Document:

Letter Amendment

 Exhibit 10.1 
  
 LETTER AMENDMENT 
  
             November 22, 2004 
 To the Lenders parties to the 

	    Credit	Agreement referred to below 

  
 Gentlemen: 
  
 We refer to the
Credit Agreement dated as of December 16, 2002, as amended by Amendment No. 1 dated as of March 3, 2003, Amendment No. 2 dated as of December 15, 2003 and Amendment No. 3 dated as of March 10, 2004 (the “Credit Agreement”) among the
undersigned, you and Wells Fargo Bank, National Association, as your Agent. Unless otherwise defined herein, the terms defined in the Credit Agreement shall be used herein as therein defined. 
  
 It is hereby agreed by you and us that the Termination Date of the Credit
Agreement should be amended to extend the term of the Credit Agreement to March 14, 2005. 
  
 You have indicated your willingness to so agree. Accordingly, it is hereby agreed by you and us that the Credit Agreement is, effective as of the date first above written, hereby amended by amending the definition of
“Termination Date” by substituting for the date “December 13, 2004”, the date of “March 14, 2005”. 
  
 On and after the effective date of this letter amendment, each reference in the Credit Agreement to “this Agreement”, “hereunder”,
“hereof” or words of like import referring to the Credit Agreement, and each reference in the Notes to “the Credit Agreement”, “thereunder”, “thereof” or words of like import referring to the Credit Agreement,
shall mean and be a reference to the Credit Agreement as amended by this letter amendment. The Credit Agreement, as amended by this letter amendment, is and shall continue to be in full force and effect and is hereby in all respects ratified and
confirmed. 
  
 If you agree to the terms and provisions hereof,
please evidence such agreement by executing and returning at least two counterparts of this letter amendment to Shearman & Sterling LLP, 525 Market Street, San Francisco, CA 94105, Attention of Eldyne Perrou; Telephone: (415) 616 1125;
Facsimile: (415) 616 1325. This letter amendment shall become effective as of the date first above written when and if counterparts of this letter amendment shall have been executed by us and all of the Lenders. This letter amendment is subject to
the provisions of Section 8.01 of the Credit Agreement. 
  
 This
letter amendment may be executed in any number of counterparts and by any combination of the parties hereto in separate counterparts, each of which counterparts shall be an original and all of which taken together shall constitute one and the same
letter amendment. 

			
	 Very truly yours,

	
	 GREATER BAY BANCORP

		
	 By
	 	 /s/ James Westfall

	 	 	 Title: Executive Vice President and
 Chief Financial
Officer

		
	 By
	 	 /s/ Kamran Husain

	 	 	Title: Senior Vice President

  
 Agreed as of the date first
above written: 
  

			
	 WELLS FARGO BANK, NATIONAL ASSOCIATION,

	 as Agent and Lender

		
	 By
	 	 /s/ Robert McFadden

	 	 	Title: Senior Relationship Manager
	
	 U.S. BANK NATIONAL ASSOCIATION,

	 as Lender

		
	 By
	 	 /s/ Jon Beggs

	 	 	Title:
	
	 HARRIS TRUST AND SAVINGS BANK,

	 as Lender

		
	 By
	 	 /s/ T. E. Broccolo

	 	 	Title: Managing Director
	
	 BANK OF AMERICA, N.A.,

	 as Lender

		
	 By
	 	 /s/ Mary Riggins

	 	 	Title: Senior Vice President
	
	 M&I MARSHALL & ILSLEY BANK,

	 as Lender

		
	 By
	 	 /s/ Kurts Strelnieks

	 	 	Title:Ageement on Technology & Business Right Transfer

 Exhibit 10.4 
  
 AGREEMENT on TECHNOLOGY & BUSINESS RIGHT TRANSFER 
  
 between 
 Cardio Vascular Genetic Engineering Inc. 
 (a Delaware Corporation) 
  
 and 
 Korea Biotechnology Development Co., Ltd. 
 (a Korean Corporation) 
  
 Dated December 15, 2000 
  
 < Introduction > 
  
 Cardio Vascular Genetic Engineering Inc. desires to form a joint venture business arrangement with Korea Biotechnology
Development Co., Ltd. (hereinafter KBDC) for the development and commercialization of its biotechnology in certain areas of Asia. 
  
