Ex Parte Kokai-Kun et alDownload PDFBoard of Patent Appeals and InterferencesAug 29, 200810323907 (B.P.A.I. Aug. 29, 2008) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE ____________________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________________ Ex parte JOHN FITZGERALD KOKAI-KUN, SCOTT MICHAEL WALSH, JAMES JACOB MOND, and TATYANA IVANOVA CHANTURIYA, Appellants ____________________ Appeal 2008-4627 Application 10/323,9071 Technology Center 1600 ____________________ Decided: August 29, 2008 ____________________ Before CAROL A. SPIEGEL, RICHARD M. LEBOVITZ, and JEFFREY N. FREDMAN, Administrative Patent Judges. SPIEGEL, Administrative Patent Judge. DECISION ON APPEAL 1 Application 10/323,907 ("the 907 application"), "Methods and Formulations for Eradicating or Alleviating Staphylococcal Nasal Colonization using Lysostaphin," filed 20 December 2002, claims benefit under 35 U.S.C. § 119 of provisional application 60/341,802, filed 21 December 2001. The real party in interest is said to be BIOSYNEXUS INCORPORATED (Corrected Appellants' Brief, filed 19 December 2007 ("App. Br."), at 3). Appeal 2008-4627 Application 10/323,907 I. Statement of the Case This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 17-27, 30-53, and 56-60. Claims 28, 29, 54, and 55, the only other pending claims, stand objected to (FR2 1). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. The subject matter on appeal is directed to nasal administration of a composition comprising at least 0.125% lysostaphin in either a cream-based or polymer-containing liquid-based viscous formulation to reduce or eliminate bacterial colonization in the nose to prevent subsequent infection. Claim 17 and 51 are illustrative and read (App. Br. 16 and 20): 17. A method for treating a patient comprising, administering to the nose of said patient via one or more instillations, an effective amount of a composition comprising a) a viscous formulation, wherein said viscous formulation is selected from the group consisting of a cream-based formulation and a viscous liquid-based formulation comprising a polymer, and b) at least 0.125% lysostaphin, wherein said composition is effective at treating or preventing bacterial colonization. 51. A method for treating a patient by administering to the nose of said patient via one or more installations an effective amount of a lysostaphin intranasal consisting of a viscous formulation, wherein said viscous formulation is selected from the group consisting of a cream- based formulation and a viscous liquid-based formulation comprising a polymer, and at least 0.125% lysostaphin. 2 Final Office action mailed 26 October 2006. 2 Appeal 2008-4627 Application 10/323,907 The Examiner has rejected claims 17-27, 30-53, and 56-60 under 35 U.S.C. § 103(a) as unpatentable over Fischetti 954,3 Fischetti 324,4 Climo,5 and O'Callaghan6 (FR 2-3; Ans.7 3-5). Appellants have not argued the patentability of claims 18-25, 28-33, 35-50, and 54-60 apart from the independent claims on which they depend. Consequently, we decide this appeal on the basis of independent claims 17, 34, 51, and 52. 37 CFR § 41.37(c)(1)(v). II. Findings of Fact ("FF") The following findings of fact, and those set forth in the Discussion, are supported by a preponderance of the evidence of record. A. Appellants' invention [1] Appellants' invention "relates to the administration of lysostaphin intranasals to the nares to alleviate or block staphylococcal nasal colonization" (Spec. ¶ 9). [2] Lysostaphin is an endopeptidase which cleaves cross-linking pentaglycine bridges in the cell walls of staphylococci (Spec. ¶ 8). [3] Intranasal administration of a 0.5% lysostaphin saline spray to treat staphylococcal colonization is known in the art (Spec. ¶¶ 35-37). 3 U.S. Patent 6,056,954, "Use of Bacterial Phage Associated Lysing Enzymers for the Prophylactic and Therapeutic Treatment of Various Illnesses," issued 2 May 2000, to Fischetti et al. ("Fischetti 954"). 4 U.S. Patent 6,248,324 B1, "Bacterial Phage Associated Lysing Enzymes for Treating Dermatological Infections," issued 19 June 2001, to Fischetti et al. ("Fischetti 324"). 5 U.S. Patent 6,028,051, "Method for the Treatment of Staphylococcal Disease," issued 22 February 2000, to Climo et al. ("Climo"). 6 U.S. Patent 6,315,996 B1, "Topical Lysostaphin Therapy for Staphylococcus Ocular Infections," issued 13 November 2001, to Richard J. O'Callaghan ("O'Callaghan"). 7 Examiner's Answer mailed 18 March 2008 ("Ans."). 