Ex Parte Al-AbedDownload PDFPatent Trial and Appeal BoardFeb 1, 201710594641 (P.T.A.B. Feb. 1, 2017) 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. 10/594,641 03/28/2008 Yousef Al-Abed 50425/262 1663 1912 7590 02/03/2017 AMSTER, ROTHSTEIN & EBENSTEIN LLP 90 PARK AVENUE NEW YORK, NY 10016 EXAMINER EWOLDT, GERALD R ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 02/03/2017 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): PTODOCKET@ARELAW.COM PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte YOUSEF AL-ABED1 Appeal 2015-008264 Application 10/594,641 Technology Center 1600 Before MELANIE L. McCOLLUM, TAWEN CHANG, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. McCOLLUM, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35U.S.C. § 134 involving claims to a method for inhibiting the development of type 1 diabetes. The Examiner has rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellant identifies the real party in interest as The Feinstein Institute for Medical Research (App. Br. 3). Appeal 2015-008264 Application 10/594,641 STATEMENT OF THE CASE Claims 29-33 are on appeal (App. Br. 3).2 The claims subject to each rejection have not been argued separately and therefore stand or fall together. 37 C.F.R. § 41.37(c)(l)(iv). Claims 29 and 33 are representative and read as follows: 29. A method of inhibiting the development of type 1 diabetes in a mammal at risk for type 1 diabetes, the method comprising administering to the mammal a pharmaceutical composition comprising an amount of an agent effective to inhibit the development of type 1 diabetes in a mammal at risk for type 1 diabetes, wherein the agent comprises a binding site of an antibody that binds specifically to macrophage migration inhibitory factor (MIF). 33. The method of claim 29, wherein the antibody is a humanized antibody. Claims 29-32 stand rejected under 35 U.S.C. § 103(a) as obvious over Bojunga3 in view of Nishihira4 and Shoelson5 (Ans. 2). Claim 33 stands rejected under 35 U.S.C. § 103(a) as obvious over Bojunga in view of Nishihira, Shoelson, and Queen6 (Ans. 4). 2 Claims 36 and 37 are also pending but have been withdrawn from consideration (App. Br. 3). 3 Jorg Bojunga et al., Macrophage Migration Inhibitory Factor and Development of Type-1 Diabetes in Non-Obese Diabetic Mice, 21 Cytokine 179-86 (2003). 4 Jun Nishihira & Akihiko Ogata, Macrophage Migration Inhibitory Factor as a Target Molecule in Multiple Sclerosis, 2 Current Opinion Investigational Drugs 778—82 (2001). 5 Shoelson, US 6,468,755 Bl, Oct. 22, 2002. 6 Queen et al., US 5,530,101, June 25, 1996. 2 Appeal 2015-008264 Application 10/594,641 Claims 29-32 stand rejected under 35 U.S.C. § 103(a) as obvious over Al-Abed7 in view of Nishihira and Shoelson (Ans. 4). Claim 33 stands rejected under 35 U.S.C. § 103(a) as obvious over Al-Abed in view of Nishihira, Shoelson, and Queen (Ans. 5). I In rejecting representative claim 29, the Examiner relies on Bojunga for teaching “the treatment of diabetes comprising the administration of a MIF inhibitor” (Ans. 2). The Examiner finds: “Figure 3 of the reference further teaches that increased MTF-RNA expression precedes that onset of disease. Figure 4 of the reference teaches that from the time of MIF administration 4-10 weeks is required before the onset of disease.” (Id.) The Examiner relies on Nishihira for teaching “the treatment of autoimmune diseases with an anti-MIF antibody and a small organic molecule and that the treatments are essentially . . . interchangeable” (id.). The Examiner finds that the “reference further teaches that MIF is essential for T cell activation” (id.). The Examiner relies on Shoelson for teaching “the interchangeability of an antibody and a small molecule in the context of inhibiting a specific protein activity for the treatment of type-1 diabetes” (id. at 3). The Examiner concludes: It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to treat diabetes, as taught by Bojunga et al., with an anti-MIF antibody because Nishihira . . . teach[es] that small organic molecules are interchangeable with antibodies in the context of the treatment of 7 Al-Abed et al., WO 01/32606 Al, May 10, 2001. 