 This agreement confirms the rights and duties of the relating two parties regarding to a technology and business right transfer for the manufacturing and
the exclusive marketing territory of the Cardio Vascular Genetic Engineering Inc. and it’s biotechnology products. 
  
 The following are the basic terms of the agreement ; 
  

	1.	Time and Territory 

  
 Cardio Vascular Genetic Engineering Inc. shall transfer all of the biotechnology to KBDC for its product and medical treatment for 
  
 (a) Time Frame : 99 years 
  
 (b) Territory : all of Korea, China and Taiwan 
  

	2.	Limitation 

  
 KBDC will assure Cardio Vascular Genetic Engineering Inc. that it will not allow the distribution of any products utilizing the Cardio technology out side
of the territory defined in #l-(b). 
  

 And KBDC while it shall own the technology agreed to, for the first 20 years life of the licensing
agreement, the Phage bio-manufacturing process will be 100% under the operational and management control of Cardio Vascular Genetic Engineering Inc., the USA company or its designate, Phage Biotechnology Corporation USA. If at any time the control
of the phage bio-manufacturing process is interfered with by anyone or any entity, the licensing agreement is forfeited by KBDC and of its transferees. 
  

	3.	Consideration 

  
 In exchange for technology & business right transfer, manufacturing technology and exclusive marketing territory, KBDC, as consideration for the above
technology, manufacturing rights and exclusive marketing territory, shall pay the following consideration to Cardio Vascular Genetic Engineering Inc.; 
  
 (a) KBDC has arranged investing U$3,500,000 to Cardio Vascular Genetic engineering Inc. in 2000. 
  
 (b) KBDC agrees to fund all of the cost of regulatory approval process in
Korea for any products of Cardio technology presented by the USA partner. 
  
 (c) KBDC agrees to pay a Royalty of 10% of net revenues to Cardio Vascular Genetic Engineering Inc. and will be paid for the life of this agreement. 
  

					
	Agreed	 	 	 	 
			
	 /s/ Mr. Daniel C. Montano
	 	 	 	 /s/ Mr. Joong-Ki Baik

	Mr. Daniel C. Montano	 	 	 	Mr. Joong-Ki Baik
	President	 	 	 	President
	Cardio Vascular Genetic Engineering Inc.	 	 	 	Korea Biotechnology Development Co., Ltd.
			
	Dated December 15, 2000	 	 	 	Dated December 15, 2000Agreement Dated July 13, 2001

 Exhibit 10.10 
  
 DaVinciTM 
  
 Biomedical research Prod. 
  
 PROTOCOL 
  
 ACTIVITY INVOLVING VERTEBRATE ANIMAL MODELS 
  
 Cardiotoxicity Study of Fibroblast Growth Factor (FGF-1) in Dogs 
  
 DaVinci Study Number: DB-19 
  

			
		
	 Sponsor:
	  	 Cardio Vascular Genetic Engineering Corp.
 Phage Biotechnology Corp.
 14270 Franklin Ave. Suite 110
 Tustin, CA 92780

		
	 	  	 Telephone Number: 714-368-1520, ext.15
 Fax
Number: 714-368-1517

		
	 Sponsor Contact:
	  	Jack Jacobs
		
	 e-mail Address:
	  	jjacobs@phagebiotech.com
		
	 Project Site:
	  	 DaVinci Biomedical Research Products
 40
Maple Ave
 So. Lancaster, MA 01561

		
	 	  	 Telephone Number: (978) 368-3477
 Fax
Number:            (978) 368-3579

		
	 Facility Contact Person:
	  	Mario PioVillani
		
	 Protocol Issue Date:
	  	July 13, 2001

  
 DaVinci Biomedical Research
ProdTM 40 Maple Ave So. Lancaster MA 01561 Tel
978-368-3477 Fax 978-368-3579 
  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 2 of 12

  

	1.	OBJECTIVE/LAY SUMMARY: The objective of this study is to evaluate the toxicity that may occur during a 3-28 day post-dosing period following the acute administration of FGF-1
directly into the ischemic heart of a dog. 

