Department of Health and Human Services April 9, 2013 – Federal Register Recent Federal Regulation Documents

Under the provisions of Section 3507(a)(1)(D) of the Paperwork Reduction Act of 1995, the National Institutes of Health (NIH), has submitted to the Office of Management and Budget (OMB) a request to review and approve the information collection listed below. This proposed information collection was previously published in the Federal Register on February 1, 2013 (Volume 78, Page 7437) and allowed 60-days for public comment. No public comments were received. The purpose of this notice is to allow an additional 30 days for public comment. The National Cancer Institute (NCI), National Institutes of Health may not conduct or sponsor, and the respondent is not required to respond to, an information collection that has been extended, revised, or implemented on or after October 1, 1995, unless it displays a currently valid OMB control number. Direct Comments To OMB: Written comments and/or suggestions regarding the item(s) contained in this notice, especially regarding the estimated public burden and associated response time, should be directed to the: Office of Management and Budget, Office of Regulatory Affairs, OIRA_submission@omb.eop.gov or by fax to 202-395-6974, Attention: NIH Desk Officer. Comment Due Date: Comments regarding this information collection are best assured of having their full effect if received within 30-days of the date of this publication.

Notice is hereby given that the Office of Research Integrity (ORI) has taken final action in the following case: Andrew Aprikyan, Ph.D., University of Washington: Based on the report of an investigation conducted by the University of Washington (UW), the UW School of Medicine Dean's Decision, the Decision of the Hearing Panel at UW, and additional analysis conducted by ORI, ORI found by a preponderance of the evidence that Dr. Andrew Aprikyan, former Research Assistant Professor, Division of Hematology, UW, engaged in research misconduct in research supported by National Cancer Institute (NCI), National Institutes of Health (NIH), grant CA89135 and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, grant DK18951, and applies to the following publications and grant applications: Blood pre-published online on January 16, 2003 (``NEM'') Experimental Hematology 31:372-381, 2003 (``CMA'') Blood 97:147-153, 2001 (``ISB'') R01 CA89135-01A1 R01 HL73063-01 R01 HL79615-01 Blood pre-published online on January 16, 2003, has been retracted and Experimental Hematology 31:372-381, 2003, has been corrected. Specifically, ORI finds that by a preponderance of the evidence, Respondent falsified and/or fabricated results relating to the above publications and grants. Specifically, Respondent: 1. Falsely reported sequencing data in the NEM manuscript to strengthen the hypothesis that NE mutations contributed to the phenotype observed in severe congenital neutropenia (SCN) patients. Specifically: a. Respondent falsely reported in Figures 2A and 3 that patient 3 had the R191Q neutrophil elastase (NE) mutation, when the majority of the sequencing experiments showed that the mutation was not present. b. Respondent fabricated text (p. 12) reporting that sequencing of RT-PCR products confirmed the expression of the NE mutants in the SCN patients and that no mutations were present in the granulocyte colony stimulating factor receptor (G-CSFR) gene and the Wiskott-Aldrich Syndrome (WAS) gene in SCN patients, when based on the lack of original records the experiments were not performed. The false claim for G-CSFR sequencing was also reported in CA89135-03. 2. Falsely reported a two-fold increase in apoptosis of human promyelocytic (HL-60) cells transfected with NE mutants compared to wild type NE in Figure 4A, NEM, Figure 6A, CMA, Figure 8, HL73063-01, and Figure 7, HL79615-01. Respondent used arbitrary flow cytometry data files to generate histograms with the desired result. The false results supported the hypothesis that the NE mutations were sufficient for impaired survival of human myeloid cells. 3. Falsified NE and [szlig]-actin Western blots in Figure 4B Blood, pre-published online January 16, 2003, Figure 5B of the manuscript initially submitted to Blood April 2002, and Figure 6B Experimental Hematology 31:372-381, 2003, by falsely labeling lanes to support the hypothesis that accelerated apoptosis in mutant NE transfect HL-60 cells was due to the mutation and not the level of protein present. Specifically: a. Respondent used portions of a single NE Wester blot to represent: Figure 4B as HL-60 cells transfected with L92H, R191Q, and wtNE, when the cells were transfected with R191Q, P110L, and D145-152; Figure 5B as HL-60 transfected with wtNE, mutNE, and EGFP when they were cells transfected with NE mutants, P110L, D145-152, and 194 b. Respondent used portions of a single [szlig]-actin Western blot to represent: Figure 4B as HL-60 cells transfected with L92H, R191Q, and wtNE, when they were cells transfected with I31T, P110L, and G185R mutants; Figure 5B as HL-60 cells transfected with wtNE, mutNE, and EGFP, when they were cells transfected with P110L, I31T, and INE; Figure 6B as HL-60 cells transfected with G185R, mock, D145-152, and P110L NE mutants, when they were cells transfected with I31T, P110L, G185R, and 32. The false [szlig]-actin Western blot in Figure 6B was also included in HL73063-01, Figure 8 (where the I31Tlane was labeled correctly), and HL79615-01, Figure 7. 4. Falsified the reported methodology for flow cytometry experiments in Figure 4A, NEM, Figures 1 and 2, and Tables 2 and 3, CMA, and Figures 4, 5, and 6, ISB, to validate the key hypothesis showing accelerated apoptosis in SCN and CN patients. The methodology claimed that flow cytometry experiments were gated for GFP+ populations, or that cell purity was greater than 96%, when based on the available original records, the experiments were not performed as stated. 5. Falsified Figure 2, CMA, Figure 2, HL73063-01, Figure 3, HL79615-01, and Figure 5, CA89135-01A1, demonstrating that the overnight cultures of CD34+ and CD33+ bone marrow cells from SCN/AML patients showed normal cell survival, and only the CD15+ overnight cultures showed accelerated apoptosis, when the actual record available contradicted this result. Respondent used flow cytometry data files to generate histograms with the desired result to support the hypothesis that the progression from SCN to leukemia (AML) involves acquired G- CSFR mutations that override the pro-apoptotic effect of the NE mutations in primitive progenitor cells. Dr. Aprikyan has entered into a Settlement Agreement in which he denied ORI's findings of research misconduct based on the UW Faculty Adjudication Hearing Panel decision. The settlement is not an admission of liability on the part of the Respondent. Respondent entered into the Agreement solely because contesting the findings would cause him undue financial hardship and stress, lead to lengthy and costly appellate proceedings, and he wished to seek finality. Respondent agreed not to appeal the ORI findings of research misconduct set forth above. He has agreed, beginning on March 12, 2013: (1) If within two (2) years from the effective date of the Agreement, Respondent receives or applies for U.S. Public Health Service (PHS) support, Respondent agreed to have his research supervised for a period of two (2) years; Respondent agreed that prior to the submission of an application for PHS support for a research project on which his participation is proposed and prior to his participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of his duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of his research contribution; Respondent agreed that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agreed to maintain responsibility for compliance with the agreed upon supervision plan; (2) If within two (2) years from the effective date of the Agreement, Respondent receives PHS support, Respondent agreed that for two (2) years, any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and (3) Respondent agreed not to serve in any advisory capacity to PHS including, but not limited to, service on any PHS advisory committee, board, and/or peer review committee, or as a consultant for a period of two (2) years beginning with the effective date of the Agreement.