3 Appeal 2015-008264 Application 10/594,641 autoimmune disease, and, in view of [Shoelson], particularly in the context of inhibiting a specific protein activity for the treatment of type-1 diabetes. . . . Additionally, it would be obvious to treat a patient at risk of developing disease given the teachings of Bojunga et al. that, a) increased MIF-RNA expression precedes that onset of disease, and b) MIF administration precedes the onset of disease in the experiments of the reference, and c) Nishihira . . . teach[es] that MIF is essential for T cell activation. Clearly T cell activation precedes disease onset (given that T cells are disease effectors) thus, it would be obvious to block the disease-causing effects of MIF as well as T cell activation before the onset of disease. (Id.) With regard to claim 33, the Examiner additionally relies on Queen for teaching humanized antibodies (id. at 4). Analysis Upon review of the Final Rejection and Examiner’s Answer, we conclude that the Examiner has set forth a prima facie case, which is summarized above, that claim 29 would have been obvious over Bojunga, Nishihira, and Shoelson and that claim 33 would have been obvious over Bojunga, Nishihira, Shoelson, and Queen. Appellant argues, however, that “the art as a whole shows there was ... no reasonable expectation of success of the claimed method at the time of filing” (App. Br. 4). We are not persuaded. Bojunga investigates “the potential role of MIF in the development of autoimmune-mediated diabetes mellitus” (Bojunga 179). Bojunga discloses: MTF-mRNA expression was markedly increased in splenic lymphocytes of spontaneously diabetic NOD [non-obese diabetic] mice as well as in 8-week-old NOD mice treated with cyclophosphamide[, which accelerates spontaneous diabetes,] 4 Appeal 2015-008264 Application 10/594,641 compared with 2-week-old non-diabetic NOD and healthy . . . control mice. Western blot analyses showed decreased lymphocytic MIF-protein content in diabetic as well as in cyclophosphamide-treated animals compared with 2-week-old non-diabetic NOD and healthy . . . mice, probably as a consequence of increased protein secretion. Furthermore, treatment of NOD mice with recombinant MIF-protein at 25 jig twice a week, from age 6 to 11 weeks, led to an increased diabetes incidence (86%; n = 7) compared with untreated control groups (55%; n = 20) at week 34. {Id. at 179-180.) Bojunga concludes that their data “suggests that anti-MIF therapeutic strategies might serve to attenuate various autoimmune processes like type-1 diabetes” {id. at 185). We understand Appellant’s position that “Bojunga did not demonstrate that the elevation of MIF mRNA expression was associated with an elevated level of endogenous MIF protein” and that “the claimed treatment comprises an anti-MIF protein antibody binding site, not an anti- mRNA agent” (App. Br. 6). We also acknowledge Appellant’s position, which relies on Lutz8 and Cusi,9 10that the “diabetes art does not show any predictable correlation between mRNA levels and protein levels, and in the specific case of MIF, Ogata[10] and Bojunga do not show a predictable correlation” and that, therefore, there “is no reasonable predictability that 8 AJ Lutz & WM Pardidge, Insulin Therapy Normalizes GLUT1 Glucose Transporter mRNA but not Immunoreactive Transporter Protein in Streptozocin-Diabetic Rats, 42 Metabolism 939-44 (1993) (Abstract only). 9 KJ Cusi et al., Exercise Increases Hexokinase II mRNA, but not Activity in Obesity and Type 2 Diabetes, 50 Metabolism 602—06 (2001) (Abstract only). 10 Akihiko Ogata et al., Identification of Macrophage Migration Inhibitory Factor mRNA Expression in Neural Cells of the Rat Brain by in situ Hybridization, 246 Neuroscience Letters 173—77 (1998). 5 Appeal 2015-008264 Application 10/594,641 simply because elevated MIF mRNA was observed, elevated MIF protein was present, especially when no elevated MIF protein was measured” (id. at 7). In addition, we acknowledge Appellant’s argument, relying on D’Hertog,11 that it was “known, specifically in diabetes research, that mRNA offers little or no guidance as to therapeutic targets” (id. ). However, as pointed out by the Examiner (Ans. 8; see also Ans. 2, referencing Bojunga Fig. 4), in addition to the mRNA data, Bojunga discloses that they “tested the effect of MIF-protein treatment on diabetes incidence in [their] NOD mice colony” and that “MIF treatment at 25 jig/mouse twice a week from age 6 to 11 weeks—the ‘vulnerable phase’ of diabetes development. . . —led to an increase in diabetes incidence to 86% (6/7) compared with untreated NOD mice, which became diabetic in 55% (11/20)” (Bojunga 