  

	2.	REGULATORY REFERENCE: This study will be performed under Good Laboratory Practice Regulations; The Standard Operating Procedures of the test facility will be followed, and
all appropriate study documentation’s will be maintained in the study file. 

  

	3.	STUDY DESIGN: During the ischemic insult and dose administration procedure the following values will be obtained every 10-15 minutes: electrocardiograms (ECG’s), heart
rate (HR), systolic arterial pressure(SAP), diastolic arterial pressure(DAP), and mean arterial pressure(MAP) will be monitored and recorded. BP and ECG changes occur during ischemic insult, or any time thereafter including dose administration,
values will be monitored until baseline values are established, but not to exceed 30 minutes post. A printout of ECG’s will be performed when values change and every 10-15 minutes, thereafter. 

  
 The following groups of animals will be used on study: 
  

							
	 Group 1
	  	Vehicle	  	5 dogs (3 male and 2 female)	  	28 day post-dosing necropsy
	 Group 2
	  	0.02 mg/kg FGF	  	5 dogs (3 male and 2 female)	  	28 day post-dosing necropsy
	 Group 3
	  	0.2 mg/kg FGF	  	5 dogs (3 male and 2 female)	  	28 day post-dosing necropsy
	 Group 4
	  	Vehicle	  	3 dogs (2 male and 1 female)	  	3 day post-dosing necropsy
	 Group 5
	  	0.2 mg/kg FGF	  	3 dogs (2 male and 1 female)	  	3 day post-dosing necropsy

  
 Treatment Regimen: 

 
 Each dog will receive an ischemic insult to the heart, using a balloon-tipped catheter,
where injury and thrombus formation are directed at the left circumflex coronary artery. The ischemic insult will be monitored angiographically and by electrocardiograms. The animals will have a 7 day recovery period prior to dosing with the test
article or vehicle. The total dosage is given. Each animal will receive two injections of FGF-1, one injection in the general area of the ischemic insult and one injection in healthy heart tissue. Group 2 will receive two injections of 0.02 mg/kg
FGF-1 and group 3, two injections of 0.2 mg/kg FGF-1. The injections of the vehicle or test article will be made directly into the cardio-ventricular wall via a mini-thoracotomy. The volume of each injection will be 0.25 ml and will contain the
growth factor and heparin in a physiologic saline solution. The amount of heparin in each injection will at a fixed ratio of 1000 IU heparin/mg FGF-1, the same as will be used in the proposed clinical trial. The Sponsor will include the heparin in
each dose and in the vehicle. Both the high and low dose of heparin will be represented in the vehicle groups. 
  
 Cardiovascular Measurements: 
  

	1.	Angiograms: A total of 4 angiograms will be performed on each dog including a base-line angiogram, one after the ischemic insult, one after dosing of vehicle or test substance and
one prior to necropsy. 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 3 of 12

  

	2.	Electrocardiograms (ECG’s): Baseline prior to procedure, post coronary occlusion, prior to dose administration, and post administration 3-5 days, and prior to necropsy,

  
 Blood Draws For Assays: Blood will be drawn at the
following times to permit measurement of assays to assess cardiac damage and for PK studies by the Sponsor. Pre-ischemic time point, post-ischemic time points at 7 days, and post-dosing time points of: 30 min, 1, 3, 6, 24 hours, day 3 and 7 and then
weekly during the post-dose observation period. Blood will be obtained via the jugular or other suitable vein and shipped on dry or wet ice to 1) contract lab to perform the cardiac enzyme assays, and 2) Sponsor. A 2.5 ml sample in serum separator
tube. The Sponsor will be notified before any samples are shipped to verify the number of samples to be analyzed. 
  
