Ex Parte Steffan et alDownload PDFPatent Trial and Appeal BoardMar 28, 201610476627 (P.T.A.B. Mar. 28, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 10/476,627 10/30/2003 23363 7590 03/30/2016 Lewis Roca Rothgerber Christie LLP POBOX29001 Glendale, CA 91209-9001 FIRST NAMED INVENTOR Joan S. Steffan 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 ATTORNEY DOCKET NO. CONFIRMATION NO. Rl:00044 1926 EXAMINER DRAPER, LESLIE A ROYDS ART UNIT PAPER NUMBER 1629 NOTIFICATION DATE DELIVERY MODE 03/30/2016 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): pair_cph@firsttofile.com pto@lrrc.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JOANS. STEFFAN, LESLIE M. THOMPSON, and J. LAWRENCE MARSH Appeal2013-009503 Application 10/476,627 Technology Center 1600 Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and JACQUELINE T. HARLOW, Administrative Patent Judges. MILLS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134. The Examiner has rejected the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). WE AFFIRM. Appeal2013-009503 Application 10/476,627 STATEMENT OF CASE The following claim is representative. 1. A method of treating neurodegeneration in a patient, comprising: administering a therapeutically effective amount of a deacetylase inhibitor to a patient diagnosed with protein-aggregation-related neurodegeneration related neurodegeneration, such that the effects of at least one neurodegenerative disease-causing protein on acetyltransferase activity within the patient is mitigated. Cited References Schreiber et al. WO 97/35990 Oct. 2, 1997 (hereinafter "Schreiber") Steven D. Gore & Michael A. Carducci, Modifj;ing histones to tame cancer: clinical development of sodium phenyl butyrate and other histone deacetylase inhibitors, 9 EXP. OPIN. INVEST. DRUGS 2923-2934 (2000). Grounds of Rejection 1. Claims 1, 5, and 9 are rejected under 35 U.S.C. § l 02(b) as being anticipated by Schreiber. 2. Claims 1, 4, 5, 8, 9, and 12 are rejected under 35 U.S.C. § 103(a) as being unpatentable over Schreiber in view of Gore. FINDINGS OF FACT The Examiner's findings of fact are set forth in the Answer at pages 3-23. PRINCIPLES OF LAW In making our determination, we apply the preponderance of the evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F .2d 1422, 1427 (Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings 2 Appeal2013-009503 Application 10/476,627 before the Office). The Board "determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction 'in light of the specification as it would be interpreted by one of ordinary skill in the art."' Phillips v. A WH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004). "In rejecting claims under 35 U.S.C. § 103, the examiner bears the initial burden of presenting a prima facie case of obviousness. Only if that burden is met, does the burden of coming forward with evidence or argument shift to the applicant." In re Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993) (citations omitted). In order to determine whether a prima facie case of obviousness has been established, we consider the factors set forth in Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content of the prior art; (2) the differences between the prior art and the claims at issue; (3) the level of ordinaP; skill in the relevant art; and (4) objective evidence of nonobviousness, if present. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Rejection I-Anticipation Claims 1, 5, and 9 are rejected under 35 U.S.C. § 102(b) as being anticipated by Schreiber. We find that the Examiner has not provided evidence to support a prima facie case of anticipation. 3 Appeal2013-009503 Application 10/476,627 Appellants note that "Schreiber et al.: (i) discloses hundreds to thousands of different compounds and cites numerous disease conditions associated with defects in cellular replication." App. Br. 4. While not wholly adopting the Appellants' argument, we do acknowledge that Schreiber discloses multiple histone deacetylase compounds for the treatment of multiple proliferative disorders (p. 82, 11. 