10937403 (B.P.A.I. Mar. 9, 2009)

Ex Parte Snider

Board of Patent Appeals and InterferencesMar 9, 2009

10937403 (B.P.A.I. Mar. 9, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE ____________________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________________ Ex parte DENIS P. SNIDER1 ____________________ Appeal 2008-6010 Application 10/937,403 Technology Center 1600 ____________________ Decided: March 09, 20092 ____________________ Before JAMES T. MOORE, Vice Chief Administrative Patent Judge, RICHARD E. TORCZON and SALLY G. LANE, Administrative Patent Judges. MOORE, Vice Chief Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE The Appellant appeals under 35 U.S.C. § 134 (2002) from a final rejection of claims 1-2 and 4-8.3 We have jurisdiction under 35 U.S.C. § 6(b) (2002). 1 The real party in interest is McMaster University. (App. Br. 2). 2 The two-month time period for filing an appeal or commencing a civil action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date shown on this page of the decision. The time period does not run from Mail Date (paper delivery) or Notification Date (electronic delivery). Appeal 2008-6010 Application 10/937,403 2 The Appellant’s claims are directed to methods of generating an immune response to an antigen in a host comprising intranasally administering an antigen coupled to a monoclonal antibody, or fragment thereof, that is a targeting moiety specific for surface structures of antigen- presenting cells. Claim 1 is the only independent claim in the application. The Appellant does not argue any claims or rejections separately. Therefore, we select independent claim 1 to decide the appeal. See 37 C.F.R. § 41.37(c)(1)(vii)(2006). Accordingly, the remaining claims stand or fall with claim 1. Claim 1 reads as follows: 1. A method of generating an immune response to an antigen in a host, which comprises: intranasally administering to said host an antigen coupled to a targeting moiety specific for surface structures of antigen- presenting cells, wherein said targeting moiety is a monoclonal antibody or a fragment thereof. (App. Br. 10, Claims Appendix). THE EXAMINER’S EVIDENCE The Examiner relies upon the following as evidence in support of the rejections: Estrada, et al., Intestinal immunization of mice with antigen conjugated to anti-MHC class II antibodies. Vaccine 13:901-907 (1995). 3 Claims 3 and 9 have been canceled. (App. Br. 2). Appeal 2008-6010 Application 10/937,403 3 Wu, et al., Induction of Mucosal Immunity by Intranasal Application of a Streptococcal Surface Protein Antigen with the Cholera Toxin B Subunit. Infection and Immunity, 61:314-322 (1993). Hameleers, et al., An immunohistochemical study on the postnatal development of rat nasal-associated lymphoid tissue. Cell Tissue Res. 256:431-438 (1989). THE APPELLANT’S EVIDENCE The Appellant relies upon the following additional evidence in support of the appeal: Koornstra, et al., Immunohistology of Nasopharyngeal (Waldeyer’ Ring Equivalent) Lymphoid Tissue in the Rat. Acta Otolarynogol., 113:660- 667 (1993). Tamura, et al., Synergistic action of cholera toxin B subunit (and Eschericia coli heat-labile toxin B subunit) and a trace amount of cholera whole toxin as an adjuvant for nasal influenza vaccine. Vaccine 12:419-426 (1994). Tamura, et al., Effects of Cholera Toxin on Delayed-type Hypersensitivity to Sheep Red Blood Cells Inoculated Intranasally into Mice. Microbiol. Immunol., 32:1145-1161 (1988). Lycke, et al., The Adjuvant Action of Cholera Toxin is Associated with an Increased Intestinal Permeability for Luminal Antigens. Scand. J. Immunol. 33:691-698 (1991). van Heyningen, Cholera Toxin: Interaction of Subunits with Ganglioside GM1. Science 183:656-657 (1974). King, et al., Deactivation of Cholera Toxin by a Sialidase-Resistant Monosialosylganglioside. J. Infect. Dis. 127, 639-647 (1973). Middlebrook, et al., Bacterial Toxins: Cellular Mechanisms of Action. Microbiol. Rev. 48, 199-221 (1984). Appeal 2008-6010 Application 10/937,403 4 Spangler, Structure and Function of Cholera Toxin and the Related Eschericia coli Heat-Labile Enterotoxin. Microbiol. Rev. 56, 622-647 (1992). Snider, The Mucosal Adjuvant Activities of ADP-Ribosylating Bacterial Enterotoxins. Crit. Rev. Immunol. 15:317-348 (1995). Holmgren, et al., Cholera Toxin, Ganglioside Receptors and the Immune Response. Immunol. Comm. 5(9):737-756 (1976). THE REJECTIONS The following rejection is before us for review: Claims 1, 2 and 4-8 stand rejected under 35 U.S.C. § 103(a) over the combination of Estrada, Wu, and Hameleers. We AFFIRM. ISSUE Has the Appellant established that the Examiner erred in determining that it would have been obvious to one of ordinary skill in the art at the time the invention was made to intranasally administer a composition known to generate an immune response to an antigen in a host by other routes of administration? FINDINGS OF FACT The record supports the following findings of fact by a preponderance of the evidence. 1. Estrada describes a method of generating an immune response to an antigen in a mouse by administering an antigen coupled to monoclonal antibodies having specificity for, i.e., targeting, murine (mouse) major Appeal 2008-6010 Application 10/937,403 5 histocompatibility class II cells (“MHC- II”) expressed by antigen- presenting cells (“APC”). (Estrada p. 901, Abstract and col. 2). 