 The following cardiac enzyme assays will be diagnosed: 
  

					
	 l.Creatine phosphokinase
	  	Shipped frozen to Ani-	  	 
	 (CK)
	  	Lytics	  	 
	 Total [creatine kinase]
	  	 	  	 
	 Cardiac [CK(MB)]
	  	 	  	 
			
	 2. Lactate Dehydrogenase
	  	 	  	 
	 (LDH)
	  	Shipped on wet ice to Ani-	  	 
	 Total [Lactate
	  	Lytics	  	 
	 Dehydrogenase]
	  	 	  	 
	 Cardiac [LDH (CH4)]
	  	 	  	 

  
 Clinical Blood Draws:

  
 The following blood samples will be collected: 
  
 CBC, Clinical Chemistry. 1.8ml serum separation, and 0.5ml EDTA sample will be taken.

  
 Timepoints: Prior to surgery, post ischemia, day 1 post test article
administration, and pre-necropsy. 
  
 Parameters: Kidney- BUN, and Creatinine.
Liver- ALT, AST, Alkaline phosphatase, and total Bilirubin. 
  
 Eye
examinations: The eyes of all animals will be examined using an indirect ophthalmoscope and slit lamp microscope to check for any signs of angiogenesis in the eyes. The examinations will be performed prior to dosing and prior to necropsy.

  
 Rationale for using animals: 
  
 Written Narrative Description for Alternatives to Painful
Procedures...References: Animal Welfare Act section 3(a)(B) and 9CFR, and Part 2 section 2.31(d, 1, and ii). 
  

	 	a.	Animal Species: 

  
 This product requires evaluation of using in vivo model, as its anticipated use will be in humans. Dogs are an established animal species for
cardiovascular and pharmacokinetic studies. There are no alternatives to intact animal models in conducting myocardial infarction studies such as these. A MedLine search of over 11 million citations revealed no similar studies have been performed in
the past. 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 4 of 12

  

	 	 
pharmacokinetic studies. There are no alternatives to intact animal models in conducting myocardial infarction studies such as these.

  

	 	b.	Number of Animals: Thirty seven animals is the minimum needed to show statistical significance, and allows 6 additional animals for experimental error associated with this
model. 

  

	 	c.	Level of Discomfort and/or Pain: Please check one of the following. 

  

	 	 ̈	B. very low, temporary pain or discomfort 

  

	 	x	C. Short term pain and/or discomfort (surgical procedure-use of analgesic, anesthetic and tranquilization drugs to eliminate or minimize discomfort and pain)

  

	 	 ̈	D. chronic pain (anesthetics and analgesic to be provided) 

  

	 	 ̈	E. procedures with the involvement of pain (where pain can not be eliminated) 

  

	 	d.	If C,D&E of section c are chosen have you looked at alternatives and if no alternatives give explanation?( Narrative Description Needed) 

  

	4.	TEST SYSTEM: The procedure described will be performed in accordance to the Standard Operating Procedure of the Test Facility. 

  

	 	A.	Animals: Animals may be referred to by tattoo, species, or animal number in study file. 

  
 Common Name: Dog (beagle) 
 Species: Canis familiaris 
 Number of Males: 21 
 Number of Females: 16 
 Age of Onset: Documented on file 
 Weight at Onset: Documented on file 
  

	 	B.	Source: Animals will be obtained from test facilities certified vendors and will be documented on study file. 

  

	 	C.	Quarantine: Animals will be quarantine for seven days, and released by the veterinarian after physical exam. 

  

	 	D.	Randomization: Randomization of animals for treatment will be done by random number selection. 

  

	 	E.	Identification: Each animal will be identified tattoo. That will also be posted outside the animals cage and/or enclosure. 

  

	 	F.	Disposition of Animals: At the conclusion of the study the animals be euthanized in accordance with the AVMA panel on Euthanasia, 2l8 (5): 668-696, 2001.

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 5 of 12

  

	5.	ANIMAL CARE PROCEDURE: The procedures described and performed below will be conducted in accordance with the Guide for the Care and Use of Laboratory Animals, USDA APHIS,
Animal Welfare Act and/or in accordance with the Standard Operating Procedures of DaVinci Biomedical Research Prod. 

