein the anti-inflammatory agent is cortisone or acetaminophen (claim 10). Cortisone is a steroid. Spec. ¶ 56. Leshchiner does not disclose budesonide or fluticasone as the steroidal anti-inflammatory agent in its composition. However, like Leshchiner, Cagle teaches that “nasal infections are frequently accompanied by inflammation of the infected . . . nasal tissues.” Cagle 2:18–19. “Thus, there is also a need for . . . nasal pharmaceutical compositions that combine the anti-infective activity of one or more antibiotics with the anti- inflammatory activity of one or more steroid or non-steroid agents in a single composition.” Id. at 2:21–24. Cagle discloses “the use of a potent new class of antibiotics to treat . . . nasal infections.” Id. at 2:28–29. “The compositions preferably also contain one or more anti-inflammatory agents to treat inflammation associated with infections of . . . nasal tissues.” Id. at 3:5–6. “The anti- inflammatory agents utilized in [Cagle’s] invention are broadly classified as Appeal 2018-004521 Application 14/127,846 6 steroidal or non-steroidal. The preferred steroidal anti-inflammatory agents are glucocorticoids.” Id. at 7:13–15. “The preferred glucocorticoids for nasal use include mometasone, fluticasone, beclomethasone, flunisolide, triamcinolone and budesonide.” Id. at 7:18–20. Based on these teachings, it would have been obvious to include budesonide or fluticasone, along with the PVP-I in Leshchiner’s composition. The references provide ample reason to make the combination, because both are directed to compositions for treating nasal infections, both contain an anti-infective agent (PVP-I in Leshchiner, an antibiotic in Cagle), both suggest including a steroidal anti-inflammatory agent in the composition, Leshchiner discloses a specific embodiment comprising cortisone, and Cagle discloses budesonide and fluticasone as preferred steroidal anti-inflammatory agents for nasal use. A skilled artisan would have had a reasonable expectation of success in making the combination because both references describe their compositions as suitable for treating nasal infections. Appellants argue that “other than the general mentioning of steroidal and non-steroidal anti-inflammatory agents in Paragraph [0011] in the ‘Description of the Related Art’, nowhere else has Leshchiner specifically mentioned any anti-inflammatory agent, be it steroidal or nonsteroidal.” Br. 4. This argument is unpersuasive, because Leshchiner describes compositions comprising either a steroidal (cortisone) or non-steroidal (acetaminophen) anti-inflammatory agent. Leshchiner, claim 10. Even without that specific disclosure, however, Leshchiner’s express suggestion to include “anti-inflammatory . . . agents” in its composition, Leshchiner Appeal 2018-004521 Application 14/127,846 7 ¶ 31, would be sufficient reason to include an anti-inflammatory agent known for use in compositions for treating nasal infections. Appellants also argue that they “carried out experiments to prepare compositions containing PVP-I and ketorolac tromethamine, a well-known and popular non-steroidal anti-inflammatory agent. The results show that PVP-I readily reacted with ketorolac tromethamine.” Br. 5. This argument is unpersuasive, because it is unsupported by any objective evidence. Appellants, in the brief, state results that were purportedly obtained in the ketorolac experiments, but no data are provided, nor is any citation to a part of the record describing the actual experiments. The results set out in the Appeal Brief therefore amount to nothing more than attorney argument. 9 In addition, Appellants do not explain why the results found for a non-steroidal anti-inflammatory agent would be predictive of results expected for the steroidal agents budesonide and fluticasone. Appellants also argue that, “as Cagle requires its compositions contain antibiotics, whereas Leshchiner is silent on antibiotics, these two references essentially require the opposites.” Br. 5. This argument is also unpersuasive. Both Leshchiner and Cagle disclose that their compositions are useful for treating nasal infections and 9 Appellants later state that “[t]he data from the test with the non-steroidal anti-inflammatory agent, i.e., ketorolac tromethamine, were presented on page 7, last paragraph, in Applicant’s initial response to the Final Office Action filed on March 8, 2017.” Br. 9. The cited passage, however, is also attorney argument and does not include data supporting the purported results. Appeal 2018-004521 Application 14/127,846 8 contain an antimicrobial agent. Leshchiner ¶ 30, Cagle 7:5–7. The references use different antimicrobial agents, but they do not “require the opposites,” as Appellants argue. Appellants argue that “it had been well known in the art that iodine would react with olefin bonds in a steroid backbone even under mild conditions and a person skilled in the art would not have combined the teachings of Leshchiner and Cagle.” Br. 6. Appellants cite to three references submitted during prosecution and included as Exhibits A (“Woodward”),10 B (“Ellington”),11 and C (”Overton”)12 in the Evidence Appendix of the Appeal Brief. We have considered the cited references, but find