Ex Parte Allison et alDownload PDFPatent Trial and Appeal BoardSep 18, 201310854000 (P.T.A.B. Sep. 18, 2013) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte JAMES PATRICK ALLISON, DANA R. LEACH, and MATTHEW E. KRUMMEL ____________ Appeal 2013-004811 Application 10/854,000 Technology Center 1600 ____________ Before DONALD E. ADAMS, ERIC GRIMES, and JOHN G. NEW, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL1 This appeal under 35 U.S.C. § 134 involves claims 13, 15-18, and 20-30 (App. Br. 3). Examiner entered rejections under 35 U.S.C. § 102(e) and 35 U.S.C. § 102(e)/103(a). We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 The Real Party in Interest is the Regents of the University of California, as well as the following licensees and sub-licensiuuees: Gilead Sciences, Inc.; Medarex, Inc.; Bristol-Myers Squibb; Pfizer, Inc.; and NeXstar Pharmaceuticals, Inc. (App. Br. 1). Appeal 2013-004811 Application 10/854,000 2 STATEMENT OF THE CASE The claims are directed to an activated human T cell in a patient and a composition. Claim 13 is representative and is reproduced below: 13. An activated human T cell in a patient consisting essentially of an anti-CTLA-4 antibody or a fragment thereof bound to said T cell in vivo to increase the response of said T cell to antigenic stimulation from a tumor or pathogen antigen, wherein said antibody or antibody fragment specifically binds to the extracellular domain of CTLA-4 on said T cell and inhibits CTLA-4 signaling. Claims 13, 15-18, and 20-30 stand rejected under 35 U.S.C. § 102(e) as anticipated by or, in the alternative, under 35 U.S.C. § 103(a) as obvious over Gribben2 as evidenced by Abbas3 and/or Sternberger.4,5,6 ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Gribben, as evidenced by Abbas and/or Sternberger, anticipates or in the alternative makes obvious Appellants’ claimed invention? 2 Gribben et al., US 6,719,972 B1, issued April 13, 2004. 3 Abul K. Abbas, M.B.B.S, et al., CELLULAR AND MOLECULAR IMMUNOLOGY 54 (eds., W.B. Saunders Company, Philadelphia, USA) (1991). 4 L. A. Sternberger, M.D., et al., THE ESTIMATION OF CIRCULATING ANTIBODY-ANTIGEN COMPLEX, 98(5) J. EXP. MED. 451-60 (1953). 5 We recognize Examiner’s separate rejection under 35 U.S.C. § 102(e) over the same prior art, which is cumulative to the rejection under 35 U.S.C. § 102(e)/103(a) (see April 9, 2012 Final Rej. 4 and 11; Cf. id. at 10 and 14). Therefore, we consolidated the rejections. 6 We vacate Examiner’s separate rejections under 35 U.S.C. § 102(e) and 35 U.S.C. § 102(e)/103 over Linsley (US 5,968,510, issued October 19, 1999) as evidenced by Abbas and/or Sternberger as cumulative to the rejection over Gribben as evidenced by Abbas and/or Sternberger. Appeal 2013-004811 Application 10/854,000 3 FACTUAL FINDINGS (FF) Background: FF 1. T cell activation requires “stimulation through the antigen receptor (TCR)” and “signaling through co-stimulatory surface molecules such as CD28” (Spec. 2: ¶ [0005]; Gribben, col. 1, ll. 10-21). FF 2. “Lack of co-stimulation, and the concomitant inadequacy of IL-2 production, prevent subsequent proliferation of the T cell and induce a state of non-reactivity termed ‘anergy’” (Spec. 2: ¶ [0006]; Gribben, col. 1, ll. 42- 45; see also Gribben, col. 1, ll. 56-59 (“antibodies reactive with B7-1 and/or B7-2 have been used to inhibit T cell proliferation and IL-2 production in vitro and inhibit primary immune responses to antigen in vivo”)). FF 3. “CTLA-4 is not detected on resting cells but is induced during T cell activation” (Linsley II7,8 289: col. 2, ll. 13-14; see also Gribben, col. 38, ll. 27-29 (“Following T cell activation, CD28 engagement by B7-1 down regulates CD28 synthesis and function … as CTLA4 expression increases”)). FF 4. “CTLA-4 mediated signals apparently inhibit cell cycle progression and IL-2 expression” (Spec. 5-6: ¶ [0030]; Cf. Spec. 7: ¶ [0034] (“An agent that blocks CTLA-4 signaling will cause an increase in the T cell activation, as measured by proliferation and cell cycle progression, release of IL-2, 7 Peter S. Linsley, Distinct roles for CD28 and Cytotoxic T Lymphocyte- associated Molecule-4 Receptors during T Cell Activation, 182 J. EXP. MED. 289-292 (1995); see App. Br., Exhibit D. 8 Appellants direct attention to Linsley II as, apparently, representative of the state of the