  
 A. Animal Husbandry and Maintenance: Animals will be individually housed during the test period. During the holding and testing period husbandry
maintenance and environmental conditions will be maintained as in the quarantine period, unless changes are needed which will be noted in the protocol. 
  
 B. Environmental Conditions: The conditions in the room will be maintained as follows: room temperature will be maintained 64-84deg F and the
humidity will range 30-70%, and the room will have 12/12 light/dark cycle. 
  
 C. Water: Tap water will be provided to the animals ad libitum (unless the animal is being fasted. Water analysis will be performed biannually and made available for the study file. Water will be analyzed by an
independent contract facility. The results will include the following: heavy metals, chlorinated hydrocarbons, organophosphates, nitrates, nitrites, total trihalomethanes, dissolved minerals, and a standard plate count. 
  
 D. Diet: LabChows, Lab Diet Certified Canine Chow Brand will be fed
to the animal daily. The lot and expiration will be documented and recorded on file. Chow may differ if specified by sponsor. 
  

	6.	TECHNICAL PROCEDURES: The procedures described will be performed in accordance will the Standard Operating Procedures of DaVinci Biomedical Research Prod. Data collected will
be documented manually. 

  
 A. Body Weights:
Individual body weights will be recorded prior to surgery on the surgery form and prior to necropsy. 
  
 B. Fasting of Animals: All animals will be fasted at least 12-24 hours prior to surgery((NPO) no food or water). 
  
 C. Preoperative Procedure: 
  
 Anesthesia: Each animal will be anesthetized with butorphenol (0.2
mg/kg), acepromazine (0.l mg/kg), and atropine (0.02 mg/kg) IM as a pre-medicated cocktail and then Propofol will be administered at 4 mg/kg IV for anesthesia at a rate of 1 ml/10kg/min prior to surgery preparation. The animal will be immediately
intubated and maintained under anesthesia with inhalant isoflurane anesthetic at 2.5%-4% for induction and 0.5-2.5% for maintenance delivered through either a volume-regulated respirator or rebreathing apparatus. An intravenous catheter will be
placed in a peripheral vessel for 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 6 of 12

  

 
drug administration if needed, and Lactated Ringer solution to be administered at l0ml/kg/hr. If emergency drugs are needed they will be administered through
this line and the drug, dose, route, and site of administration will be documented in the surgical file. 
  
 Surgical Preparation: The animal will be clipped over the femoral artery and will be positioned supine. The operative area will be cleaned with a
three alternating scrubs of povidone-iodine scrub and 70% alcohol, once the alternating scrubs are done a final application of povidone-iodine solution will be applied and allowed to dry. (the area will be draped for aseptic surgery). 
  
 D-1. Surgical Procedure: 
 Induced myocardial ischemia: Once the surgical site has been aseptically draped and is prepared for surgery a Slazenger needle will be used to make
an arteriotomy into the femoral artery, upon successful insertion into the artery a guide wire will be introduced through the needle into the artery, the needle will be removed and the introducer will be placed over the guide wire into the artery.
With the use of an Angio-catheter and fluoroscopic guidance the catheter will be advanced up and over the aortic arch and into the ostia and placement will be confirmed by coronary arteriogram with contrast media (MD-76, Mallinkrodt Medical) of the
left coronary artery. A guide-wire will be used to advance into the circumflex artery and an appropriate sized balloon will be used to advance over the guidewire to the position of choice. The balloon will be expanded and the intimal layer of the
artery will be injured, this will be performed by push-pull mechanism. Post injury the balloon will be deflated and withdrawn from the injury site, and will be inflated distally to acquire stasis. Occlusion will occur quickly and a pre and post
ischemic image will be taken. 
  

	 	E.	Postoperative Procedures: Post surgery the surgical sites will be monitored and checked once daily for any evidence of infection, bleeding dehiscence, or swelling.

  

	 	1)	Recovery: The animal will be allowed to recover from anesthesia, and the animal will be extubated when the swallowing reflex has returned. 