that they do not support the position that a skilled artisan would have expected the PVP-I in Leshchiner’s composition to react with budesonide or fluticasone. Woodward describes cis-hydroxylation of a steroid intermediate. Woodward 209, title. Woodward states that, when the intermediate “is treated in acetic acid with iodine (1.05 equivalents), silver acetate (2.25 equivalents) and water (1.0 equivalent) and finally heated at 90–95° for three hours, oxidation of the 6,7-double bond occurs.” Id. at 209–210. Appellants have provided no basis for concluding that the reaction conditions described by Woodward, 10 R. B. Woodward & F. V. Brutcher, Jr., cis-Hydroxylation of a Synthetic Steroid Intermediate with Iodine, Silver Acetate and Wet Acetic Acid, unidentified journal, vol. 80, pp. 209–211 (1958). 11 P. S. Ellington et al., Hydroxy-Steroids. Part VI. Reactions of Olefins with Silver Salts and Iodine. J. Chem. Soc. C. 1327 (1966) (abstract only). 12 Steroid Properties and Reactions, Terpenoids and Steroids, K.H. Overton (ed.), page 297 (1971). Appeal 2018-004521 Application 14/127,846 9 including the presence of acetic acid and silver acetate, are similar to the conditions that would result from using budesonide or fluticasone as the steroidal anti-inflammatory agent in Leshchiner’s composition. Thus, Appellants have not shown that a skilled artisan would have expected Woodward’s reaction to occur if the teachings of Leshchiner and Cagle were combined. Ellington describes “[m]ild conditions . . . for carrying out the Woodward cis-hydroxylation of olefinic bonds.” Ellington, abstract. Although Ellington does not fully describe the reaction conditions, it makes clear that all of the reactions include a silver compound. Id. Again, Appellants have not explained why a skilled artisan would have expected the reactions described by Ellington to occur if budesonide or fluticasone was used in Leshchiner’s composition. Overton describes a reaction involving “iodine azide (IN3), which readily attacks olefinic steroids . . . to give iodo-azides.” Exhibit C 297. Leshchiner’s composition, however, comprises PVP-I as the iodine-releasing agent, not iodine azide. Appellants have not explained why Overton’s reaction would be predictive of the effect of using budesonide or fluticasone in Leshchiner’s composition. In summary, Appellants’ evidence does not support a conclusion that a person of ordinary skill in the art would have expected the PVP-I in Leshchiner’s composition to react with the budesonide or fluticasone suggested by Cagle as preferred steroidal anti-inflammatory agents. Appellants argue that “the affinity of free iodine (I2) for reaction with -OH, -SH, and -NH functional groups is well described in the literature and Appeal 2018-004521 Application 14/127,846 10 forms the basis for the anti-microbial activity of iodine-containing solutions. See, e.g., H. Rackur et al., J. Hosp. Infect., 1985; 6: 13–23 (copy attached as Exhibit D) and references therein.” Br. 7. Appellants, however, do not point to any specific disclosure in Rackur that supports their position, and we decline to speculate on what disclosure Appellants intend to rely on in the Rackur reference or in the “references therein.” Thus, Appellants have not identified any specific evidence supporting their argument that a skilled artisan would have expected the -OH groups in budesonide to react with the iodine released from Leshchiner’s PVP-I. Appellants argue that “the compositions of claim 1 of the present invention have proven to be unexpectedly stable.” Br. 7. Appellants point to “[s]tability test data described in the present application, starting at Paragraph [0069] through Paragraph [0080], including Tables 1–10” as “show[ing] that the compositions of claim 1 . . . are unexpectedly and remarkably stable, even at a high temperature of 60 °C.” Id. Appellants argue that the Liang Declaration13 “shows the head-to-head comparison of one of the two steroidal anti-inflammatory agents specifically recited in claim 1, against another steroid that is not within the claim scope of the present application. Unexpected results in stability of the compositions were shown by the test with budesonide.” Id. at 9. Appellants also argue that “the compositions of claim 1 of the present invention have been observed to be much more homogenous than the control 13 Declaration under 37 C.F.R. § 1.132 of Bo Liang, filed June 8, 2017. Appeal 2018-004521 Application 14/127,846 11 samples, illustrating that budesonide unexpectedly became much more soluble due to the addition of PVP-I to the compositions of claim 1.” Id. at 8. “Lastly [Appellants argue], the compositions of claim 1 . . . have also shown unexpected therapeutic effects, as described in Examples 8–10 of the present application (Paragraphs [0081]–[0098], including Tables 11–15).” Id. We have considered the cited evidence but are not persuaded that it supports a conclusion that the claimed composition would have been nonobvious. Appellants assert three unexpected properties for the claimed compositions: stability, solubility, and therapeutic effect. Regarding stability, Appellants point to the Specification’s paragraphs 69–83 and Tables 1–10, as well