Ex Parte Zaghouani et alDownload PDFPatent Trial and Appeal BoardJun 27, 201310681788 (P.T.A.B. Jun. 27, 2013) Copy Citation 1 UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte HABIB ZAGHOUANI and RENU JAIN __________ Appeal 2012-009223 Application 10/681,788 Technology Center 1600 __________ Before ERIC GRIMES, LORA M. GREEN, and SHERIDAN K. SNEDDEN, Administrative Patent Judges. SNEDDEN, Administrative Patent Judge. DECISION ON APPEAL This appeal1 under 35 U.S.C. § 134 involves claims directed to a method of preventing or delaying onset of Type 1 diabetes. The Examiner entered rejections under 35 U.S.C. §112, first paragraph, under the judicially-created doctrine of obviousness-type double patenting, and under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We affirm the obviousness-type double patenting rejections. 1 Appellants identify the Real Party in Interest as The Curators of The University of Missouri (App. Br. 2). Appeal 2012-009223 Application 10/681,788 2 STATEMENT OF THE CASE Claims 1-5, 7, 13, 15-19, 22-24, and 26-30 are on appeal.2 Claim 1, the only independent claim on appeal, is representative and reads as follows: 1. A method of preventing or delaying onset of Type 1 diabetes in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable composition comprising a soluble fusion protein, wherein the fusion protein comprises at least one immunoglobulin having a variable region comprising a CDR1, a CDR2, or a CDR3 region, the at least one immunoglobulin having at least one protein fragment or peptide inserted within the variable region; wherein (a) the protein fragment or peptide is GAD2 represented by SEQ. ID NO 4, (b) the subject has undergone insulin autoantibody seroconversion prior to said administering step and (c) the composition is administered to the subject in one or more dosage administrations. The claims stand rejected as follows: I. Claims 1-5, 7, 13, 15-19, 22-24 and 26-30 under 35 U.S.C. §112, first paragraph, for lack of enablement. II. Claims 1-5, 7, 13, 15-19, 22-24 and 26-30 under 35 U.S.C. §112, first paragraph, for lack of written description. III. Claims 1, 2, 4, 5, 7, 13, 15-19, 22-24, 26 and 28-30 under 35 U.S.C. § 103(a) as being obvious over the combination of Zaghouani3 and Chao.4 2 Appellants state that claim 25 is on appeal, however, claim 25 is withdrawn from consideration (App. Br. 4). Accordingly, we understand that claim 25 is not currently rejected and not before this Board on appeal. Appeal 2012-009223 Application 10/681,788 3 The Examiner has also provisionally rejected claims 1-5, 7, 13, 15-19, 22-24, and 26-30 under the judicially-created doctrine of obviousness-type double patenting as being unpatentable over claims 1-7 and 13-16 of US Application No. 11/290,070 and over claims 1-7 and 13-16 of US Application No. 11/425,084. Appellants have not traversed the merits of this rejection (App. Br. 16-17). We therefore summarily affirm each of these rejections. See MANUAL OF PATENT EXAMINING PROCEDURE § 1205.02 (“If a ground of rejection stated by the examiner is not addressed in the appellant’s brief, that ground of rejection will be summarily sustained by the Board.”). I. ENABLEMENT The Examiner rejected claims 1-4, 6, 7, 10-12, and 14-16 under 35 U.S.C. § 112, first paragraph, on the basis that “the specification provides insufficient evidence that the claimed method could effectively function as a method for preventing or delaying the onset of type I diabetes (IDDM) in humans” (Ans. 6). The Examiner finds that While the mechanism of action for the method of the instant claims is not disclosed, it appears to require inducing tolerance to a GAD peptide. Tolerance-inducing peptide immunotherapy is well known in the immunological arts. In some cases significant results have been demonstrated in in- bred small animal models. However, said results have not been repeated in human trials. 3 Zaghouani, WO 98/30706, published July 16, 1998. 4 C.C. Chao et al., The role of MHC class II molecules in susceptibility to type I diabetes: Identification of peptide epitopes and characterization of the T cell repertoire, 96 PROC. NATL. ACAD. SCI. USA 9299-9304 (1999). Appeal 2012-009223 Application 10/681,788 4 (Ans. 6, citing Marketletter.5) The Examiner finds that Marketletter “teaches the complete failure in human trials of two peptides designed for tolerance induction” (id.). The Examiner further relies on Pozzilli6 and Skyler7 as evidence that treatments based on the induction of immune tolerance failed in human clinical trials despite providing successful results in inducing tolerance in small in-bred animal models. Marketletter discusses the failure of the drugs Myloral (for multiple sclerosis, MS) and Colloral (for rheumatoid arthritis, RA) in Phase III clinical trials (id. at 8). Pozzilli summarizes an unsuccessful human trial where oral insulin was tested for its ability to act as a tolerogen in patients with Type 1 Diabetes mellitus (id.). Skyler reported the failure of another human trial involving the administration of insulin for the prevention of Type 1 Diabetes (id.). The Examiner next relies on Dong,8 Harats,9 Goodnow,10 Kraus,11 and Bell12 to support the contention that practice of the instant claims would 5 Autoimmune shares collapse on Colloral data in rheumatoid arthritis. Marketletter. MARKETLETTER PUBS (UK) 1999. 