3 Appeal 2008-4627 Application 10/323,907 [4] According to the 907 specification, "the inventors have demonstrated that administration of lysostaphin in a cream formulation improves retention of lysostaphin in the nares and they believe that a viscous liquid formulation would also improve the retention time in the nares" (Spec. ¶ 40). B. The prior art 1. Fischetti8 [5] Fischetti discloses administering a species-specific bacteriophage lysin (lytic enzyme) in the form of a topical ointment or cream to treat bacterial infections associated with topical or dermatological infections (Fischetti 954 at 3:47-51; Fischetti 324 at 3:62-66). [6] For example, the bacteriophage lysin formulation may be directly applied by nasal sprays, nasal drops, nasal ointments, nasal washes, nasal injections, and nasal packings or by ointments applied to the nasal nares (Fischetti 954 at 5:1-8; Fischetti 324 at 5:21-28; emphasis added). [7] According to Fischetti, lysostaphin, an enzyme which lyses Staphylococcus aureus, and/or conventional antibiotics, such as bacitrin, may also be included in the bacteriophage lysin topical ointment or cream (Fischetti 954 at 3:51-58, 11:1-17; Fischetti 324 at 4:1-7, 11:18-34). [8] Fischetti expressly states the bacteriophage lysin formulation 8 Fischetti 954 issued based on application 09/395,636 (Fischetti 954 cover page, § 21). Fischetti 324 issued based on application 09/671,879, which is a continuation of application 09/395,636 (Fischetti 324 cover page, §§ 21 and 63). Fischetti 954 and 324 share common disclosures which are referred to in this Decision as "Fischetti." 4 Appeal 2008-4627 Application 10/323,907 may further comprise the enzyme lysostaphin for the treatment of any Staphylococcus aureus bacteria. Mucolytic peptides, such as lysostaphin, have been suggested to be efficacious in the treatment of S. aureus infections of humans . . . Lysostaphin . . . exerts a bacteriostatic and bactericidal effect upon S. aureus by enzymatically degrading the polyglycine crosslinks of the cell wall. . . . [R]ecombinant mucolytic bactericidal protein, such as r-lysostaphin, can potentially circumvent problems associated with current antibiotic therapy because of its targeted specificity, low toxicity and possible reduction of biologically active residues. Furthermore, lysostaphin is also active against non-dividing cells, while most antibiotics require actively dividing cells to mediate their effects . . . . There is a degree of added importance in using both lysostaphin and the lysin enzyme in the same therapeutic agent. Frequently, when a body has a bacterial infection, the infection by one genus of bacteria weakens the body or changes the bacterial flora of the body, allowing other potentially pathogenic bacteria to infect the body. One of the bacteria that sometimes co-infects a body is Staphylococcus aureus. Many strains of Staphylococcus aureus produce penicillinase, such that Staphylococcus, Streptococcus, and other gram positive bacterial strains will not be killed by standard antibiotics. Consequently, the use of the lysin and lysostaphin, possibly in combination with antibiotics, can serve as the most rapid and effective treatment of bacterial infections. (Fischetti 954 at 11:18-60; Fischetti 324 at 11:35- 12:9) (citations omitted.) 5 Appeal 2008-4627 Application 10/323,907 2. Climo [9] According to Climo, administration of single or short course, relatively high dosages of lysostaphin (at least 50-100 mg/kg body weight in a 24-hour period) is a dramatically effective therapy for the treatment of staphylococcal infections, particularly infections that are resistant to treatment, and/or typically associated with significant morbidity and mortality (Climo 3:29-35 and 49-54). [10] Climo also discloses that lysostaphin may be coadministered with other antimicrobial agents to treat an infectious disease more effectively (Climo 6:11-14). 3. O'Callaghan [11] According to O'Callaghan, "[l]ysostaphin is more effective than any currently available drug for treating Staphylococcus keratitis. When applied as a single drop (0.3%) every 30 min from 4 to 9 hr post- infection, or from 10 to 15 hr post-infection, lysostaphin caused significant reductions in the number of Staphylococcus CFU per cornea" (O'Callaghan 5:5-10). [12] Further according to O'Callaghan, "lysostaphin may also be mixed with pharmaceutically acceptable carriers to form an ointment" (O'Callaghan 8:7-9). III. Discussion A. Obviousness A claimed invention is not patentable if its subject matter would have been obvious to a person of ordinary skill in the art. 35 U.S.C. § 103(a); KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1734 (2007). Facts relevant to a determination of obviousness include (1) the scope and content of the prior 6 Appeal 2008-4627 Application 10/323,907 art, (2) any differences between the claimed invention and the prior art, (3) the level of ordinary skill in the art and (4) relevant objective evidence of nonobviousness. KSR, 127 S.Ct. at 1734. The test for obviousness is what the combined teachings of the references would have suggested to one of ordinary skill in the art. In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991); In re Keller, 642 F.2d 413, 425 (CCPA 1981). In evaluating such references it is proper to take into account not only the specific teachings of the references but also the inferences