art at the time of Appellants’ claimed invention (App. Br. 25). Appeal 2013-004811 Application 10/854,000 4 upregulation of CD25 and CD69, etc.”); see also Spec. 3: ¶ [0011] and 5: ¶ [0030]; Linsley II 290: col. 2, ll. 16-17). FF 5. “Both CD28 and CTLA-4 bind the same counter-receptors, members of the B7 family[, specifically B7-1 (CD80) and B7-2 (CD86)] on APCs” (Linsley II 289: col. 1, ll. 6-7; see also Spec. 2: ¶ [0005]; see also Gribben, col. 1, ll. 21-31). FF 6. Linsley II discloses that the state of the art at the time of Appellants’ claimed invention suggests that: anti-CTLA-4 mAbs can either stimulate or inhibit T cell activation, depending on experimental conditions. … Does this mean that CTLA-4 and CD28 have intrinsically opposite effects during T cell activation? Not necessarily. Experience in other signaling systems has taught us that it is quite common for receptor triggering to be context dependent, i.e., opposite effects are elicited under different experimental conditions. … We should keep in mind that, generally speaking, a receptor that has only one effect is one that has not been fully studied. Perhaps the main message from the studies … is that CTLA-4 has come of age. Thus, we now realize that CTLA-4 is a receptor with its own unique properties and its own mechanisms of integrating with the lymphocyte signal transduction machinery. (Linsley II 290: col. 2, ll. 16-17 and 28-47.) Appellants’ disclosure of “blocking agents” or “binding molecules”: FF 7. Appellants disclose blocking agents or “[b]inding molecules that specifically interact with the CTLA-4 antigen, but do not activate signaling …, are combined with T cells, in vitro or in vivo” (Spec. 3: ¶ [0011]; see also id. at 3: ¶ [0029]). Appeal 2013-004811 Application 10/854,000 5 FF 8. Appellants define the term “CTLA-4 blocking agents” as “molecules [including, inter alia, antibodies] that [(1)] specifically bind to the extracellular domain of CTLA-4 protein, … [(2)] block the binding of CTLA-4 to its counter-receptors, e.g. CD80, CD86, etc.,” are (3) “substantially unreactive with related molecules to CTLA-4, such as CD28 and other members of the immunoglobulin superfamily[, thereby excluding] [m]olecules such as CD80 and CD86 … as blocking agents,” and (4) “do not activate CTLA-4 signaling” (Spec. 6: ¶ [0032]; id. at 7: ¶ [0035]). Gribben: FF 9. Gribben teaches that During an ongoing immune response … [e]ither cross- linking of CD28 or the common binding region of CD28/CTLA4 by mAbs or their natural ligands B7-1 or B7-2 provides such a positive costimulatory signal resulting in IL-2 accumulation. … Following T cell activation, CD28 engagement by B7-1 down regulates CD28 synthesis and function … as CTLA4 expression increases. Under conditions when the proliferative response is waning, crosslinking of CTLA4 in the absence of CD28 mediated costimulation can then induce cellular deletion of previously activated cells. … CTLA4 crosslinking mediates antigen specific clonal deletion since it also requires a signal through the TCR. (Gribben, col. 38, ll. 12-41 (emphasis added); see also id. at col. 4, ll. 27-31; id. at col. 5, ll. 51-52 (“Preferred antibody fragments for inducing apoptosis are those which are capable of crosslinking their target antigen”)). FF 10. Gribben teaches a ligand, which is “an antibody, or antibody fragment, which binds the T cell surface molecule CTLA4 … [at] an epitope on CTLA4 that is distinct from the epitope(s) recognized by the known Appeal 2013-004811 Application 10/854,000 6 CTLA4 ligands B7-1 and B7-2” (Gribben, col. 2, ll. 35-39; id. at col. 6, ll. 25-35; see generally April 9, 2012 Final Rej. 4; Ans. 3 and 18). FF 11. Gribben teaches that “[a] preferred human CTLA4 epitope to which a CTLA4 ligand of the invention binds includes or encompasses, an amino acid sequence: (Xaa)n-Leu-Thr-Phe-Leu-Asp-Asp-(Xaa)n (SEQ ID NO: 33), wherein Xaa is any amino acid and n=0-20” (Gribben, col. 6, ll. 42-47; see also id. at col. 33, l. 49 - col. 34, l. 12 (Gribben teaches antibodies, CTLA4.1-4.4 (“mAbs 4D3, 3D6, 3D8 and 4E3” respectively) that recognize the epitope “having the amino acid sequence L-T-F-L-D-D (SEQ ID NO: 29”)); id. at 32, l. 65 - col. 34, l. 12; Ans. 20 and 62-63). FF 12. Gribben teaches that a non-crosslinking antibody or fragment thereof, such as anti-CTLA4.1 Fab, does