  

	 	2)	Postoperative Analgesia: If needed post ischemia insult analgesia will be given. Analgesia will be given post dose administration. In addition to the preoperative
administration of Butorphenol (0.2 mg/kg,IM), a 3 day post surgery regimen of Buprenorphine @0.02 mg/kg BID SC will be given. In some cases additional doses may be needed at the discretion of the facility veterinarian. 

  
 D-2. Route and Rationale of Test Article Administration: 

The route of administration of the FGF-1 will be by two direct injections into the cardio-ventricular wall; one injection will be administered in 0.25
ml of a heparin/saline solution in the general area of the heart that has suffered an ischemic injury. The second injection of 0.25 ml will be in healthy heart tissue. The site of both injections will be marked with a suture. This route of
administration was selected because the test article is intended to be 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 7 of 12

  

 
injected directly into the heart of human patients in order to stimulate new blood vessel formation. 
  
 F. Follow-up Dose Administration: 
  
 Approximately seven days after ischemic insult, the animal
will be Anesthetized in accordance to section 6. C, and either femoral site, and left lateral rib cage will be clipped and prepped for aseptic surgery. Upon surgical preparation and aseptic draping of the animal, an introducer and guide catheter
will be placed as in the initial surgery, a angiogram will be taken of the circumflex artery. Upon completion of the angiogram a thoracotomy will be made between the 4-5 intercostal space to expose the pericardium (prior to thoracotomy bupivacaine
will be administered IM intercostal at a dose of 2mg/kg). The pericardium will be incised and 2-0 suture will be used to harness and elevate heart. The area of insult will be located and the test article or vehicle dose will be administered by
needle puncture into the myocardium. A thoracic catheter will be placed and the intercostal space will be closed with 2-0 non absorbable suture. The catheter will be exteriorized from a separate intercostal space to the subcutaneous space and the
air from the thoracic cavity will be removed using a 60cc syringe. Upon removal of all air the catheter will be removed and the exit site will be closed. 
  
 G. Post operative Observations: Post surgery the animal will be observed once daily for 3-5days for any abnormalities. The animal will be observed
for any abnormalities in: skin, hair, respiratory, lethargy, fecal output, food consumption, dehiscence of surgical sites, edema, infection, and vocalization. All observations will be documented in the study file. If abnormal observations are
evident the study director or the attending veterinarian will be notified immediately. 
  
 H. Animals Found Dead or Moribund: Any animals found with life threatening signs which would indicate that they would not survive until the next observation day will be immediately reported to the study
director or the attending veterinarian. The time of death if applicable will be documented appropriately, and a full necropsy will be performed to evaluate the cause of death. 
  

	7.	Animal Observations: 

  

	 	1)	Cageside observations: Cageside observations will be performed twice daily for mortality and moribundity. 

  

	 	2)	Monitoring Procedures: 

  
 a). Electrocardiogram: Electrocardiogram (ECG) tracings (lead II) will be obtained using the Datascope Passport II. 
  
 b). Direct Blood Pressure and Heart Rate: Heart rate,
and direct blood pressure parameters for MAP, SAP, and DAP will be monitored on day -7 pre and post ischemia formation on day 0 pre and post treatment, and at necropsy pre euthanasia. 
  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	June 7, 2001
Page 8 of 13

  

	8.	SAMPLE COLLECTION: 

  

	 	A.	Blood Collection: Blood samples for PK measurements and cardiac enzyme determinations will be collected, processed for serum, aliquotted, and placed on wet or dry ice for
shipment to the appropriate lab for analysis. PK samples will be sent to the Sponsor, and cardiac enzyme samples will be sent to Analytics Lab, 200 Girard St, Suite 200, Gaithersburg MD 20877. CPK samples will be frozen prior to shipment, and LDH
samples will be shipped on wet ice. The Sponsor will be notified before any samples are shipped to verify the number of samples to be analyzed. 

  

	9.	NECROPSY: 

  

	 	A.	Euthanasia: All dogs euthanized in extremis or surviving until the scheduled necropsy will be anesthetized by an intravenous injection of sodium pentobarbital and
exsanguinated. 