which one skilled in the art would reasonably have been expected to draw therefrom. In re Preda, 401 F.2d 825, 826 (CCPA 1968). B. The Examiner's findings and conclusions The Examiner found Fischetti discloses compositions for therapeutic and prophylactic treatment of bacterial infections of the upper respiratory tract and mucous membranes comprising lysostaphin (Ans. 3). The Examiner further found Fischetti discloses the composition may (a) include antibiotics, such as bacitracin, (b) be applied as a nasal ointments and (c) comprise carriers, such as polymer thickeners, surfactants and emulsifiers (Ans. 4). The Examiner also found the compositions can be directed to the mucosal lining where the enzymes in the compositions will be able to kill colonizing bacteria (Ans. 4). The Examiner found Fischetti failed to disclose the concentration of lysostaphin in the composition (Ans. 4). The Examiner found Climo discloses large doses of lysostaphin, i.e., at least 50 mg/kg body weight, are effective in eradicating staphylococcal infections (Ans. 4). The Examiner concluded it would have been obvious to formulate a viscous nasal formulation of lysostaphin for administration to a patient in 7 Appeal 2008-4627 Application 10/323,907 need thereof and to include antibiotics, such as bacitrin, in the formulation because Fischetti teaches beneficial administration of lysostaphin-containing compositions to mucosal surfaces of the upper respiratory tract as well conventional inclusion of antibiotics in the compositions (Ans. 4). The Examiner further concluded it would have been within routine skill in the art to optimize the percent of lysostaphin in the formulation "since Climo . . . teaches that larger amounts are desirable and will result in discernable reductions in staphylococci . . . within 24 hours" (Ans. 4-5). According to the Examiner, the disclosure in O'Callaghan of topical administration of a 0.3% lysostaphin formulation for treatment of ocular staphylococcus infection provides further motivation to formulate an ointment for topical administration to sensitive surfaces for the treatment of staphylococci and a reasonable expectation of success (Ans. 5). C. Arguments and Analysis 1A. Argument: "The cited references fail to enable the presently claimed invention and fail to provide a reasonable expectation of success for carrying out the claimed invention" (App. Br. 7). Appellants argue Fischetti treats bacterial infections by administering bacteriophage lysin (phage lytic enzyme) formulations, which may optionally contain one or more other materials selected from a vast array of materials which happen to include lysostaphin (App. Br. 7-9; Reply Br.9 4- 7). Appellants contend there is no motivation in any of the cited references to select lysostaphin from this broad selection of materials useful in combination with phage lytic enzymes or in the absence of phage lytic enzymes (App. Br. 9-12; Reply Br. 7-9). 9 Appellant's Reply Brief filed 19 May 2008 ("Reply Br."). 8 Appeal 2008-4627 Application 10/323,907 Appellants point out that all the specific examples and experimental data of Fischetti use phage lytic enzyme formulations, i.e., none use the claimed cream-based or polymer-containing liquid-based viscous formulation containing at least 0.125% lysostaphin as recited claims 17, 34, 51, and 52 (App. Br. 9-10; Reply Br. 6-7). According to Appellants, this lack of data and detail in the cited references, individually or in combination, "fail[s] to enable one of ordinary skill in the art to practice the claimed invention, fail[s] to foretell the functionality of the claimed methods and compositions of the claimed invention, and fail[s] to provide a reasonable expectation of success for carrying out the claimed invention" (Reply Br. 5). 1A. Analysis A reference must be considered for everything it discloses. In re Burckel, 592 F.2d 1175, 1179 (CCPA 1979). Here, Fischetti teaches that lysostaphin is a known bacteriostatic and bacterioside for Staphylococcus aureus (FF 8) which may be directly applied as part of a therapeutic nasal ointment or cream (FF 5-7). Climo also teaches that lysostaphin, at high doses, is a "dramatically effective therapy" for treating staphylococcal infections (FF 9). Similarly, O'Callaghan teaches use of lysostaphin to treat staphylococcal infection (FF 11). In sum, as pointed out by the Examiner (Ans. 5-6), all the cited references disclose treating staphylococcal infections with lysostaphin. As also pointed out by the Examiner, the open "comprising" language of claims 17 and 34 (Ans. 6), permits the inclusion of both bacteriophage lysin and lysostaphin in the same therapeutic formulation as taught by Fischetti. Indeed, in the paragraph referenced by the Examiner (Ans. 6), Fischetti states that infection by one genus of bacteria may potentiate 9 Appeal 2008-4627 Application 10/323,907 infection by a second pathogenic bacteria, that Staphylococcus aureus is one of these co-infecting bacteria, and that using bacteriophage lysin and lysostaphin, “possibly in combination with antibiotics, can serve as the most rapid and effective treatment of bacterial infections†(FF 8). Fischetti also suggests administering lysin, which is explicitly described in combination with lysostaphin (see above), as a therapeutic nasal ointment or cream (FF5, 6). In short, this argument is not persuasive of reversible Examiner error. 