not induce clonal deletion or apoptosis (Gribben, col. 36, ll. 41-48; id. at col. 3, ll. 11-13; id. at 38, l. 5 (non-crosslinking “CTLA4.1 Fab could block apoptosis”)). FF 13. Gribben teaches a method wherein “[a] blocking form of a CTLA4 antibody or fragment thereof (e.g., Fab fragment) or a blocking soluble form of the CTLA4 ligand can be used to inhibit T cell apoptosis” (Gribben, col. 3, ll. 50-57; id. at col. 5, ll. 58-60 (“a noncrosslinking antibody fragment (e.g., a[] Fab fragment) can be used to block or inhibit apoptosis”); id. at col. 27, ll. 5-20; Ans. 3, 18, and 39). FF 14. Gribben teaches that “antibodies, or fragments thereof (e.g., Fab) fragments, that specifically bind this ‘apoptotic epitope[’]) but which do not crosslink CTLA4 or induce apoptosis can be used therapeutically to inhibit T cell apoptosis” (Gribben, col. 9, ll. 18-21; id. at col. 27, ll. 42-46 (“anti- tumor responses may be enhanced by inhibiting an interaction between CTLA4 and an apoptotic CTLA4 ligand by, for example, administering a Appeal 2013-004811 Application 10/854,000 7 blocking agent … to a tumor-bearing subject.”); see generally April 9, 2012 Final Rej. 5 and 8; Ans. 3, 18, and 39). FF 15. Gribben teaches that “T cell responses to pathogens, such as viruses, bacteria, fungi, parasites and the like, may be enhanced and prolonged by inhibiting CTLA4 mediated T cell apoptosis as described herein” (Gribben, col. 27, ll. 51-55; Ans. 4; see generally April 9, 2012 Final Rej. 5; Ans. 3-4, 14, 18, and 39). Abbas and Sternberger: FF 16. Examiner relies on Abbas as evidence that the binding constant of an antibody specific for an antigen of interest “usually varies from about 10-7 M to 10-11 M” (April 9, 2012 Final Rej. 4 and 12). FF 17. Examiner relies on Sternberger as evidence that in vivo administration of an antibody to an animal results in the production of complexes, “which form as the consequence of the interactions of antibodies, which are present in the circulation of the immunized animal, and the antigen” (April 9, 2012 Final Rej. 5 and 12). Declarations: FF 18. Allison9 declares that “one would not extrapolate from … [Gribben] a beneficial result for a cancer patient by combining anti-CTLA-4 antibodies with a tumor antigen preparation,” because Gribben’s “aim … was to use anti-CTLA-4 antibodies to cause T cells to die by apoptosis upon activation, in the context of the purging of bone marrow grafts of potential alloreactive T cells” (Allison Decl. ¶ 4). 9 Declaration of James P. Allison, submitted Dec. 7, 2005. Appeal 2013-004811 Application 10/854,000 8 FF 19. Korman10 declares that “[i]t is now well established that engagement of CTLA-4 by its ligands B7-1 and B7-2 inhibits T cell proliferation and IL- 2 production by inhibiting cell cycle progression … and does not induce apoptosis” (Korman Decl. ¶ 5). FF 20. Korman declares that “antibodies which enhance immune responses must block the interaction between the known B7 ligands and CTLA-4 and interrupt this signal” (Korman Decl. ¶ 5). FF 21. Korman declares that Gribben “teaches away from the … [present] approach because it directs researchers away from blocking CTLA-4 interaction with B7-1 and B7-2 for the purpose of immune stimulation” (Korman Decl. ¶ 10). FF 22. Bluestone11 declares that “Gribben et al. suggest that an anti-CTLA- 4 mAb that blocks the ability of CTLA-4 to induce apoptosis could enhance immunity. In my opinion, no one skilled in the art would ever be able to make such antibodies based on this description, since their data is not repeatable, their premise is incorrect and they fail to teach by example or assay how to generate or screen for such a response” (Bluestone Decl. ¶ 3; id. at ¶ 5 (“there is no description in … [Gribben] of how one could make or obtain such blocking antibodies”); see also Korman Decl. ¶¶ 6-7; Allison Decl. ¶ 5 (Gribben’s “propos[al] that CTLA-4 can deliver a costimulatory signal under some conditions … is … not supported by the bulk of subsequent work and is, in the opinion of leaders in the field, incorrect”). FF 23. Bluestone declares that antibodies prepared against the peptides identified in Gribben “would not work … because there is no apoptotic 10 Declaration of Dr. Alan Korman, submitted Oct. 4, 2006. 