  

	 	B.	Macroscopic Examination: A complete necropsy will be conducted on all animals (whether dying spontaneously or euthanized, in extremis or at the scheduled necropsy).
Animals in Groups 4 and 5 will be necropsied on Day 3, while animals in Groups 1,2, and 3 will be necropsied on Day 28. The necropsy will include examination of the external surface, all orifices, and the oral, cranial, thoracic, abdominal and
pelvic cavities, including contents. The entire epicardial surface of the heart will be examined before opening. Any noticeable gross lesion will be documented. The heart will be opened along the path of normal blood flow (along the length of each
ventricle at the midpoint of each ventricular free wall [right and left]), and through the left and right AV valves into the atria, avoiding any gross lesions. The entire endocardial surface will be examined. The heart will be fixed in toto
in 10% neutral buffered formalin. In addition, highly perfused organs (e.g., lung, liver, kidneys) will be removed and fixed in formalin. Any eyes showing signs of abnormal angiogenesis on ophthalmic exam will be removed and fixed.

  

	 	C.	Microscopic Examination: The fixed heart will be shipped to Mass Histology Service, Worcester, Massachusetts, for preparation and evaluation. Microscopic examination of
hematoxylin and eosin (H & E) stained paraffin sections and/or T.T.C stained sections will be performed on the heart tissue. The heart will be sectioned at trimming. Approximately 6 sections from the ischemic ventricular wall area and 6 sections
from the non-ischemic ventricle wall area will be obtained. In addition, approximately 2 sections from the interventricular septum will be obtained, as well as 1 or 2 sections of each atrium. The site of each injection of the test substance or
vehicle, marked by sutures, will be examined. In addition, an examination to determine whether new blood vessels have formed in the area of test substance injection will be conducted, if feasible. 

  

	10.	VETERINARY SUPPORT: The procedures described below will be performed in accordance with the Test Facility’s Standard Operating procedures. 

  

	 	A.	Concurrent Therapy: In accordance with accepted veterinary practice, the animals may be administered treatment of minor infections, fluid therapy, pain relief, antibiotic
therapy, and any other therapy for which necessity may become evident in the course of 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 9 of 12

  

 A. Euthanasia: If animals are to be euthanized at the conclusion of the project the animals
will be injected with sodium pentobarbital to cause euthanasia, which will be performed in accordance to the American Veterinary Medical Association (AVMA) Panel of Euthanasia, and Journal of the American Veterinary Medical Association, 218 (5):
668-696,2001. 
  

	11.	PROTOCOL CHANGES: If necessary to change an approved study protocol, changes must be made in writing between the study director and the sponsor. The changes and the
justification for the changes must be included in the section which will be replaced, and the new application must be approved by the study director and the sponsor, of which both parties must sign and date. The amendment will be attached to the
protocol. 

  

	12.	STUDY DEVIATIONS: In the case which a deviation from the protocol, and Standard Operating Procedure occurs, the reason for the deviation, the action taken, and the
impact on the study(if any) will be reported by the study director to the sponsor as soon as possible(if a significant impact is evident). 

  

SPONSOR INFORMATION REQUIRED  
  
 SHIPPING: 
  
 Sample Shipping Information 
  

									
	 Type of Sample

	  	When

	  	Conditions-1

	  	Method

	  	 Advance
 Notification-2 Y/N

	 Blood samples
	  	TBD	  	dry ice	  	o/n	  	y

  
 -1Specify condition of shipping,
dry ice, wet ice, cold packs, ambient temperature etc. 
 -1Specify courier © , overnight service (o/n), or standard (std) 
  
 -2Notification of person to receive package specified below. 
  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 10 of 12

  

 Samples shipped to: 
  

			
	Name:	  	Jack Jacobs, Ph.D.
		