23-35). Because there is a level of picking and choosing amongst the various histone deacetylase compounds and various disorders, we agree with Appellants that Schreiber does not serve as anticipatory reference for the treatment of neurodegeneration, and the anticipation rejection over Schreiber is reversed. Rejection 2-0bviousness Claims 1, 4, 5, 8, 9, and 12 are rejected under 35 U.S.C. § 103(a) as being unpatentable over Schreiber in view of Gore. Appellants do not argue the claims separately, therefore, \'X/e select claim l as representative. Schreiber, International Publication WO 97 /35990 claims priority to a United States Patent Application 08/624,735 which resulted in two patents, U.S. 8,426,597 and US 8,329,996. Thus the PCT disclosure of Schreiber includes patentable subject matter. According to the Examiner, "Schreiber et al. teaches compounds useful for the inhibition of HDxs (also known as histone deacetylase genes; please see p.2, 1.15-18)." Ans. 5. The Examiner further finds that, Schreiber et al. further teaches that the disclosed HDx therapeutics, wherein Schreiber et al. defines the term "HDx therapeutics" as including any of the preparations disclosed in the reference, including the disclosed inhibitory preparations (i.e., which includes those inhibitory compounds described at 4 Appeal2013-009503 Application 10/476,627 p.8, 1.22-p.10, 1.3; see also p.82, 1.10-13) are useful forthe treatment of differentiative disorders that result from de- differentiation of tissue that may also be accompanied by abortive reentry into mitosis, e.g., apoptosis, such as, inter alia, Huntington's chorea (p.82, 1.23-29). Ans. 5. "Schreiber et al. fails to teach the use of sodium phenylbutyrate as the histone deacetylase inhibitor of the disclosed method for treating, inter alia, Huntington's chorea as instantly claimed (see, e.g., present claims 4, 8 and 12)." Ans. 6. However, Schreiber does teach that sodium butyrate is a well known histone deacetylase inhibitor. Schreiber, p. 49, 1. 13; p. 84, 1. 8. Gore is relied on by the Examiner as teaching that sodium phenylbutyrate was known in the art to be a potent inhibitor ofhistone deacetylase (abstract, p. 2923). Ans. 6. The Examiner concludes that One of ordinary skill in the art at the time of the invention would have found it prima facie obvious to employ the histone deacetylase inhibitor sodium phenylbutyrate as disclosed by Gore et al. in place of the histone deacetylase inhibitor compounds disclosed by Schreiber et al., which are explicitly disclosed as being useful for the treatment of, inter alia, Huntington's chorea, to elicit the predictable result of inhibiting histone deacetylase and thereby effecting the treatment of Huntington's chorea. Such a person would have been clearly motivated to do so in order to predictably effect the inhibition of histone deacetylase which, according to Schreiber et al., is effective to treat Huntington's chorea and such a person would have had a reasonable expectation of success in doing so because the art clearly recognized the ability of sodium phenylbutyrate to inhibit histone deacetylase and also 5 Appeal2013-009503 Application 10/476,627 recognized that the inhibition of histone deacetylase was effective for treating Huntington's chorea. Ans. 6. We find that the Examiner has provided sufficient evidence to support a prima facie case of obviousness. Appellants do not provide separate argument addressing the obviousness rejection over Schreiber and Gore, but instead rely on their arguments presented to address the anticipation rejection over Schreiber. App. Br. 12. We therefore address Appellants' previous arguments with respect to the Schreiber anticipation rejection here. Appellants argue that Schreiber does not provide an enabling disclosure for the claimed invention citing, Impax Labs., Inc. v. Aventis Pharms. Inc., 496 F.Supp.2d 428, 432 (D. Delaware 2007), affd, 545 F.3d 1312 (Fed. Cir. 2008)). App. Br. 3. Appellants further argue that analysis of the Wands 1 enablement factors in the present case supports a finding that Schreiber is a non=enabling reference. \X/ e are not persuaded. "[W]e therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling. As long as an examiner makes a proper prima facie case of anticipation by giving adequate notice under§ 132, the burden shifts to the applicant to submit rebuttal evidence of nonenablement." In re Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir. 2012). In the present case, Appellants have failed to provide any evidence, as opposed to attorney argument, that 1 See, In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). 