Here's one where you claim, and then argue about IND for this Phase III in the late 1990's. Again, you only concentrate on the manufacturing portion only.
And clearly, the IND was created after the agreement went in place to create it. Let's start by saying your claim was wrong, and so your arguments around it should be reviewed
IND # 10206
Date of IND: mid-late 1990s
Study: (no study; used in ongoing DCVax-L Ph III trial)
Manufacturing process (you can translate from German protocol):
The tumor is excised by a neurosurgeon and a portion thereof removed for pathological examination. All remaining tumor tissue is diced and digested to a single cell suspension using an enzyme mix. Next, the tumor cell suspension is filtered through a strainer and then centrifuged for 10 minutes to pellet the tumor cells. The aspirate is removed and the cell pellet is resuspended in RPMI1640 without phenol red, and transferred to cryovials previously labeled with patient ID information. The cell suspension in cryovials is then subjected to freeze thaw cycles to effectively lyse the tumor cells. The tumor lysate is pooled and centrifuged.The supernatant is then filtered through a 0.2 µM filter. Sealed vials containing the tumor lysate are frozen and stored at -80C in controlled inventory until used for loading DC generated from the patient.
Dendritic Cell Preparation Peripheral blood mononuclear cells are isolated by leukapheresis from the patient before treatment begins. MNC are purified by density gradient centrifugation, and either used fresh or cryopreserved until further processing. After thawing of the MNC, if cryopreserved, adherent cells are cultured ex vivo for 6 days with IL4 and GMCSF to generate DC. The DC are collected and combined with the tumor lysate antigen for 16 hours to prepare DCVax L. After the incubation, the final product is harvested and cryopreserved for shipment to the clinical site for patients who are randomized to the treatment cohort. -- PYRR
And so, my claims in this need to be reviewed due the fact that you admit UCLA patents to create the IND are VALID.
"UCLA Sponsored Research Agreements. In April 2001, we entered into an agreement with the Regents of the University of California, Los Angeles, pursuant to which scientists at that institution will assist us in our Phase I clinical trials for DCVax-Lung. In August 2001, we entered into another agreement with the Regents of the University of California, Los Angeles, pursuant to which scientists at that institution will assist us in our Phase II clinical trials for DCVax-Brain."
"We own, or have rights under licenses to a variety of issued patents and pending patent applications. However, the patents on which we rely may be challenged and invalidated, and our patent applications may not result in issued patents. Moreover, our patents and patent applications may not be sufficiently broad to prevent others from practicing our technologies or from developing competing products. We also face the risk that others may independently develop similar or alternative technologies or design around our patented technologies." .
EXHIBIT 10.22
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA UNIVERSITY OF CALIFORNIA, LOS ANGELES AGREEMENT NO. 01124242
This Agreement is entered into this August 22, 2001, by and between THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, a California corporation, on behalf of its Los Angeles Campus, hereinafter called "University," and NORTHWEST
BIOTHERAPEUTICS, INC., hereinafter called "Sponsor."
1. Statement of Work
Work under this Agreement will commence on the date hereof and be performed by the University on a best effort basis in accordance with the statement of work attached as Exhibit A hereof ("Work").
2. Deliverables
A final technical report to Sponsor upon conclusion of work performed hereunder will be the only deliverable under this Agreement unless additional deliverables are set forth in Exhibit B hereof. 3. Performance Period
Work under this Agreement will be performed during the period of July 1, 2001 through June 30, 2002 ("Performance Period") unless earlier terminated pursuant to Article 15.
"Development and Validation of Dendritic Cells Pulsed with Autologous Glioblastoma Tumor Peptides"
EXHIBIT A - STATEMENT OF WORK
This exhibit defines the nature, scope and content of work to be performed under the direction of Dr. Linda Liau, M.D., Ph.D., as Principal Investigator, working on behalf of the UNIVERSITY (UCLA) and to be delivered to the SPONSOR (NORTHWEST BIOTHERAPEUTICS, INC.) in accordance with the terms of this contract.