	Company:	  	Phage Biotechnology Corp
		
	Address:	  	14272 Franklin Ave
		
	 	  	Suite 110
		
	 	  	Tustin, CA 92780
		
	Phone:	  	714-368-1520
		
	Fax:	  	714-368-1517

  

			
	Records Maintained:
	 Facility Records:

	 	  	Animal room temperature and humidity
	 	  	Water Analysis
	 	  	Feed identification and usage
	 In-Vivo Phases:

	 	  	Animal receipt and disposition
	 	  	Quarantine Data
	 	  	Animal Randomization
	 	  	Fasting
	 	  	Body Weights
	 	  	Surgical Procedures
	 	  	Treatment
	 	  	Animal Observation
	 	  	Monitoring Procedures
	 	  	Sample collection
	
	 Clinical Pathology:

		
	 	  	Clinical Pathology Data
	
	 Pathology Records:

		
	 	  	Pathology data

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 11 of 12

  

 PROTOCOL APPROVAL 
  
 Cardiotoxicity Study of Fibroblast Growth Factor (FGF-1) in Dogs 
  
 DaVinci Protocol Number: DB-19 
  

			
	Sponsor:	  	 Cardio Vascular Genetic Engineering / Phage Biotechnology Corp
 14272 Franklin Ave Suite 110
 Tustin CA 92780

  

					
			
	 /s/ Jack Jacobs
	  	 	  	7-17-01
	 Signature
	  	 	  	Date
			
	 Sponsor Representative
	  	Jack Jacobs, Ph.D.	  	 
			
	 Facility Performing
	  	DaVinci Biomedical Research ProdTM	  	 
	 Project:
	  	40 Maple Ave	  	 
	 	  	So. Lancaster, MA 01561	  	 
			
	 /s/ Mario Pio Villani
	  	 	  	7-17-01
	 Signature
	  	 	  	Date
	 Mario Pio Villani
	  	 	  	 
	 Study Director
	  	 	  	 

  

			
	 DaVinci Biomedical Research ProdTM
 Cardiotoxicity Study of
Fibroblast Growth Factor (FGF-1) in Dogs
 Study Number: DB-19
	  	July 13, 2001
Page 12 of 12

  

 IACUC COMMITTEE REVIEW: 
  

			
	 CHAIRMAN:                                    
                                        
                            
	  	TODAY’S
DATE:                        
		
	 VETERINARIAN:                                    
                                        
                
	  	TODAY’S
DATE:                        
		
	 THIRD COMMITTEE MEMBER:                                
                                       
 
	  	TODAY’S
DATE:                        
		
	 FOURTH COMMITTEE MEMBER:                                
                                       
 
	  	TODAY’S
DATE:                        

  

  
 Total Revised GLP:
$237,433.75 
  
 TERMS & CONDITIONS 
  

			
	 Comments:
	 	For Pathology: If you would like Digital or standard pictures, for future reference, please, advice. Pathology will be conducted on all abnormal findings when other organs are viewed during
necropsy. This may increase costs!
		
	 Charges:
	 	1) A change in procedure, quantities, protocol, abnormalities and time needed, et. may also change costs. We normally do not change cost for minor changes. They would have to be
significant!
		
	 Time:
	 	Per discussion and agreement between Mr. J. Villani of DaVinci and Dr. Jack Jacobs. Note: The sooner it is known, when the project will begin, the better it will be to schedule canines to be
delivered and set-up in there own holding room!
		
	 Terms:
	 	Payment of 50% prior to procedures and 50% upon completion.
		
	 Cancellation Policy:
	 	In the event that the sponsor can not perform the project on the day scheduled and needs to cancel the date, a cancellation fee of $1,500 per day will be charged to the sponsor unless
cancellation of day is conveyed two weeks in advance. In the event that the project is canceled, all Animals, material purchased for project, labor, et, will be charged to client.

  

					
	DaVinci Biomedical Research Products, Inc.	 	 	 	 
			
	 Mr. Joseph Villani:
	 	 /s/ Joseph Villani
	 	7/13/01
	 Sales Executive
	 	Signature	 	Date
			
	 Mr. Mario Pio Villani:
	 	 	 	___________________
	 Surgical Specialist
	 	Signature	 	Date
			
	 Dr. Jack Jacobs:
	 	 /s/ Jack Jacobs
	 	7/13/01
	 Project MGR
	 	Signature	 	Date

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