This is notice, in accordance with 35 U.S.C. 209(c)(1) and 37 CFR 404.7(a)(1)(i), that the National Institutes of Health, Department of Health and Human Services, is contemplating the grant of an exclusive license to practice the inventions embodied in U.S. Patent Application 61/172,099 entitled ``Anti-human ROR1 Antibodies'' [HHS Ref. E-097-2009/0-US-01], U.S. Patent Application 60/703,798 entitled ``Mutated Pseudomonas Exotoxins with Reduced Antigenicity'' [HHS Ref. E-262-2005/0-US-01], U.S. Patent Application 60/969,929 entitled ``Deletions in Domain II of Pseudomonas Exotoxin A that Remove Immunogenic Epitopes with Affecting Cytotoxic Activity'' [HHS Ref. E- 292-2007/0-US-01], U.S. Patent Application 61/241,620 entitled ``Improved Pseudomonas Exotoxin A with Reduced Immunogenicity'' [HHS Ref. E-269-2009/0-US-01], U.S. Patent Application 61/483,531 entitled ``Recombinant Immunotoxin Targeting Mesothelin'' [HHS Ref. E-117-2011/ 0-US-01], U.S. Patent Application 61/495,085 entitled ``Pseudomonas Exotoxin A with Less Immunogenic T-Cell/or B-Cell Epitopes'' [HHS Ref. E-174-2011/0-US-01], U.S. Patent Application 61/535,668 entitled ``Pseudomonas Exotoxin A with Less Immunogenic B-Cell Epitopes'' [HHS Ref. E-263-2011/0-US-01], and all related continuing and foreign patents/patent applications for the technology family, to SPEED BioSystems, LLC. The patent rights in these inventions have been assigned to the Government of the United States of America. The prospective exclusive evaluation option license territory may be worldwide and the field of use may be limited to pre-clinical evaluation of lead therapeutic candidates for the development and use of anti-tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunotoxins for the treatment of human ROR1 expressing cancers, wherein the immunotoxin comprises an anti-ROR1 antibody designated as 2A2 and Pseudomonas exotoxin A (PE). Upon expiration or termination of the exclusive evaluation option license, SPEED will have the right to execute an exclusive patent commercialization license which will supersede and replace the exclusive evaluation option license with no broader territory than granted in the exclusive evaluation option license and the field of use will be commensurate with the commercial development plan at the time of conversion.

The Food and Drug Administration (FDA) is amending the animal drug regulations to reflect a change of sponsor for 43 approved new animal drug applications (NADAs) and 3 approved abbreviated new animal drug applications (ANADAs) from Boehringer Ingelheim Vetmedica, Inc. to Strategic Veterinary Pharmaceuticals, Inc.