EXHIBIT 10.16
AGREEMENT
This agreement effective as of the 1st day of February, 1991, between
Photoelectron Corporation, a corporation of the Commonwealth of Massachusetts,
having a principal place of business at 000 Xxxxxx Xxxxxx, Xxxxxxx,
Xxxxxxxxxxxxx 00000 (hereinafter "PHOTOELECTRON"), and The General
Hospital Corporation, doing business as Xxxxxxxxxxxxx Xxxxxxx Xxxxxxxx, Xxxxx
Xxxxxx, Xxxxxx, Xxxxxxxxxxxxx 00000 (hereinafter "GENERAL")
WITNESSETH;
WHEREAS, PHOTOELECTRON has developed a miniaturized x-ray generator
("DEVICE") which has potential application in the treatment of tumors;
WHEREAS, GENERAL through Xx. Xxxxxxxx Xxxxxx and others, has developed
certain scientific and clinical information and expertise pertaining to the
treatment of tumors and the use of animal models for evaluation of instrument
efficacy;
WHEREAS, GENERAL wishes to perform certain tests with the DEVICE in
animal models and PHOTOELECTRON desires that it do so;
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NOW THEREFORE, in consideration of the premises and of the faithful
performance of the covenants herein contained, the parties hereto agree as
follows:
1. DEFINITIONS
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1.1 The term "PROJECT" shall mean the animal studies described in the
Protocol attached hereto as Appendix A.
1.2 The term "PRINCIPAL INVESTIGATOR" shall mean Xx. Xxxxxxxx Xxxxxx.
1.3 The term "INVESTIGATOR" shall mean PRINCIPAL INVESTIGATOR and any
other member of GENERAL's professional staff, graduate student, postdoctoral
fellow, undergraduate student, or employee of GENERAL who shall participate
under the direction of the PRINCIPAL INVESTIGATOR in the performance of PROJECT.
1.4 The term "RESULTS" shall mean any test results, data, and other
information produced in the performance of PROJECT.
2. OBLIGATIONS OF GENERAL AND PHOTOELECTRON
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(a) During the term of this Agreement, GENERAL shall:
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(i) through PRINCIPAL INVESTIGATOR and any other INVESTIGATOR
perform PROJECT;
(ii) promptly and systematically disclose to PHOTOELECTRON the
RESULTS, which PHOTOELECTRON shall be entitled to use to the
extent such use does not infringe any patent assigned or
licensed to GENERAL which is not assigned to PHOTOELECTRON.
(b) During the term of this Agreement, PHOTOELECTRON shall:
(i) provide GENERAL with DEVICE;
(ii) provide INVESTIGATORS with information and instruction
pertaining to DEVICE as needed to perform the PROJECT;
(iii) repair and maintain DEVICE as needed at GENERAL to assure its
proper functioning in the performance of the PROJECT.
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(iv) to facilitate INVESTIGATORS' performance of the PROJECT,
PHOTOELECTRON shall, subject to the approval of the PRINCIPAL
INVESTIGATOR, have the right to be present at the animal studies
hereunder.
3. CONFIDENTIALITY AND PUBLICATION RIGHTS
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GENERAL cannot assure confidential treatment of any PHOTOELECTRON
proprietary information that might be disclosed to GENERAL or any
INVESTIGATOR, or of RESULTS. In the event that PHOTOELECTRON wishes to disclose
to an INVESTIGATOR any information which relates to PROJECT that PHOTOELECTRON
considers confidential, PHOTOELECTRON may enter into a separate Confidentiality
Agreement with the INVESTIGATOR. Such Confidentiality Agreement must be approved
as to form by the Director, Office of Technology Affairs at GENERAL and shall
provide a means for clearly identifying the information PHOTOELECTRON considers
to be proprietary and not abridge GENERAL's or the INVESTIGATOR's traditional
rights to publish and communicate with academic colleagues regarding the results
of research conducted at GENERAL. Without limiting the generality of the
foregoing, it is understood and acknowledged that the PRINCIPAL INVESTIGATOR has
entered into a Confidentiality
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Agreement with PHOTOELECTRON, dated November 1, 1989 which is acceptable to
GENERAL.