184). As noted by Appellant (App. Br. 9), Bojunga states that “this trend was statistically not significant (p = 0.07)” (Bojunga 184). Nevertheless, we conclude that Appellant has not adequately countered the Examiner’s position that this is data that one of ordinary skill in the art would have reasonably relied upon to select MIF as a target (Ans. 8-9). In addition, we recognize that Bojunga states that their data “suggests that anti-MIF therapeutic strategies might serve to attenuate various autoimmune processes like type-1 diabetes” (Bojunga 185 (emphasis 11 Wannes D’Hertog et al., Type 1 Diabetes: Entering the Proteomic Era, 3 Expert. Rev. Proteomics 223—36 (2006). We note that this reference is not prior art and therefore may not reflect what was known in the art at the time of the invention. 6 Appeal 2015-008264 Application 10/594,641 added)). However, we do not agree with Appellant that use of the term “might” is sufficient to demonstrate that there would not have been a reasonable expectation for success. We also understand, as taught by Lan,12 that “[gjenes whose expression levels change in a disease state may or may not be related to the etiology or pathology of the underlying disease” (Lan 240). In addition, we acknowledge that Lan discloses that “[t]his was particularly evident in diabetes research” (id.). However, as discussed above, we conclude that the MIF treatment data supports the Examiner’s position that there would have been a reasonable expectation for success. With regard to Nishihira, Appellant argues: [I]t is stated in the “Perspectives” section that “the therapeutic use of anti-MIF antibodies and small molecules inhibiting MIF activity could be promising for septic shock...” There is no statement of general interchangeability here. Moreover, there is no broad extrapolation that inhibiting MIF can treat “autoimmune diseases” in general and also diabetes. (App. Br. 10.) Furthermore, Appellant argues that, “while [Shoelson] is cited for the notion of ‘interchangeability of an antibody and a small organic molecule in the context of inhibiting’ a protein known as IKK-Beta for the treatment of type-1 diabetes, IKK-Beta is not MIF” (id.). We are not persuaded. Nishihira and Shoelson are relied upon by the Examiner to demonstrate that it would have been obvious to use anti-MIF antibodies, as 12 Hong Lan et al., Distinguishing Covariation From Causation in Diabetes A Lesson From the Protein Disulfide Isomerase mRNA Abundance Trait, 53 Diabetes 240-44 (2004). 7 Appeal 2015-008264 Application 10/594,641 well as small molecules, in the anti-MIF therapeutic strategies of Bojunga (Ans. 2—3). We understand that Nishihira does not teach diabetes and that Shoelson does not teach MIF. However, Appellant’s arguments do not persuade us that Nishihira and Shoelson do not suggest using anti-MIF antibodies in Bojunga’s anti-MIF therapeutic strategies. In addition, as noted by the Examiner (Ans. 9), Nishihira does conclude that “it is expected that. . . anti-MIF therapy could be used for various immune-mediated diseases, including MS” (Nishihira 781 (emphasis added)), suggesting broader applicability that just the diseases mentioned in Nishihira. In addition, Appellant argues that it was “known in the diabetes literature, on a more overarching level, that trying to predict the success of a potential treatment based on a mechanistic theory, rather than empirical animal model results, has been difficult” (App. Br. 10). In support of this position, Appellant refers to Fraenkel,13 Sparre,14 and Jiang15 (id.). In view of this evidence, Appellant argues that, “absent applicant’s work disclosed in the specification, there was no reasonable expectation nor predictability that 13 Merav Fraenkel et al., mTOR Inhibition by Rapamycin Prevents fi-Cell Adaption to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes, 57 Diabetes 945—57 (2008). We note that this reference is not prior art and therefore may not reflect what was known in the art at the time of the invention. 14 Thomas Sparre et al., Unraveling the Pathogenesis of Type 1 Diabetes with Proteomics, 4 Molecular & Cellular Proteomics 441—57 (2005). 15 Yong-Liang Jiang et al., Alteration of the Proteome Profile of the Pancreas in Diabetic Rats Induced by Streptozotocin, 28 Inf 1 J. Molecular Medicine 153—60 (2011). We note that this reference is not prior art and therefore may not reflect what was known in the art at the time of the invention. 