2B. Argument: "The Cited References Do Not Teach Each Element of the Present Invention and Actually Teach Away From the Claimed Invention" (App. Br. 12). Appellants argue that, since claims 51 and 52 expressly exclude phage lytic enzymes in the recited formulations, Fischetti teaches away from the claimed invention (App. Br. 12-13; Reply Br. 9-10), citing the following Fischetti disclosure: There is a degree of added importance in using both lysostaphin and the lysin enzyme in the same therapeutic agent. Frequently, when a body has a bacterial infection, the infection by one genus of bacteria weakens the body or changes the bacterial flora of the body, allowing other potentially pathogenic bacteria to infect the body. One of the bacteria that sometimes co- infects a body is Staphylococcus aureus. Many strains of Staphylococcus aureus produce penicillinase, such that Staphylococcus, Streptococcus, and other gram positive bacterial strains will not be killed by standard antibiotics. Consequently, the use of the lysin and lysostaphin, possibly in combination with antibiotics, can serve as the most rapid and effective treatment of bacterial infections. (Fischetti 954 at 11:46-59; Fischetti 324 at 11:63-12:9.) 10 Appeal 2008-4627 Application 10/323,907 2B. Analysis "[T]he suggestion to modify the art to produce the claimed invention need not be expressly stated in one or all of the references used to show obviousness. 'Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.'" Cable Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015, 1025 (Fed. Cir. 1985) (quoting In re Keller, 642 F.2d 413, 425 (CCPA 1981). This argument is unpersuasive because it fails to address the combined teachings of the references. Fischetti, Climo, and O'Callaghan all teach treating bacterial (staphylococcal) infections with lysostaphin. Fischetti teaches that a combination of lysin and lysostaphin, possibly in combination with antibiotics, can serve as the most rapid and effective treatment of bacterial infections (FF 8). In particular, Fischetti teaches that the phage lytic enzymes are used to treat organisms other than Staphlococcus aureus (see Fischetti 954 4:3-7), so an ordinary artisan would have recognized that the lytic enzymes need not be included in the treatment composition with the lysostaphin when Staphlococcus aureus alone was the infective agent, as in the situations disclosed by Climo and O’Callaghan. Climo teaches that high dose lysostaphin is an effective treatment for even resistant staphylococcal infections (FF 9). Moreover, as pointed out by the Examiner (Ans. 6-7), Fischetti and O'Callaghan both teach cream or ointment formulations containing lysostaphin for topical application (FF 5-7 and 12). Thus, this argument is not persuasive of reversible Examiner error. 3C. Argument: "The 37 C.F.R. 1.137 Declaration by John Kokai Kun, Ph.D. Evidences The Absence Of An 11 Appeal 2008-4627 Application 10/323,907 Expectation of Success for Carrying Out the Claimed Methods" (App. Br. 14). Finally, Appellants assert that the declaration of inventor John Kokai- Kun, Ph.D. is objective evidence of unexpected results sufficient to rebut the Examiner's prima facie conclusion of obviousness (App. Br. 14-15; Reply Br. 10). According to Appellants, "[c]ontrol experiments indicated that small molecule anti-infectives were effective at diffusing out of creams and forming clear zones, but that the larger lysostaphin protein molecule would not diffuse out of the cream" (App. Br. 14-15). Surprisingly, however, the lysostaphin cream cleared Staphylococcus aureus nasal colonization in the cotton rat nose with a single dose (App. Br. 15). Appellants conclude the declaration rebuts the prima facie case of obviousness (App. Br. 15). 3C. Analysis 1. The Declaration [13] John Kokai-Kun testified he is co-inventor of the subject matter and employee of the assignee of the 907 application (Declaration10 ¶1). [14] According to Dr. Kokai-Kun, "[w]hile small molecules like conventional antibiotics have long been formulated in cream or ointment bases, there is little to no experience with formulation of proteins for use as topical treatments rather than systemic treatments" (Declaration ¶ 2). [15] Dr. Kokai-Kun testified, As an initial screen for the efficacy of this formulation, an assay similar to a disk diffusion 10 Declaration of Applicant Under 37 C.F.R. 1.132, executed 22 June 2006, by John Kokai-Kun, Ph.D., and filed 29 June 2006 ("Declaration"). 