PRINCIPAL INVESTIGATOR shall have the right to present or publish RESULTS
and shall provide an early draft of any such presentation or manuscript for
review by PHOTOELECTRON at least thirty (30) days prior to its presentation or
submission for publication. At the end of such thirty (30) days, PRINCIPAL
INVESTIGATOR shall have the right, in his/her discretion, to make such
presentation or to submit such manuscript for publication. PRINCIPAL
INVESTIGATOR and PHOTOELECTRON shall cooperate in identifying and removing any
previously identified information which is proprietary and confidential to
PHOTOELECTRON, as appropriate. It is understood, however, that GENERAL shall not
be responsible for any INVESTIGATOR's failure to remove such PHOTOELECTRON
proprietary and confidential information. Proper reference will be given to
PHOTOELECTRON as the developer of the DEVICE.
4. INVENTIONS
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Any INVESTIGATOR who shall make an invention, solely or jointly, in the
performance of PROJECT (hereinafter referred to as INVENTION) shall promptly
report in writing such INVENTION to PHOTOELECTRON and GENERAL and shall, upon
written request of PHOTOELECTRON given within ninety (90) days of
PHOTOELECTRON's
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receipt of such report, assign all of his or her rights, title and interest in
the INVENTION to PHOTOELECTRON.
5. LIABILITY
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GENERAL and PHOTOELECTRON shall each be responsible and shall hold the
other harmless for any injury to persons or damage to property to the extent
that such injury or damage is caused by the negligence or willful misconduct of
their employees or staff in carrying out the PROJECT; provided, however, that
PHOTOELECTRON will defend, indemnify and hold harmless GENERAL and its trustees,
employees and staff against any and all actions, suits, claims, demands or
prosecutions that may be brought or instituted against GENERAL and/or its
trustees, employees and staff based on or arising out of the manufacture, use,
sale or other distribution of a commercially available device by PHOTOELECTRON,
its affiliates or licensees except to the extent any such action, suit, claim,
demand or prosecution is based on the negligence or willful misconduct of
GENERAL and/or its trustees, employees or staff in the use of such device. In
the event that an assignment of an INVENTION is made pursuant to Paragraph 4
above, the provisions of this paragraph 5 shall be replaced by the provisions of
Appendix B attached hereto.
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6. TERM AND TERMINATION
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6.1 This Agreement shall have a term of one year beginning with the
EFFECTIVE DATE of this Agreement and may be extended thereafter by mutual
agreement.
6.2 If either party shall fail to faithfully perform any of its
obligations under this Agreement, the nondefaulting party may give written
notice of the default to the defaulting party. Unless such default is corrected
within thirty (30) days after such notice, the notifying party may terminate
this Agreement upon thirty (30) days prior written notice.
7. MISCELLANEOUS
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7.1 Each party agrees that it will not use the name or logo of the other
party or of any employee, staff member or student of the other party in any
advertising, promotional material or sales literature, or any other publication
without the prior written approval of the party or person whose name or logo is
to be used.
7.2 This Agreement constitutes the entire understanding between the
parties with respect to the subject matter thereof, and supersedes and replaces
all prior agreements, understandings, writings and discussions between the
parties relating to said subject matter.
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7.3 This Agreement may be amended and any of its terms or conditions may
be waived only by a written instrument executed by the parties or, in the case
of a waiver, by the party waiving compliance.
7.4 The obligations of the parties under Sections 3, 4, 5 and 7.1 shall
survive the termination of this Agreement.
7.5 This Agreement shall be governed by and construed and interpreted in
accordance with the laws of the Commonwealth of Massachusetts.
THE PARTIES have duly executed this Agreement to be effective as of the
date first above written.
PHOTOELECTRON CORPORATION THE GENERAL HOSPITAL CORPORATION
BY: /s/ Xxxxx X. Xxxxxxx BY: /s/ Xxxxxx X. Xxxxxxx
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TITLE: C.E.O. TITLE: Director Office of Technology Affairs
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DATE: Feb. 19, 1991 DATE: Feb. 8, 1991
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I have read paragraph 3 of the foregoing Agreement and agree to comply
therewith.
By: /s/ Xxxxxxxx Xxxxxx, M.D.