1. NATURE OF WORK: The University and Sponsor will jointly develop a research program defined below and also an application for a Phase II Investigational New Drug (IND) application entitled, "AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS GLIOBLASTOMA TUMOR PEPTIDES," that will be submitted by the Sponsor to the Federal Drug Administration (FDA). This Phase II IND application is specifically intended to support a clinical trial performed by UCLA investigators in conjunction with the Sponsor and may not be used by the Sponsor for any other purpose unless specified and agreed to in writing by both parties. 2. SCOPE OF WORK: The work to be performed by the University falls into 3 categories:
A. Develop and validate a protocol for preparing GMP-quality suspensions of viable glioblastoma cancer cells from patients with glioblastoma, and develop protocol for preparing GMP quality peptides derived from tumor cells. Transfer the technology to Sponsor. B. Collaborate in the design and writing of sections for the IND application. C. Perform research relevant to program as defined by University and Sponsor.
3. CONTENT OF WORK:
A. Develop and validate a protocol for preparing GMP-quality suspensions of viable glioblastoma cancer cells from patients with glioblastoma multiforme and technology developed technology to Sponsor. University investigators will collect cancer specimens from the operating room and evaluate techniques for preparing purified tumor cell suspensions from these clinical samples. The goal will be to develop a GMP-quality process by which tumors recovered at the time of surgery can be placed into a transportation media and delivered to the Sponsor's cell processing facility in the form of a viable cell suspension. In addition, techniques for purifying, characterizing and culturing the tumor cell suspension after its arrival at the Sponsor's facility will be investigated. Techniques for "stripping" peptides from the surface of tumor cells and concentration of these peptides will also be developed. Results from these investigations will be formed into a detailed written protocol that will be delivered to the Sponsor. This protocol will employ GMP-quality reagents, as feasible given their current availability. The average viability, cell yield and purity of the cancer cell suspension as well as quantities of peptides "stripped" from the tumor cell surface will be reported to the Sponsor.
B. Design and write sections of the IND protocol. University investigators will, in discussion and collaboration with the Sponsor, develop a Clinical Trial Protocol and sections of a corresponding IND application for a study entitled, "PHASE II TRIAL EVALUATING AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS GLIOBLASTOMA PEPTIDES FOR THE ADJUVANT TREATMENT OF MALIGNANT GLIOMA." The following sections will be prepared:
i. General Investigational Plan
ii. Investigators Brochure
iii. Detailed Protocol to include an Introduction, Objectives, Study Hypothesis and Endpoints, Treatment Plan, Pretreatment Evaluation, On Study Evaluation, Concomitant Medications, Adverse Events, and Criteria for Disease Evaluation.
iv. UCLA IRB application conforming to study guidelines.
UCLA / NORTHWEST BIOTHERAPEUTICS, INC. (AGREEMENT NO. 01082716) "DEVELOPMENT AND VALIDATION OF DENDRITIC CELLS PULSED WITH AUTOLOGOUS GLIOBLASTOMA TUMOR PEPTIDES"
EXHIBIT B - DELIVERABLES
This exhibit defines the deliverables to be provided by Linda Liau, M.D., Ph.D. as Principal Investigator, working on behalf of the UNIVERSITY, to the SPONSOR in accordance with the terms of this contract.
A. Develop and validate a protocol for preparing GMP-quality suspensions of viable glioblastoma cancer cells from patients with glioblastoma multiforme. This deliverable includes identification of reagents and resources for the IND protocol. University investigators will identify and make known to the Sponsor a list of products and manufacturers conforming to FDA-approved good manufacturing practices (GMP) as required to carry out the protocol. University investigators will prepare a detailed written protocol that will be delivered to the Sponsor. This protocol will employ GMP-quality reagents, as feasible given their current availability. The average viability, cell yield and purity of the cancer cell suspension will be reported to the Sponsor. These protocols for preparing materials for clinical trial will be transferred to Sponsor.