2. Estrada describes that administering the antigen-antibody conjugates either parenterally by intraduodenal injection or orally generates an immune response in the host. (Id.). 3. Estrada describes that in addition to uptake of the conjugates in APC that express MHC-II, the conjugates may also induce an immune response via M cells which overlie intestinal Peyer’s patches and can presumably take up targeting complexes and deliver them to APC in the Peyer’s patches. (Id. p. 905, col. 2). 4. Estrada does not describe administering the antigen-antibody conjugates intranasally. 5. Wu describes a method of generating an immune response by administering an antigen conjugated to cholera toxin B subunit (“CTB”) intranasally or intragastrically. (Wu Abstract). 6. Wu teaches that intranasal immunization with a protein antigen conjugated to CTB is an effective means of generating an immune response. (Id. Abstract). 7. Wu describes that intranasal immunization resulted in significantly stronger immune responses in saliva and serum than intragastric immunization. (Id. p. 316, col. 1; 320, col. 1). 8. Wu describes that one factor that may contribute to the effectiveness of intranasal immunization may be that “intranasal cavities contain less proteolytic activity than the intestinal lumen in which protein antigens can be extensively degraded....” (Id. 320, col. 1). Appeal 2008-6010 Application 10/937,403 6 9. Wu also describes that rat and mice “nasal-associated lymphoid tissue (NALT) consists of follicles covered by domes of specialized epithelium resembling the M cells of intestinal Peyer’s patches[....]” (Id. p. 320, col. 1). 10. According to Wu, intranasally administered antigens may be taken up by NALT and may induce a mucosal immune response that is analogous to stimulation of gut-associated lymphoid tissue. (Id.). 11. Wu describes that “it appears that NALT is more adept at taking up particulate rather than soluble antigens which may be more readily adsorbed through the nasal mucosa.” (Id.). 12. Hameleers describes the development of NALT in the rat. (Hameleers Abstract). 13. Hameleers describes that in young mice “a few Ia+ cells, which extend dendritic processes between epithelial cells,” have been observed in the nasal epithelium. (Hameleers p. 434, col. 2; Fig. 4). 14. Hameleers also describes observing the Ia antigen on some epithelial cells. (Id.). 15. The Examiner found that Ia is well known in the art as the murine MHC-II antigen and is expressed exclusively on APC. (Final Rejection, Apr. 3, 2006, p. 4). PRINCIPLES OF LAW “Section 103 forbids issuance of a patent when ‘the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said Appeal 2008-6010 Application 10/937,403 7 subject matter pertains.’” KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1734 (2007). ANALYSIS A. The Rejections Claims 1, 2 and 4-8 stand rejected under 35 U.S.C. § 103(a) over the combination of Estrada, Wu, and Hameleers. Specifically, the Examiner found that Estrada teaches a method of immunizing a host via the intestinal mucosa using an antigen conjugated to monoclonal antibodies. (Final Rejection, Apr. 3, 2006, p. 2). Additionally, the Examiner found that Estrada teaches that the conjugates effectively induce an immune response in mice. (Id.). According to the Examiner, Estrada describes that “immunotargeting complexes may [also] be useful for oral vaccine delivery.” (Id.)(citing Estrada p. 902, col. 1). The Examiner also found that Estrada does not teach the intranasal administration of the conjugated antigen and monoclonal antibodies. (Final Rejection, p. 2). However, the Examiner found that Wu teaches a method of immunization by intranasally administering an antigen fused to CTB. (Id.). According to the Examiner, Wu describes study results indicating that intranasal immunization produced responses in saliva and serum that were significantly stronger than intragastric immunization. (Id. pp. 2-3). Next, the Examiner found that Hameleers teaches that in the nasal epithelium of young mice a few Ia+ cells that extend dendritic processes between epithelial cells have been observed. (Id. 3). According to the Appeal 2008-6010 Application 10/937,403 8 Examiner, Ia is well known in the art as the murine MHC-II antigen that is expressed exclusively on APC. (Id.). The Examiner determined that it would have been obvious to a person of ordinary skill in the art at the time of the invention to modify the immunization method of Estrada by replacing intragastric immunization with the intranasal immunization of Wu. (Id.). According to the Examiner, one would have been motivated to make the substitution with a reasonable expectation of success based upon the teachings by Wu that the NALT of the nasal mucosa is functionally similar to the Peyer’s patches of the intestines and the teachings of Estrada that the antibody conjugates specifically target the APC in the intestine. (Id.). Additionally, the Examiner determined that one would have been further motivated, with a reasonable expectation of success, to use the antibody conjugates of Estrada intranasally because the antigen recognized by