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Name: Xxxxxxxx Xxxxxx, M.D. Date: 2/12/91
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APPENDIX B
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9(a) PHOTOELECTRON shall indemnify, defend and hold harmless GENERAL and
its trustees, officers, medical and professional staff, employees, and agents
and their respective successors, heirs and assigns (the "Indemnities"), against
any liability, damage, loss, or expense (including reasonable attorney's fees
and expenses of litigation) incurred by or imposed upon the Indemnities or any
one of them in connection with any claims, suits, actions, demands or judgments:
(i) arising out of any theory of product liability (including, but not limited
to, actions in the form of tort, warranty, or strict liability) concerning the
DEVICE or any modification thereof; (ii) arising out of any side effect or
adverse reaction, illness or injury resulting from Indemnities' performance of
the Study and occurring to any person involved in the Study; or (iii) arising
out of damage to any property resulting from and occurring during the
Indemnities' performance of the Study. GENERAL agrees to notify PHOTOELECTRON
promptly of any such claim, suit, action, demand or judgment and GENERAL and
PRINCIPAL INVESTIGATOR agree to reasonably cooperate with PHOTOELECTRON in the
handling thereof.
(b) PHOTOELECTRON's indemnification under (a)(i) shall apply to any
liability, damage, loss or expense whether or not it is attributable to the
negligent activities of the indemnitees. PHOTOELECTRON's indemnification under
(a)(ii) and (a)(iii) shall
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not apply to any liability, damage, loss or expense to the extent that it is
attributable to the: (A) negligent activities, reckless misconduct or
intentional misconduct of the Indemnities, or (B) failure of the indemnitees to
adhere to the terms of the protocol for the Study.
(c) PHOTOELECTRON agrees, at its own expense, to provide attorneys
reasonably acceptable to the GENERAL to defend against any actions brought or
filed against any party indemnified hereunder with respect to the subject of
indemnity contained herein, whether or not such actions are rightfully brought.
10. (a) At such time as DEVICE or any modification thereof is being
commercially distributed or sold (other than for the purpose of obtaining
regulatory approvals) by PHOTOELECTRON or by a licensee, affiliate or agent of
PHOTOELECTRON, PHOTOELECTRON shall, at its sole cost and expense, procure and
maintain comprehensive general liability insurance in amounts not less than
$2,000,000 per incident and $2,000,000 annual aggregate, and naming the
Indemnitees as additional insureds. Such comprehensive general liability
insurance shall provide (i) product liability coverage and (ii) broad form
contractual liability coverage for PHOTOELECTRON's indemnification under
Paragraph 9 of this Agreement. If PHOTOELECTRON elects to self-insure all or
part of the limits described above (including deductibles or retentions which
are in excess of $250,000 annual aggregate) such self-
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insurance program must be acceptable to the GENERAL and the Risk Foundation
Foundation of the Harvard Medical Institutions, Inc. The minimum amounts of
insurance coverage required under this Paragraph 10 shall not be construed to
create a limit of PHOTOELECTRON's liability with respect to its indemnification
under Paragraph 9 of this Agreement.
(b) PHOTOELECTRON shall provide GENERAL with written evidence of such
insurance upon request of GENERAL PHOTOELECTRON shall provide GENERAL with
written notice at least fifteen (15) days prior to the cancellation, non-renewal
or material change in such insurance.
(c) PHOTOELECTRON shall maintain such comprehensive general liability
insurance during (i) the period that the DEVICE or any modification thereof is
being commercially distributed or sold (other than for the purpose of obtaining
regulatory approvals) by PHOTOELECTRON or by a licensee, affiliate or agent of
PHOTOELECTRON and (ii) a reasonable period after the period referred to in
(c)(i) above which in no event shall be less than fifteen (15) years.
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Appendix A
What we are proposing to test in this pilot study is the effect on tumor
growth of a new device; a Free Electron X-Ray emitter.
The addition would be to Xx. Xxxxxxx existing protocol "Genetic
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Alteration of Nervous System Tumors". It would be an increase of 20 rats to
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Xx. Xxxxxxx'x current protocol. The additional rats would be used to determine
the effects of the irradiation, a dose response curve, and the associated
effects on adjacent tissues. Four groups of five would be used for initial dose
response estimates. Animals in each group would receive a set dose (X, 2X, 5X,
10X 50X).
Scheme: Day 1 (X-ray Irradiation). Immediate Sacrifice
Week 1 Group 2 Sacrifice
Week 2 Group 3 Sacrifice
Week 3 Group 4 Sacrifice
The X-ray source is effectively a point source at the tip of a probe
(approx 15 gauge needle). The new x-ray source is manufactured by Photoelectron
Corporation and has been reviewed by the research Patent Office.