6 P. Pozzilli et al., No effect of oral insulin on residual beta-cell function in recent-onset Type I diabetes (the IMDIAB VII), 43 DIABETOL 1000-1004 (2000). 7 J. S. Skyler et al., Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes, 28 DIABETES CARE 1068-1076 (2005). 8 V.M. Dong et al., Transplantation tolerance: The concept and its applicability, 3 PED. Transplan. 81-192 (1999). 9 Harats et al., WO 02/053092, published July 11, 2002. 10 Christopher C. Goodnow, Pathways for self tolerance and the treatment of autoimmune diseases, 357 THE LANCET 2115-2121 (2001). 11 Thomas A. Kraus et al., Oral tolerance and inflammatory bowel disease, 21 CURR. OPIN. GASTROENTEROL 692-696 (2005). Appeal 2012-009223 Application 10/681,788 5 require undue experimentation because the field of immune tolerance is not predictable or otherwise would require “extensive empirical experimentation” (id. at 7-9, quoting Harats, p. 23, ll. 13-15). The Examiner references Leslie,13 van der Worp,14 and von Herrath15 to support the contention that mice models are not predictive of the effectiveness of treatment strategies in human trials (id. at 9-10). Finally, the Examiner notes that the Specification presents data related to the use of insulin, not the recited GAD2 peptide, and that this data does not support a finding that the method of the instant claims can function as claimed (Ans. 10). Specifically, the Examiner finds that at page 28 of the specification, it is disclosed that, “Soluble Ig- INSβ displayed dose dependent delay of diabetes when given at either stage [pre or post IAA conversion]. However, aggregated Ig-INSβ, which induced IL-10 and TGFβ-producing T cells, thus involving sustained endogenous IL-10, was protective against diabetes when given before development of insulitis but had no effect in predisposed mice positive for IAA”, emphasis added. Further, Examples 7 and 9 teach that neither soluble nor aggregated Ig-INSβ can actually prevent IDDM, but rather can only delay onset under specific conditions. (Id. at 10-11.) 12 J. Jeremiah Bell et al., In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis, 180 J. IMMUNOL.1508-1516 (2008). 13 Leslie, M. Immunology Uncaged, 327 SCIENCE 1573 (2010). 14 H. Bart van der Worp et al., Can Animal Models of Disease Reliably Inform Human Studies?, 7(3) PLOS MED. 1-8 (2010). 15 Matthias von Herrath et al., Animal models of human type 1 diabetes,10 (2) NATURE IMMUNOL. 129-132 (2009). Appeal 2012-009223 Application 10/681,788 6 Appellants contend that “[a]t most, the references properly relied on by the Examiner are only tangentially related to the presently claimed invention and/or simply do not cast any doubt, let alone any reasonable doubt, on the presently claimed invention” and that “[t]his is simply not enough to establish a prima facie case of lack of enablement” (App. Br. 9.) Appellants also rely on the Zaghouani Declaration I16 as “showing that the claimed method effectively prevents and/or delays the onset of Type 1 diabetes in the gold standard NOD mouse model for that disease” (App. Br. 14). The Zaghouani Declaration I provides a summary of results of a study conducted by co-inventor Habib Zaghouani “examining the impact of administration, initiated at the pre-diabetic stage, of soluble Ig-GAD2 to NOD mice over a period of 56 weeks” (Zaghouani Declaration I, p. 1, ¶ 6). In the study, NOD mice were assessed for blood glucose beginning at week 12 of age. Those mice that reached glucose levels of 160 - 250 mg/dl between week 14 to 25 received the following Ig-GAD2 regimen: 500 µg of soluble Ig-GAD2 i.p. daily for 5 days and then weekly injections thereafter for either 15 or 25 weeks. (Id. at 1, ¶ 7). “60% of mice undergoing the 15-week treatment regimen were protected against diabetes throughout the 25 week post-hyperglycemia monitoring period” (id. 2, ¶ 8). “When the regimen was extended to 25 weeks, 100% of the Ig-GAD2 treated animals were protected (Figure 1 A, right panel) and normoglycemia was restored in all mice (Figure 1 B, right panel). This status persisted throughout the duration of the study, which was 16 Declaration of Habib Zaghouani under 37 C.F.R. § 1.132 dated December 19, 2007 (Appellants Exhibit P). Appeal 2012-009223 Application 10/681,788 7 terminated when the mice were 52 to 56 weeks of age.” (Id. at 2. ¶ 9; see also, Jain,17 p. 208 and Figure 2). After review of the evidence on this record, we find that Appellants have the better position. Even if we assume for the sake of argument that the examiner made out a prima facie case of nonenablement, we conclude that Appellants have provided sufficient evidence to overcome it. Appellants have provided evidence in the form a Rule 132 declaration by co- inventor Habib Zaghouani and published data