the Estrada antibody is expressed in nasal mucosa, as taught by Hameleers, that the Estrada conjugate could produce high titers (Estrada p. 906, col. 2), and by the general knowledge in the art that a subject would be more likely to accept an immunoglobulin-based medicament rather than one based upon cholera toxin. (Id.). Finally, the Examiner found that a skilled artisan would be further motivated to substitute the method of intranasal administration described by Wu based upon the general knowledge in the art that intranasal administration of medicament would result in greater subject compliance than intragastric administration. (Id.). Appeal 2008-6010 Application 10/937,403 9 B. The Appellant’s Contentions The Appellant contends that the claimed invention is not obvious because Estrada does not provide a person skilled in the art a reasonable expectation of successfully obtaining an immune response by intranasally administering antigen-antibody conjugates and that the results achieved by the Applicant are surprising. (App. Br. 5-7). In particular, the Appellant asserts the antibodies of the instant claimed method “have specificity for class II MHC molecules expressed by antigen presenting cells[]” which “are only poorly expressed by non- inflamed nasal epithetial [sic] cells in young rodents....” (Id. 6)(citing Hameleers pp. 431-438). Additionally, the Appellant asserts that “there is no evidence that MHC class II molecules are expressed on the external membrane (apical surface) of rodent nasal epithelical [sic] cells.” (Id. 6). Therefore, according to the Appellant, a skilled artisan would not expect that an antibody-antigen conjugate “would bind specifically to the epithelium of nasal passages or be taken up by the epithelium based on anti-class II MHC specificity” to produce an immune response. (Id. 6). The Appellant further asserts that “[t]he only likelihood was that small amounts of the conjugate would get past the epithelium and interact with APC below the epithelium or in the draining lymph nodes.” (Id. 6). This argument is not persuasive. Hameleers discusses the nasal epithelium of rodents and describes that in young mice “[a] few Ia+ cells, which extend dendritic processes between epithelial cells,” have been observed in the nasal epithelium. (Hameleers p. 434, col. 2; Fig. 4). Hameleers also describes observing the Ia antigen on Appeal 2008-6010 Application 10/937,403 10 some epithelial cells. (Id.). As the Examiner explained, the “Ia” antigen is well known in the art as the murine MHC-II antigen which is “expressed exclusively” on APC for presentation of antigenic peptides to helper T cells whose activation stimulates an immunogenic response. (Final Rejection, p. 4; Answer pp. 7-8). Therefore, because Ia is exclusively expressed by APC, Hameleers’ teachings would suggest to an artisan that the epithelial cells in the nasal mucosa that express Ia function as MHC-II APC and assist in the stimulation of an immune response. (Answer p. 8). The Appellant does not raise any material challenge to the Examiner’s findings regarding the exclusive expression of Ia on APC or the relied upon teachings of Hameleers. Consequently, we find that the Appellant has not established that the Examiner erred in concluding that it would be obvious to a skilled artisan at the time of the invention to modify Estrada’s immunization method by administering the antibody-antigen conjugate intranasally to generate an immune response. Nor are we persuaded by the Appellant’s assertion that a skilled artisan would not have had a reasonable expectation of success in intranasally administering Estrada’s conjugate because the skilled artisan “would have understood that the epithetial [sic] layers of the nasal passages have tight junctions and that large molecules, such as antibodies and conjugates, do not pass through the epithelium, except with only poor efficiency.” (App. Br. 6). Appeal 2008-6010 Application 10/937,403 11 To begin, this contention is attorney argument and the Appellant has not provided any persuasive evidence in the record upon which the argument is based. Moreover, Wu describes successfully generating an immune response intranasally using an antigen conjugate. As the Examiner found, Wu compares intranasal and intragastric immunization with its cholera toxin- antigen conjugate in such a way that a skilled artisan would find it obvious to modify Estrada’s method by administering the antigen-antibody conjugate intranasally. In particular, Wu describes that the results of administering its conjugate to intestinal mucosa and to nasal mucosa were similar, with better results, i.e., stronger antibody responses in saliva and serum samples, following intranasal administration. (Wu pp. 316-321). Wu also teaches that lymphoid tissue in nasal mucosa is similar to lymphoid tissue in the intestine. Specifically, Wu states that the “nasal- associated lymphoid tissue (NALT) consists of follicles covered by domes of specialized epithelium resembling the M cells of intestinal Peyer’s patches[....]” (Wu p. 320, col. 1). The Peyer’s patches are presumably the lymphoid tissue targeted by Estrada’s intraduodenal administration of antibody-antigen conjugates. (Answer p. 7; Estrada p. 905, col. 2). Based on