Briefly, under anesthesia, the tumor site would be exposed as outlined in
Xx. Xxxxxxx'x protocol. The x-ray source would be positioned center mass of the
tumor, and activated for various periods of time. The animal would either be
sacrificed immediately, or surgically closed and allowed to recover for up to 3
weeks. The effects of the irradiation would be evaluated both grossly (visual
sub-renal capsule assays) and by histology for changes in tumor mass and
surrounding tissues. No pain or additional distress is expected. Animals will be
sacrificed with an anesthetic overdose as indicated.
Depending the initial results, a complete application would be submitted to
the SRAC to continue the studies.
January 27, 1992
Xx. Xxxxxx X. Xxxxxxx
Director, Office of Technology Affairs
Massachusetts General Hospital
Fruit Street
Boston, Massachusetts 02114
Re: Extension of Term of Agreement of February 1, 1991
Between Photoelectron Corporation and The General Hospital
Corporation (MGH)
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Dear Xx. Xxxxxxx
Pursuant to the above-referenced Agreement Xx. Xxxxxxxx Xxxxxx and other
members of the staff of MGH are performing animal studies in which an X-ray
source supplied by Photoelectron is being utilized to irradiate live animal
tissue. In order to complete ongoing studies, the parties desire to extend the
one year term currently specified in the Agreement. The Protocol should also be
amended to reflect the fact that MGH has conducted animal studies in
addition to those set forth in Appendix A as initially written.
Accordingly, the parties agree to amend the Agreement of February 1, 1991 as
follows:
1. The single sentence of Paragraph 6.1 is amended to read "This Agreement
shall have a term of eighteen (18) months beginning with the EFFECTIVE DATE of
this Agreement and may be extended thereafter by mutual agreement."
2. Appendix A is amended by deleting the current Appendix A and
substituting for it the document titled "Appendix A (1/27/92)", attached to and
forming part of this letter agreement.
3. Except as amended pursuant to the above-noted paragraphs 1. and 2. of
this letter agreement, all provisions of the Agreement shall remain in effect as
written.
If you agree with these amendments, please have the appropriate official of
MGH sign and date both originals of this letter in the spaces below, keep one
for your records, and return the other original to me.
Xx. Xxxxxx X. Xxxxxxx
January 27, 1992
Page 2
Thanks for your efforts. We look forward to continued cooperation and
success in these studies.
Sincerely,
PHOTOELECTRON CORPORATION
/s/Xxxxx X. Xxxxxxx
Xxxxx X. Xxxxxxx
President and
Chief Executive Officer
Accepted and agreed:
The General Hospital
By:/s/ Xxxxxx X. Xxxxxxx
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Typed/Printed
Name: Xxxxxx X. Xxxxxxx
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Title: Director Office of Technology Affairs
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Date: 20 March 1992
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60C
Appendix A 1/27/92
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This pilot study is performed to provide data on the safety in use of, and the
radiative and thermal effects caused by, a new x-ray source. This source is
effectively a point source at the top of a thin probe. The device is
manufactured by Photoelectron Corporation and has been reviewed by the Research
Patent Office.
A series of on-going animal experiments has been, and is continuing to be,
conducted in rats and dogs. A total of 13 livers of rats were irradiated in
vivo. Surgery to expose the rat liver was performed in the neurosurgery animal
laboratory at the Massachusetts General Hospital in Boston. Livers were selected
for treatment because this organ is known to be easily accessible, relatively
large, and resistant to radiation. The probe, held firmly in a stand, was
inserted between the lobes of the liver. Continual flow of a small quantity of
saline solution along the outside of the probe lubricated the tip to eliminate
frictional damage to the liver due to the relative motion, caused by breathing,
between this organ and the probe. To insure material biocompatibility, the probe
was covered by a thin latex finger cut from a surgical glove.
In the first set of experiments, nine livers were irradiated, three of which
were for 1, 2, and 3 hours with x-rays generated by a 10 uA electron beam
accelerated in the probe to the maximum voltage of 30 kV. Similarly, three more
exposures were performed for the same durations but with beam parameters of 20kV
and 15uA, and the last three at 15 kV and 23 Micro Amphs.