in Jain to support the finding that a soluble Ig-GAD2 fusion protein, containing a peptide derived from GAD65 represented as SEQ ID NO: 4 (cf. Specification 32, ¶ [0119] and Jain at 215, right col.), is operable in a mouse model for human Type 1 diabetes. In our opinion, Appellants have thus demonstrated the workability and utility of their invention and the principles on which it operates. II. WRITTEN DESCRIPTION Issue The Examiner has rejected claims 1-5, 7, 13, 15-19, and 22-24, and 26-30 under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. The Examiner finds that A review of the specification reveals that the peptide of SEQ ID NO:4 is found at page 46 of the specification. The specification, however, does not teach the peptides as part of an immunoglobulin construct. ... 17 Renu Jain et al., Innocuous IFNy induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production, 205 (1) JEM. 207-218 (2008). Appeal 2012-009223 Application 10/681,788 8 The generic disclosures of “GAD2” at pages 4, 8, 19, and 22-24 [of the Specification] cannot support the claimed method employing a specific chimeric construct, said construct comprising the specific amino acid sequence of SEQ ID NO:4 (TYEIAPVFVLLEYVT). (Ans. 14-15.) The Examiner further finds that “[e]ven assuming that the cite supports an Ig-GAD65 construct employing the peptide of SEQ ID NO:4, it does not teach said construct comprising a CDR1, CDR2, and CDR3 as is claimed” (id. at 15). Appellants identify several passages disclosing “an immunoglobulin construct comprising GAD2/SEQ ID NO: 4 for preventing or delaying onset of Type 1 diabetes” and argue “the originally filed disclosure would have conveyed to one having ordinary skill in the art that the Appellants had possession of the concept of what is being claimed” (App. Br.18-19). The issue presented is whether the Examiner established that a person of ordinary skill in the art would not credit Appellants with possession of the claimed invention. Findings of Fact The following findings of fact (“FF”) are supported by a preponderance of the evidence of record. FF1. The Specification discloses as follows: In yet another embodiment of the present invention, the composition comprises IgINS (peptides derived from human insulin), IgGAD (peptides derived from GAD), IgINSβ, IgGAD1 and IgGAD2. (Specification 23, ll. 2-4.) FF2. The Specification discloses as follows: Appeal 2012-009223 Application 10/681,788 9 Other peptides that may be inserted within the variable region within the CDR region of an Ig and utilized for creating compositions for the treatment of type 1 diabetes as taught in the present invention are: GAD 1 (Glutamic acid decarboxylase-65 also known as ‘GAD65’); corresponding to amino acid residues 524-543 of GAD 65 (Seq. I.D. No.3 [SRLSKVAPVIKARMMEYGTT]) to create chimera Ig- GAD1; and 2) GAD2; corresponding to amino acid residues 206-220 of GAD 65 (Seq. I.D. No.4 [TYEIAPVFVLLEYVT]); and other peptides derived from GAD65. (Id. at 45, l. 20, to 46, l. 2 (bracketed text appears in original.) FF3. The Specification discloses as follows: In one embodiment of the present invention, the peptide is inserted within the region selected from the group consisting of CDR 1, CDR2 and CDR3. (Id. at 25, ll. 3-4.) Principles of Law The written description requirement does not require the applicants to describe exactly the subject matter claimed in the original application. Instead, the description must clearly allow persons of ordinary skill in the art to recognize that the applicants invented what is claimed. In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989). Analysis We conclude that the Appellants have the better position. Although the Specification may not disclose the creation of the claimed construct, we agree with the Appellants that the Specification clearly conveys that the inventors were in possession of the claimed construct (see App. Br. 17-18). In re Wertheim, 541 F.2d 257 (CCPA 1976) (“It is not necessary that the application describe the claim limitations exactly, ... but only so clearly that Appeal 2012-009223 Application 10/681,788 10 persons of ordinary skill in the art will recognize from the disclosure that appellants invented processes including those limitations.”); see also, In re Chilowsky, 229 F.2d 457, 460 (CCPA 1956) (“[T]he applicant ‘may begin at the point where his invention begins, and describe what he has made that is new and what it replaces of the old. That which is common and well known is as if it were written out in the patent and delineated in the drawings.”’); Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed. Cir. 1987) (“[A] patent need not teach, and preferably omits, what is well known in the art.”). Conclusion of Law The Examiner has not established that a person of ordinary skill in the art would not credit Appellants with possession of the claimed invention. III. OBVIOUSNESS Issue The Examiner rejected claims 1, 2, 4, 5, 7, 13, 15-19, 22-24, 26 and 28-30 under 35 U.S.C. § 103(a) as being obvious over the combination of Zaghouani