B. Design and write sections of the IND protocol. University investigators will, in discussion and collaboration with the Sponsor, deliver the following written sections of a Clinical Trial Protocol and corresponding IND application for a study entitled, "PHASE II TRIAL EVALUATING AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS GLIOBLASTOMA PEPTIDES FOR THE ADJUVANT TREATMENT OF MALIGNANT GLIOMA."
i. General Investigational Plan
ii. Investigators Brochure
iii. Detailed Protocol to include an Introduction, Objectives, Study Hypothesis and Endpoints, Treatment Plan, Pretreatment Evaluation, On Study Evaluation, Concomitant Medications, Adverse Events, and Criteria for Disease Evaluation.
iv. UCLA IRB application conforming to study guidelines
C. Research results from sponsored research agreement. Quarterly reports will be delivered to Sponsor covering activities for the previous three months. EXHIBIT C - PAYMENT SCHEDULE
One fourth (25% or $19,125) of total direct and indirect costs ($76,500) will be paid to the University within ten (10) days of the signing date of this agreement. One-third of the remaining balance ($19,125) will be paid to the University at quarterly intervals
Inventorship of developments or discoveries first conceived and actually reduced to practice in the performance this Agreement ("Subject Inventions") will be determined in accordance with U.S. Patent Law and this Agreement. Except as stated below, all rights to Subject Inventions made solely by employees of University will belong solely to University and all rights to Subject Inventions made solely by employees of Sponsor will belong solely to Sponsor. All rights to Subject Inventions made jointly by employees of University and employees of Sponsor and any developments or discoveries conceived and actually reduced to practice as part of the Investigational New Drug work described in Exhibit A, Paragraph 2A and 2B, will belong jointly to University and Sponsor. To the extent that Sponsor pays all direct and indirect costs set forth in Article 4 above, and to the extent that the University is legally able, Sponsor will be granted a time-limited first right to negotiate an option or license under University's rights in any Subject Invention that belongs either solely to University or jointly to University and Sponsor. With respect to filing patents where University and Sponsor are co-inventors, University is obligated to file such patent application upon Sponsors request and will allow Sponsor the opportunity, if it so elects, to review and have right to make reasonable changes to all documents prior to filing. University will promptly disclose to Sponsor any Subject Inventions. Sponsor will hold such disclosure on a confidential basis and will not disclose the information to any third party without consent of University. Sponsor will advise the University in writing within sixty (60) days of such disclosure to Sponsor whether or not it wishes to secure an option or commercial license ("Election Period"). Sponsor will have ninety (90) days from the date of election to conclude an option or license agreement with University ("Negotiation Period"). Said license will contain reasonable terms, will require diligent performance by Sponsor for the timely commercial development and early marketing of Subject Inventions, and include Sponsor's obligation to reimburse University's patent costs for all Subject Inventions subject to the license. In the event it is necessary in the opinion of University to file any patent applications to protect a Subject Invention during the Election or Negotiation Periods, University will promptly notify Sponsor in writing of such decision and Sponsor will reimburse patent costs incurred by University during such period. If such option or license is not concluded within the Negotiation Period, neither party will have any further obligations to the other with respect to such Subject Invention. If Sponsor does not elect to secure such option or license, rights to such Subject Invention will be disposed of in accordance with University's policies, with no further obligation to Sponsor with respect to such Subject Invention. Nothing contained in this Agreement shall be deemed to grant either directly or by implication, estoppel, or otherwise, any rights under any patents, patent applications or other proprietary interests, whether dominant or subordinate, or any other invention, discovery or improvement of either party, other than the specific rights covering Subject Inventions under this Agreement.
From the agreement, determine who owns what. So who owns the patent for autologous dendritic cells pulse with autologus glioblastoma peptides (which by the way it turns out BCG is used in the pulse process)? The Regent of the University of California. “Methods for the Detection and Treatment of Neural Cancer” Patent number: 6558668 Patent number: 7192704 patents.justia.com/patent/6558668 http://patents.justia.com/patent/7192704 “Composition and Methods for the Detection and Treatment of Multiple Cancers” Patent number 7204982 http://patents.justia.com/patent/7204982
UCLA commercially licensed to NWBO (which UCLA funding the current TLR study alluded to anyway). Who owns the various patent for administration and activation of dendritic cells (including precursors) which is used in combination of the above, pulsed method? NWBO