11 Declaration of Jeffrey A. Bluestone, submitted Oct. 3, 2006. Appeal 2013-004811 Application 10/854,000 9 epitope on CTLA-4, nor is there a distinct apoptotic ligand whose signaling can be blocked” (Bluestone Decl. ¶ 5). FF 24. Bluestone declares that “inhibition of T cells function following engagement of CTLA-4 has nothing to do with apoptosis so there is no apoptotic signal to block” (Bluestone Decl. ¶ 4). ANALYSIS The claims are not argued separately and therefore stand or fall together. Claim 13 is representative and is drawn to an activated human T cell in a patient. The claimed activated human T cell consists essentially of an anti-CTLA-4 antibody or a fragment thereof bound to the T cell in vivo (see Ans. 3). Claim 13 characterizes the anti-CTLA-4 antibody or fragment thereof as an antibody or antibody fragment that (1) specifically binds to the extracellular domain of CTLA-4 on a T cell; (2) inhibits CTLA-4 signaling; and (3) increases the response of the T cell to antigenic stimulation from a tumor or pathogen antigen (see Ans. 3). While Appellants’ Specification discloses CTLA-4 blocking agents, Appellants’ claim 13 refers to an anti-CTLA-4 antibody or a fragment thereof and specifically defines the properties of this anti-CTLA-4 antibody or fragment (see Claim 13; Cf. FF 7-8). There is no requirement in claim 13 that the anti-CTLA-4 antibody, or fragment thereof, exhibit all of the properties of a “CTLA-4 blocking agent” as that term is defined in Appellants’ Specification (see FF 7-8). Specifically, there is no requirement in claim 13 that the anti-CTLA-4 antibody, or fragment thereof, block the binding of B7 to CTLA4. Appellants’ claim 13 simply requires the antibody Appeal 2013-004811 Application 10/854,000 10 or fragment thereof (1) to bind an extracellular domain of CTLA-4 and (2) inhibit, in some manner, CTLA-4 signaling, which results in (3) an increased response of the T cell to antigenic stimulation from a tumor or pathogen antigen. Appellants do not dispute Examiner’s reliance on Abbas or Sternberger as evidence establishing that, at the time Appellants’ claimed invention was made, a person of ordinary skill in this art recognized that (1) the binding constant of an antibody specific for an antigen of interest “usually varies from about 10-7 M to 10-11 M” and (2) the in vivo administration of an anti-CTLA4 antibody to a human will result in the formation of a complex that consists essentially of the anti-CTLA4 antibody and a human T cell (see FF 16-17). Anticipation: Gribben teaches a non-crosslinking anti-CTLA-4 antibody fragment that (1) specifically binds to the extracellular domain of CTLA-4 on a T cell and (2) increases the response of the T cell to antigenic stimulation from a pathogen or tumor antigen (FF 10-14). The administration of Gribben’s antibody to a patient, as taught by Gribben, will (a) inherently inhibit CTLA- 4 signaling and (b) result in an activated human T cell in a patient as required by Appellants’ claim 13 (Ans. 4; see generally April 9, 2012 Final Rej. 4-6). That is, because Gribben discloses that a non-crosslinking anti- CTLA-4 antibody fragment has the same binding property and the same effect that are recited in claim 13, it is reasonable to conclude that Gribben’s non-crosslinking anti-CTLA-4 antibody fragment inherently inhibits CTLA-4 signaling, as also recited in claim 13. Appeal 2013-004811 Application 10/854,000 11 Appellants contend that since Gribben’s antibodies do not block the binding of B7 to CTLA4, Gribben’s antibodies or fragments thereof do not read on Appellants’ claimed invention (App. Br. 10-11; Reply Br. 2-3). We are not persuaded. As explained above, claim 13 does not require the anti- CTLA4 antibody to block B7 binding to CTLA4. Appellants contend that since there is no apoptotic signaling by CTLA-4, an artisan practicing in this field would not be capable of producing Gribben’s antibodies (App. Br. 16-17; see also FF 22). We are not persuaded. Gribben provides the specific CTLA4 epitope used to produce Gribben’s antibodies (see FF 10-11). Therefore, notwithstanding the mechanism Gribben proposes for the function of the antibody, the antibody can be produced from Gribben’s disclosure. Even if later work showed that crosslinking antibodies to CTLA4 did not induce apoptosis, Appellants have not pointed to evidence showing that non-crosslinking antibodies or antibody fragments (e.g., Fab fragments) could not be made based on Gribben’s disclosure, or that they would not have the activity described by Gribben (see FF 13-14). Appellants contend, with reference to their Declaratory evidence, that the mechanism Gribben proposes for the function of the antibodies and fragments thereof, i.e. induce or inhibit T cell apoptosis, is incorrect (App. Br. 11-13; Reply Br. 3 and 4-6; FF 18-24). Therefore, Appellants contend that Gribben does not anticipate, and teaches away from, the activated human T cell in a patient, as claimed by Appellants (App. Br. 14 and 23-24; Reply Br. 3). We are not persuaded (see generally April 9, 2012 Final Rej. 9). As discussed above, Gribben teaches an activated human T cell in a patient as required by Appellants’ claim 13. See In re Papesch, 315 F.2d Appeal 2013-004811 Application 10/854,000 12 381, 391 (CCPA 1963) (“From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing.”). Appellants contend that since Gribben’s antibodies or fragments thereof do not block B7 binding to CTLA4, Gribben’s antibodies do not perform according to Appellants’ proposed mechanism of action, i.e., inhibit CTLA4 signaling (App. Br. 10-11). Appellants, however, fail to identify an evidentiary basis on this record to support this conclusion. According to Examiner, an antibody or fragment thereof that (1) binds an extracellular domain of CTLA-4, resulting in (2) an increased response of the T cell to antigenic stimulation from a tumor or pathogen antigen, as suggested by Gribben, will inherently inhibit CTLA-4 signaling (see generally Ans. 17- 18; Cf. Reply Br. 4). We find no error in Examiner’s finding (see generally Ans. 14-16). The administration of Gribben’s anti-CTLA4 antibody fragment to a patient to enhance an anti-tumor or anti-pathogen response in a tumor or pathogen bearing subject will result in Appellants’ claimed activated human T cell in a patient. Appellants’ disclosure of a different mechanism through which Gribben’s antibody fragment may operate is not sufficient to support a contrary finding. Cf. MEHL/Biophile Int’l Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999): [A] prior art reference may anticipate when the claim limitation or limitations not expressly found in that reference are nonetheless inherent in it. . . . Inherency is not necessarily coterminous with the knowledge of those of ordinary skill in the art. Artisans of ordinary skill may not recognize the inherent characteristics or functioning of the prior art. Stated differently, merely recognizing something that was not known before is not sufficient to render an old process again patentable. In re Cruciferous Sprout Litig., 301 F.3d 1343, 1351 (Fed. Cir. 2002). See also In re Appeal 2013-004811 Application 10/854,000 13 Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990); In re Omeprazole Patent Litig., 483 F.3d 1364, 1373 (Fed. Cir. 2007); see generally April 9, 2012 Final Rej. 7-8; Ans. 17-18, 24-25, and 44-45; Cf. App. Br. 17-20; Reply Br. 7. Lastly, Appellants appear to confuse Gribben’s teaching of crosslinking antibodies that induce apoptosis with Gribben’s antibody Fab fragments, or otherwise non-crosslinking antibodies, that inhibit apoptosis (see Reply Br. 5-6; Cf. FF 9 and 11-14). Notwithstanding Appellants’ contention to the contrary, Gribben makes a clear distinction between those antibodies or Fab fragments thereof that induce or inhibit what Gribben mechanistically refers to as apoptosis (FF 9 and 10-14). Obviousness: “‘[A]nticipation is the epitome of obviousness.’” Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983). Therefore, we are not persuaded by Appellants’ contentions regarding obviousness (App. Br. 21-23). CONCLUSION OF LAW The preponderance of evidence on this record supports Examiner’s finding that Gribben, as evidenced by Abbas and/or Sternberger, anticipates or in the alternative makes obvious Appellants’ claimed invention. The rejection of claim 13 under 35 U.S.C. § 102(e) as anticipated by or, in the alternative, under 35 U.S.C. § 103(a) as obvious over Gribben as evidenced by Abbas and/or Sternberger is affirmed. Claims 15-18 and 20- 30 fall together with claim 13. Appeal 2013-004811 Application 10/854,000 14 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 cdc Copy with citationCopy as parenthetical citation