6 Appeal2013-009503 Application 10/476,627 Schreiber is not an enabling reference. In particular, Schreiber discloses that a histone acetyltransferase gene (HAT 1) has been identified in yeast (Kelff et al. (1995) J. Biol. Chem. 270:24674--24677), thereby identifying the molecular entities responsible for histone deacetylation that were previously unknown in the art. Spec. 3. Schreiber discovered "a novel family of genes, and gene products, expressed in mammals, which genes are referred to hereinafter as the 'histone deacetylase' genes or 'HDx' gene family, the products of which are referred to as histone deacetylases or HDx proteins." Schreiber, p. 2, 11. 15-18. Schreiber presented evidence that the mSin3A compressor is part of a high molecular weight, multicomponent complex( es) that contains active histone deacetylase, thereby implicating histone deacetylation as a potential mechanism for mSin3A-mediated repression. Furthermore, we observe a pronounced increase in the transcriptional activity of an mSin3A-silenced reporter gene upon treatment in vivo with the specific histone deacetylase inhibitor trapoxin, suggesting that full transcriptional repression by mSin3A requires histone deacetylation. These results suggest a mechanism of gene regulation through the targeting of an enzyme that alters chromatin structure. Schreiber, p. 103, 11. 4--12. See also Schreiber Examples and Figures. Furthermore, Schreiber used chimeric transcriptional regulators to discern the effects of trapoxin on the activity of our reporter genes. The MadN35GALVP16 chimera functioned as a repressor by a mechanism that was dependent on the binding of mSin3A and that was sensitive to trapoxin. The same mutations that inactivate MadN35GALVP16 as a transcriptional repressor (i.e. Mad(pro)N35GALVP16), also block interaction between Madl and mSin3A in vitro and Madl function in vivo. Therefore, it is likely that Mad:Max heterocomplexes repress transcription in a 7 Appeal2013-009503 Application 10/476,627 manner dependent on an mSin3A-associated histone deacety lase. By co-immunoprecipitation we have demonstrated that mSin3A and HDACl associate in vivo. Schreiber, p. 103, 11. 20-28. Schreiber analyzed the human HDx sequences, while not revealing any obvious similarities to known domains or motifs, did indicate similarities with previously identified proteins from both Saccharomyces cerevisiae and Xenopus laevis. Those genes, RPD3 (SEQ ID No. 9) and Xe-RPD3 (SEQ ID No. 10), respectively, had not previously been ascribed any specific function. However, based on our observations for the function of HD 1, it is now apparent that each of these other proteins are also deacetylases, and represent potential therapeutic targets. Schreiber,p.17,11.11-23. In addition ... [Schreiber] isolated another bovine protein having an approximate molecular size of 50kD which apparently binds l!Dx proteins isolated by the trapoxin matrix, and micro sequencing of that protein demonstrated that it was related to the protein referred to in the art as RbAp48 (Qian et al. (1993) Nature 364:648; SEQ ID No. 11). RbAp48 was originally identified as a protein that binds to the retinoblastoma (Rb) gene product. The retinoblastoma (RB) gene product plays a role in tumor suppression (Weinberg, R.A., (Sept 1988) Scientific Amer. pp 44-51; Hansen et al. (1988) Trends Genet 4: 125-128). The role of RB as a tumor-suppressor protein in cell-cycle control is believed to be similar to that of another tumor-suppressor, p53 (Green (1989) Cell 56:1-3; Mowat et al (1985 Nature 314:633-636). Schreiber, p. 17, 11. 25-34. Based on the role ofhistone deacetylases as transcription regulators, Schreiber determined that 8 Appeal2013-009503 Application 10/476,627 In addition to proliferative disorders, the present invention contemplates the use of HDx therapeutics for the treatment of differentiative disorders which result from, for example, de-differentiation of tissue which may (optionally) be accompanied by abortive reentry into mitosis, e.g. apoptosis. Such degenerative disorders include chronic neurodegenerative diseases of the nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's chorea, amylotrophic lateral sclerosis and the like, as well as spinocerebellar degenerations. Schreiber, p. 82, 11. 