as the Liang Declaration. Br. 7–9. Collectively, the cited material shows that a mixture of PVP-I and budesonide is storage- stable to varying degrees under different conditions, and is more storage- stable than a mixture of PVP-I and dexamethasone sodium phosphate (a steroidal anti-inflammatory agent outside the scope of the claims). However, “[t]o be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (emphasis added). Here, the claimed composition is closest to the prior art composition defined by Leshchiner’s claim 10, which comprises PVP-I and cortisone as the steroidal anti-inflammatory agent. Appellants’ data do not show that the Appeal 2018-004521 Application 14/127,846 12 storage stability of the claimed composition is unexpectedly superior to that of the closest prior art composition, and therefore do not show that the claimed composition would not have been obvious in view of the prior art. Appellants’ evidence regarding the solubility of budesonide in the claimed composition suffers from the same defect. The Specification states that in an accelerated degradation test, the budesonide/PVP-I sample “showed a comparable stability with the control [no PVP-I] sample, but during the test, it is surprising that we observed that the sample was much more homogeneous than the control. This illustrated the solubility of the budesonide was significantly improved by addition of PVP-Iodine.” Spec. ¶ 76. The data, however, do not compare the solubility of budesonide to that of the closest prior art, Leshchiner’s cortisone/PVP-I composition. Lacking a comparison to the closest prior art, Appellants’ data do not show that the claimed composition would not have been obvious in view of the prior art. Regarding therapeutic effect, Appellants point to “Examples 8–10 of the present application (Paragraphs [0081]–[0098], including Tables 11–15).” Br. 8. The Specification’s Example 8 (¶¶ 77–83) compares the effect of a formulation comprising PVP-I and budesonide against Staphylococcus aureus and Pseudomonas aeruginosa. The control in that experiment is saline. Id. ¶ 83. The Specification’s Example 9 (¶ 84) shows a similar experiment with Candida albicans; the control again is saline. However, neither of the experiments described in Examples 8 and 9 of the Specification shows any “therapeutic” effect, because both experiments were conducted in vitro, and neither experiment shows a comparison to the closest prior art: Leshchiner’s PVP-I/cortisone composition. Appeal 2018-004521 Application 14/127,846 13 The Specification’s Example 10 (¶¶ 85–8914) does describe the effect of a PVP-I/budesonide composition on human subjects, but does not compare that composition to any other treatment. In particular, the PVP-I/budesonide composition is not compared to the closest prior art: Leshchiner’s PVP-I/cortisone composition. In summary, none of Appellants’ evidence of unexpected results shows a comparison to the closest prior art, and therefore does not persuasively show that the claimed invention is nonobvious over Leshchiner and Cagle. Furthermore, all of the cited experiments were conducted using budesonide; none of them show results for the combination of PVP-I with fluticasone, which is also encompassed by claim 1. “Evidence of unexpected results must be reasonably commensurate with the scope of the claims.” In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). “If an applicant . . . provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner [as a tested embodiment], this will generally establish that the evidence is commensurate with [the] scope of the claims.” Id. Here, the evidence shows that dexamethasone sodium phosphate is less storage-stable than budesonide. Liang Decl. ¶¶ 9–10. Appellants have not provided any evidence of fluticasone’s storage stability. The evidence of record thus does not show whether fluticasone is similar to budesonide with respect to storage stability, or whether instead it is more similar to 14 Although Appellants cite “Paragraphs [0081]–[0098],” Br. 8, the Specification has only ninety paragraphs. Appeal 2018-004521 Application 14/127,846 14 dexamethasone sodium phosphate. The evidence of record also does not show that fluticasone is similar to budesonide with respect to solubility or therapeutic effect. Thus, Appellants have not shown that the proffered evidence of unexpected results is commensurate in scope with the claims. For the reasons discussed above, we affirm the rejection of claim 1 under 35 U.S.C. § 103(a) based on Leshchiner and Cagle. Claims 2–5, 7–14, and 23 were not argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). III The Examiner has rejected claim 15 as obvious based on Leshchiner, Cagle, and Haslwanter. The Examiner has rejected claims 19–21 as obvious based on Leshchiner, Cagle, and Lulla. Appellants have waived arguments directed to the additional teachings of Haslwanter or Lulla. See Br. 10–11. We therefore affirm the rejections under 35 U.S.C. § 103(a) of claims 15 and 19–21 for the reasons set out in the Final Action and as discussed above. SUMMARY We affirm all of the rejections on appeal. 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 Copy with citationCopy as parenthetical citation