and Chao. Regarding the timing of administration of the Ig- fusion protein as set forth in claim 1, the Examiner finds that It is well-settled that the routine optimization of a claimed method is obvious. In this instance autoantibody seroconversion is a routine first observation in the development of type 1 diabetes, and an obvious time point at which to begin treatment. (Ans. 25.) Appellants argue that “[c]laim 1 and all claims depending there from specify that ‘the subject has undergone insulin autoantibody seroconversion Appeal 2012-009223 Application 10/681,788 11 prior to the administering step’” and that “[t]his limitation is simply not disclosed in the prior art of record” (App. Br. 24). Appellants further submit evidence that IAA conversion is “a relatively advanced stage of disease” as compared to, for example, the preinsulitis stage or prediabetic stage (Zaghouani Declaration II,18 5, ¶¶ 24-25). The issue presented with regard to this rejection is: Does the evidence of record support the Examiner’s conclusion that the cited prior art teaches or suggests an administration step after the subject has undergone insulin autoantibody seroconversion as recited in claim 1? Additional Findings of Fact FF4. Zaghouani Declaration II provides as follows: Surprisingly, we have found that soluble Ig-GAD2, despite the fact that it does not induce cross-linking of Fc receptors, delayed T1D when administered at the preinsulitis stage and reversed diabetes when given at the prediabetic stage whereas aggregated Ig-GAD2 (which would be expected to cross-link Fc receptors and induce IL-10 secretion by APCs) did not delay diabetes when given after IAA seroconversion (unpublished data). In my opinion, at the time of filing of the present application a person of ordinary skill in the art would not have expected that the presently claimed soluble Ig-GAD2 construct but not the aggregated Ig-GAD2 construct would delay T1D when administered after IAA seroconversion-a relatively advanced stage of disease. (Zaghouani Declaration II, 5, ¶¶ 24-25). 18 Declaration of Habib Zaghouani under 37 C.F.R. § 1.132 dated July 15, 2009 (Appellants Exhibit R). Appeal 2012-009223 Application 10/681,788 12 Analysis “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (citations omitted). However, a particular parameter must first be recognized as a result effective variable before optimization can be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 621 (CCPA 1977). In this case, the Examiner has not pointed to evidence that the prior art recognized the timing for the administration of therapies as an adjustable parameter. Without such evidence, we do not agree that it would have been within the ordinary skill in the art to optimize it. Accordingly, we agree with Appellants that the combined references fail to teach or suggest an administration step after the subject has undergone insulin autoantibody seroconversion. CFMT, Inc. v. Yieldup Intern. Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003) (“[O]bviousness requires a suggestion of all limitations in a claim.”). In addition, the Zagouani Declaration II states that the claimed method requires administering an Ig-GAD2 construct at “a relatively advanced stage” of diabetes (FF 4). The Examiner argues that it would have been obvious to begin the claimed treatment after insulin seroconversion because that is “a routine first observation in the development of type 1 diabetes” (Answer 25) but does not cite any evidence to support this assertion, which is directly contradicted by the the Zagouani Declaration II. Thus, the Examiner’s rationale in support of obviousness is not supported by a preponderance of the evidence of record in any case. Appeal 2012-009223 Application 10/681,788 13 Conclusion of Law We conclude that the preponderance of the evidence of record does not support the Examiner’s conclusion that the combination of Zaghouani and Chao discloses a method having all limitations of claim 1 and dependent claims thereto. SUMMARY We reverse the rejection of claims 1-5, 7, 13, 15-19, 22-24 and 26-30 under 35 U.S.C. §112, first paragraph, for lack of enablement. We reverse the rejection of claims 1-5, 7, 13, 15-19, 22-24 and 26-30 under 35 U.S.C. §112, first paragraph, for lack of written description. We reverse the rejection of claims 1, 2, 4, 5, 7, 13, 15-19, 22-24, 26 and 28-30 under 35 U.S.C. § 103(a) as being obvious over the combination of Zaghouani and Chao. We affirm the rejection of claims 1-5, 7, 13, 15-19, 22-24, and 26-30 under the judicially-created doctrine of obviousness-type double patenting as being unpatentable over claims 1-7 and 13-16 of US Application No. 11/290,070. We affirm the rejection of claims 1-5, 7, 13, 15-19, 22-24, and 26-30 under the judicially-created doctrine of obviousness-type double patenting as being unpatentable over claims 1-7 and 13-16 of US Application No. 11/425,084. Appeal 2012-009223 Application 10/681,788 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 lp Copy with citationCopy as parenthetical citation