23-29. Similarly, Appellants' Specification discloses that The present inventors have demonstrated that expanded polyglutamine Httexp 1 coaggregates with p53 in inclusions generated in cell culture, and interacts in vitro with CBP and mSin3A; moreover, CBP localizes to neuronal nuclear inclusions in a transgenic mouse model of Huntington's disease. See FIGs. 2-4, 7 and 8. As discussed above, such protein aggregations reduce acetylation levels in cells by sequestering cellular proteins having acetyltransferase activity, such as the transcription factor CBP, leading to neurodegeneration and cell death. The present inventors have demonstrated that such reduced acetylation levels are compensated by the addition of deacetylase inhibitors, suppressing the pathogenic phenotype. This indicates that neurodegenerative diseases characterized by protein aggregation also involve sequestration of acetyltransferases and, as a result, altered acetylation levels. For example, amyloid precursor protein, a protein implicated in nerve cell damage in Alzheimer's disease, has been shown to interact with histone acetyltransferase (Cao, X. and Sudhof, T.C. (2001) Science 293, 115-120), which, in view of the present inventors' findings, suggests a role for altered acetylation levels in the Alzheimer's disease state. Accordingly, 9 Appeal2013-009503 Application 10/476,627 deacetylase inhibitors such as SAHA and butyrate have therapeutic potential for the treatment of aggregation disease such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Pick' s disease, prion disease and other spongiform encephalopathies. Spec. 24. Appellants' arguments with respect to how the Wands factors apply to the disclosure of Schreiber is cursory at best. In other words, Appellants fail to comment or provide specific evidence as to what the studies of Schreiber, the associated experiments, Figures and graphs would or would not have suggested to one of ordinary skill in the art at the time of the invention. Appellants have failed to provide evidence that one of ordinary skill in the art at the time of the invention would have considered the histone deacetylase studies and conclusions of Schreiber as speculative. While Appellants make generalized statements that Schreiber is not enabling based on the Impax case la\~1, they provide no specific evidence that one of ordinary skill in the art at the time of the invention would have been unable to determine dosage amounts of histone deacetylase inhibitors based on the disclosure of Schreiber. For Example, Schreiber provides that When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.1 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. Schreiber p. 81, 11. 1-5. Schreiber also discloses that The selected dosage level will depend upon a variety of factors including the activity of the particular deacetylase inhibitor employed, or the ester, salt or amide thereof, the route of administration, the time 10 Appeal2013-009503 Application 10/476,627 of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other· drugs, compounds and/or materials used in combination with the particular deacetylase inhibitor employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Schreiberp. 81, 1. 23 -p. 82, 1. 2. Furthermore, the Examiner's obviousness rejection is based on the combination of Schreiber and Gore. Gore is relied on by the Examiner to show that it was well known to one of ordinary skill in the art at the time of the invention how to determine dosages of sodium phenylbutyrate, a histone deacetylase inhibitor. Ans. 6. Gore disclosed that, "the inhibition of HDAC may alleviate gene repression." Page 2924, col. 1. Gore also disclosed that butyric acid derivatives function as histone deacetylase inhibitors and are potential antineoplastic agents. Page 2924, col. 2. See also, Merck v. Biocraft, IO USPQ 2d 1843, (Fed. Cir. 1989) where the court found that the timing and care to arrive at dosage amounts is "nothing more than routine" to those of skill in the art. In addition, although "working examples are desirable in complex technologies ... examples are not required to satisfy section 112, first paragraph." In re Strahilevitz, 668 F.2d 1229, 1232 (CCPA 1982) (emphasis in original). Appellants present no specific evidence that one of ordinary 11 Appeal2013-009503 Application 10/476,627 skill in the art reviewing the Examples and Figures present in Schreiber, would have considered the specific disclosure of Schreiber non-enabling or the lack of further working examples to be critical. On balance, when the evidence of record is weighed, Appellants have failed to rebut the Examiner's prima facie case of obviousness. The obviousness rejection over Schreiber in view of Gore is affirmed. CONCLUSION OF LAW The cited references support the Examiner's obviousness rejection, which is affirmed. The Examiner's anticipation rejection is reversed. All pending claims fall. AFFIRMED 12 Copy with citationCopy as parenthetical citation