8 Appeal 2015-008264 Application 10/594,641 simply administering an anti-MIF antibody could inhibit the development of T1D [type 1 diabetes] in a subject” (id. at 11). Instead, Appellant argues that “it is clear the skilled artisan could not have a reasonable expectation that a potential therapeutic agent directed against a target identified by a mechanistic theory could be successfully used to treat diabetes until the therapeutic agent was proven efficacious in an animal model” (id. ). We are not persuaded. Fraenkel shows that hypotheses regarding potential therapeutic agents are not always correct (Fraenkel, Abstract). However, we do not find this evidence sufficient to demonstrate that, in the present case, there could be no reasonable expectation of success “until the therapeutic agent was proven efficacious in an animal model” (App. Br. 11). Sparre, the only one of the three references cited in this argument that could be prior art and therefore more likely to reflect what was known in the art at the time of the invention,16 discloses: “[I]t is beyond any doubt that T1D is a multifactorial polygenic disease of largely unknown etiology. . . . [SJeveral proteins seem to be involved in the pathogenesis of diabetes and . . . no single protein can be accused of being ‘The Diabetes Protein.’” (Sparre 452.) However, we do not agree that Appellant has shown that Sparre, or Jiang, demonstrates that the teachings of Bojunga “that anti-MIF therapeutic strategies might serve to attenuate various autoimmune processes like type-1 diabetes” (Bojunga 185) would not have been believed. 16 Sparre appears to indicate that it was published on February 7, 2005, which is before the PCT filing date of the present application, but after the claimed benefit date. 9 Appeal 2015-008264 Application 10/594,641 Conclusion The evidence supports the Examiner’s conclusion that Bojunga, Nishihira, and Shoelson suggest the method of claim 29. We therefore affirm the obviousness rejection of claim 29 over these references. Claims 30—32 fall with claim 29. The evidence also supports the Examiner’s conclusion that Bojunga, Nishihira, Shoelson, and Queen suggest the method of claim 33. We therefore affirm the obviousness rejection of claim 33 over these references. II In a second set of rejections, the Examiner relies on Al-Abed for teaching “the treatment or prevention of type 1 (insulin dependent) diabetes comprising the administration of a MIF inhibitor” (Ans. 4). The Examiner relies on Nishihira and Shoelson as discussed above {id. at 5). The Examiner concludes: It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to treat or prevent diabetes, as taught by [Al-Abed], with an anti-MIF antibody because Nishihira . . . teach[es] that small organic molecules are interchangeable with antibodies in the context of the treatment of autoimmune disease and, in view of [Shoelson], particularly in the context of inhibiting a specific protein activity for the treatment of type-1 diabetes. {Id.) With regard to claim 33, the Examiner additionally relies on Queen for teaching humanized antibodies (id. at 5—6). Analysis Upon review of the Final Rejection and Examiner’s Answer, we conclude that the Examiner has set forth a prima facie case, which is 10 Appeal 2015-008264 Application 10/594,641 summarized above, that claim 29 would have been obvious over Al-Abed, Nishihira, and Shoelson and that claim 33 would have been obvious over Al-Abed, Nishihira, Shoelson, and Queen. Appellant argues, however, that Al-Abed “in the combination of cited art does not change the conclusion from the prior art as a whole that there would be no reasonable predictability and no reasonable expectation of success of the claimed method ... at the time of filing” (App. Br. 13). We are not persuaded for the reasons discussed above. Conclusion The evidence supports the Examiner’s conclusion that Al-Abed, Nishihira, and Shoelson suggest the method of claim 29. We therefore affirm the obviousness rejection of claim 29 over these references. Claims 30—32 fall with claim 29. The evidence also supports the Examiner’s conclusion that Al-Abed, Nishihira, Shoelson, and Queen suggest the method of claim 33. We therefore affirm the obviousness rejection of claim 33 over these references. 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 11 Copy with citationCopy as parenthetical citation