these teachings, the Examiner found that a skilled artisan at the time of the invention “would reasonably predict that the application of antibody-antigen conjugates to the nasal lymphoid tissue would be similar to the application of those conjugates to the Peyer’s patches in the intestine.” (See Answer p. 7; Final Rejection, p. 3). Appeal 2008-6010 Application 10/937,403 12 We agree with the Examiner and find that the balance of the evidence supports the Examiner’s position. Consequently, the Appellant has not established error with persuasive evidence. The Appellant next asserts that Wu and Hamaleers do not “remedy the defects” of Estrada regarding an alleged lack of a reasonable expectation of success for intranasal immunization using antigen conjugates. (App. Br. 7). Specifically, the Appellant asserts that “the immunization of mouse nasal passages with CTB, as described by Wu et al, works only poorly, unless large quantities of CTB are used or small amounts of cholera toxin are also available, allowing increased permeability of the epithelium to antigens[.]” (Id.)(citing Tamura and Lycke). The Appellant further asserts that “[i]t is submitted that it is a surprising result that such a high degree of induction of antigen-specific immunity was achieved in applicant’s experimentation by application to the external surfaces on the nasal passages of mice.” (Id.). We disagree. Wu does not describe that its method of intranasally immunization “works only poorly.” Rather, Wu specifically states that “[i]ntranasal (i.n.) immunization has been successfully used to induce antibodies to a variety of antigens administered with CTB or [free cholera toxin].” (Wu p. 314, col. 2)(emphasis added). Additionally, Wu states that “i.n. immunization with a protein antigen and free or coupled CTB is an effective means of generating IgA antibody responses expressed at several mucosal sites where protective immunity may be beneficial.” (Id. Abstract)(emphasis added). This argument of error fails. Appeal 2008-6010 Application 10/937,403 13 The Appellant also challenges the Examiner’s reliance on Wu by asserting that immune responses generated by Wu’s CTB conjugates in nasal mucosa do not predict similar responses by antigen-antibody conjugates because Wu’s CTB is not a targeting moiety specific for APC. (App. Br. 7- 8). The Appellant asserts that CTB instead has specificity for the GM1- ganglioside, which “is displayed on the apical surface of all epithelial cells.” (Id. 8)(citing van Heyningen and King). According to the Appellant, Wu’s conjugates provide immune stimulation by binding “directly to the apical epithelium of nasal epithelium....” (Id.). Therefore, according to the Appellant, the mechanism of functionality of the Wu CTB conjugates would not predict that the antigen-antibody conjugates of the claimed invention would act in a manner similar to the CTB conjugates. (Id.). This argument is also unpersuasive. The Appellant has asserted a difference between the specificity of Wu’s CTB and Estrada’s monoclonal antibodies. We have no doubt that there is a difference. However, the Appellant has not persuasively established that the difference is so material such that one of ordinary skill of the art would disregard the motivation and expectation of success that the combined teachings otherwise provide. The Examiner relied on Wu for teaching that immunization comprising administering an antigen conjugate intragastrically is also effective, and even more so, when administered intranasally. Wu specifically describes that intranasally administered antigens are likely taken Appeal 2008-6010 Application 10/937,403 14 up by NALT that structurally resembles intestinal Peyer’s patches, which is presumably the target for the conjugates administered by Estrada’s method. Consequently, we are not persuaded that the Examiner erred in concluding that a skilled artisan at the time of the invention would find it obvious to modify Estrada’s immunization method by administering the antigen-antibody conjugates intranasally. Finally, the Appellant challenges the Examiner’s reliance on Hameleers by asserting that “[t]his reference would not appear to add to the combination of Estrada and Wu.” (See App. Br. 9). Hameleers’ contribution to the combination is the description of the rodent nasal epithelium. Because the Appellant has not raised any meaningful challenge to the Examiner’s reliance on the reference, we do not find that the Appellant has established error on the part of the Examiner. Accordingly, we affirm the Examiner’s rejections. CONCLUSION OF LAW On the record before us, the Appellant has not shown error on the part of the Examiner. It would have been obvious to one of ordinary skill in the art at the time the invention was made to intranasally administer a composition known to generate an immune response to an antigen in a host by other routes of administration. DECISION The Rejection of claims 1, 2 and 4-8 under 35 U.S.C. §103(a) as being unpatentable over the combination of Estrada, Wu, and Hameleers is AFFIRMED. Appeal 2008-6010 Application 10/937,403 15 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv) (2006). AFFIRMED MAT Sim & McBurney 330 University Avenue 6th Floor Toronto, ON M5G 1R7 Canada