12 Appeal 2008-4627 Application 10/323,907 assays was performed using the lysostaphin formulated in cream. A culture of S. aureus was inoculated onto a solid agar media and then a strip of lysostaphin cream was over-laid on the agar . . . Instead of observing inhibition of bacterial growth by lysostaphin, we were surprised to find S. aureus growing on the cream. In control experiments we overlaid the agar with cream containing a small molecule anti-infective and this formed a zone of inhibition suggesting that the anti-infective diffused out the cream into the agar. . . . At this point we considered abandoning the project, however we decided instead to try the cream in our cotton rat model of S. aureus nasal colonization, and much to our surprise the lysostaphin cream was actually capable of clearing S. aureus nasal colonization in the cotton rat nose with a single dose (an unanticipated finding based on the observed in vitro data) (Declaration ¶ 2.) 2. Analysis As noted by the Examiner (Ans. 7), Dr. Kokai-Kun did not explain what specific components were in the various cream formulations. Dr. Kokai-Kun did not explain the experimental protocol used for the diffusion assay or explain the cotton rat model assay at all. For example, Dr. Kokai- Kun did not testify as to whether a disk was used in the "assay similar to a disk diffusion assay†and, if so, what was the pore size of the strip/disk (the size of the pores would determine what size molecules would be able to diffuse out of the pores) what concentrations of active agents were used, whether these concentrations normalized to the same LD50, e.g., for comparison, whether all active agents stabile under the test conditions, what size innocula were used, were the same ratios of active agent concentration 13 Appeal 2008-4627 Application 10/323,907 to bacterial count used in both the assays, etc. Moreover, instead of comparing one protein cream formulation to another protein cream formulation, e.g., a bacteriophage lysin cream formulation to a lysostaphin cream formulation, the diffusion assay was tested versus a "small molecule" cream formulation. Appellants contend that the Declaration indicates that one of ordinary skill in the art, conducting experiments in an effort to develop embodiments of the present invention, would not have expected a claimed composition (i.e., a composition comprising a. a viscous formulation selected from the group consisting of a cream-based formulation and a viscous liquid-based formulation comprising a polymer, and b. at least 0.125% lysostaphin) to be successful at inhibiting bacterial growth, let alone at treating a patient (e.g., for inhibiting or clearing nasal bacterial colonization). (App. Br. 14). This argument is not persuasive. First, Dr. Kokai-Kun did not expressly state that “one of ordinary in the art†would not have expected at the time of the invention that a viscous formulation would have been successful at inhibiting bacterial growth. This statement is made in the Appeal Brief, but not by the declarant. Secondly, even had Dr. Kokai-Kun made such statement – and assuming that he did – Fischetti expressly states that its antibacterial formulations can be a nasal ointment (FF 6), evidence contrary to this position. When we weigh the evidence, we conclude that the preponderance of the evidence in this record supports the Examiner’s position that nasal ointments comprising lysostaphin would have been obvious to persons of ordinary skill in the art. For similar reasons, we do not find Appellants’ argument convincing that “the declaration of Dr. Kokai-Kun exemplifies the fact that at the time of the invention, one of ordinary skill in the art would have had little to no 14 Appeal 2008-4627 Application 10/323,907 experience with a cream formulation comprising lysostaphin†(Reply Br. 10). To the contrary, Fischetti provides explicit evidence to the contrary. Furthermore, the Declaration is not commensurate in scope with the claims, which are not limited to cream-based formulations. Therefore, we find the Kokai-Kun Declaration is entitled to little, if any, weight. Consequently, balancing the weight of the evidence of record for both obviousness and non-obviousness, we conclude that the evidence weighs in favor of a prima facie conclusion of obviousness. D. Conclusion Based on the foregoing, we sustain the rejection of claims 17-27, 30- 53, and 56-60 under § 103 over Fischetti 954, Fischetti 324, Climo, and O'Callaghan. IV. Order Upon consideration of the record, and for the reasons given, it is ORDERED that the decision of the Examiner rejecting claims 17-27, 30-53, and 56-60 under 35 U.S.C. § 103(a) as unpatentable over Fischetti 954, Fischetti 324, Climo, and O'Callaghan is AFFIRMED; and FURTHER ORDERED that 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 rvb Casimir Jones, S.C. 440 Science Drive Suite 203 Madison, WI 53711 15 Copy with citationCopy as parenthetical citation