In the 30 kV and 20 kV tests, x-ray emission was sufficiently intense near the
probe surface to produce small lesions by the end of the treatment. All rats
were sutured after irradiation. Those irradiated by x-rays generated with the 30
kV, 10 Micro Amphs electron beams for 1, 2 and 3 hours were sacrificed,
respectively after 7, 10 and 13 days. Complete tissue necrosis was observed in a
region around the probe ranging in diameter from 5mm for the shortest radiation
time to 10 mm for the longest. A sharp demarcation was noted between the
necrotic and normal tissues with little inflammatory response in the periphery.
In one experiment (rat irradiated for 3 hours with x-rays generated by the 20
kV, 15 Mirco Amphs beam) a thermometer was placed in contact with the probe.
During the treatment, a stable maximum rise in temperature of 9.5C was measured
(from an initial value 31C). With a saline drip of 1 drop each 2 minutes along
the probe, this increase fell slightly to 8C.
Subsequently, 3 more livers of rats were irradiated, each for 3 hours with x-
rays generated by a beam with higher current of 25 Micro Amphs accelerated to
the maximum voltage of 30 kV. These rats were sutured, and two died within the
next 11 days. The last one was sacrificed after 13 days and a similar 6-7 mm
diameter lesion was observed to have formed. In comparison to the previously
studied animal the size of this lesion was smaller than expected. A final liver
was irradiated at the same conditions as the three previous animals were. This
animal died within 3 hours of irradiation, apparently due to complications
caused by the anesthesia. An 8-9 mm lesion was seen with incomplete necrosis.
Rat C6 glioma cells were seeded subcutaneously in order to provide a test
vehicle for studying the effects of probe irradiation of tumors. Although
several tumors did grow most spontaneously regressed and disappeared before any
x-ray treatment
was performed. However, it was possible to place the probe tip in contact with
one such tumor and using a 25 Micro Amphs electron beam accelerated to 30 kV x-
rays were generated for 2 hours. However, the animal died from anesthesia
complications. Tissue necrosis was observed throughout the tumor, including
within areas not irradiated by the probe, suggesting that tumor cells were being
destroyed by the rat's immune system.
A total of 4 dog brains were irradiated by the x-ray probe. Three of these were
acute dogs, sacrificed right after treatment, which had primarily been used in
other experiments. The objective of irradiating these brains was to determine
the degree to which hyperthermia might be generated by heat dissipation from the
probe.
In 2 of the dogs the probe was intradural and placed in contact with the exposed
cortex. The source was operated for 1 hour with a 25 Micro Amphs electron beam
accelerated to 30 kV. Temperature rise, as measured by a thermistor
(manufactured by Yellow Springs) placed 1-2 mm from the probe, recorded an
increase of 7 and 8C, respectively, from a starting 32 C for the 2 dogs.
Pathological examination showed no changes. In the third dog the probe was
inserted 5 mm into the brain tissue. With the source operating at the same
conditions as for the other two dogs, the thermistor measured an increase of 6C
from an initial temperature of 32 C at 1-2 mm from the probe. Subsequent
pathology tests showed no formation of necrotic tissue. Accordingly, from the
results of these three dog experiments hyperthermia should not be a contributing
process to tissue necrosis during use of the x-ray source.
A chronic fourth dog was exposed to the x-ray source operating at the same
conditions with the probe tip inserted 1.5 cm into the right lobe
(mid-frontal). From air measurements and MCNP code predictions the dose at 1 cm
from the probe center was determined to be 850 rads. This dog was sutured after
treatment and sacrificed after 1 day because it had become comatose and
hypothermic and had experienced seizures on the contralateral side. Pathological
examination revealed that in all likelihood the hypothalmus and possibly the
thalmus had been affected by the proximity of the probe to these glands. The
area around the probe showed signs of hemorrhage.
A total of 5 dog livers were irradiated by the x-ray probe. The conditions at
which the probe was operated were 30 kV, 15 Micro Amphs, 1 hour (except one
which was irradiated for 45 minutes). Two dogs were acute, and one of these (the
one irradiated for 45 minutes) provided data on temperature rise in liver tissue
caused by thermal dissipation from the target in the probe. Thermistor
measurements 1 mm from the probe inserted 7 mm into the liver recorded a stable
increase of 2.5 C after 10 minutes, from an initial temperature of 34.5 C. After
the probe was turned off the temperature returned to its initial value.
Two other dogs were chronic, and the first of these, which had the probe
inserted 2 cm into its liver, was sacrificed after 3 days. Pathological
examination showed coagulation necrosis and hemorrhage around the probe hole,
but no radiation-induced necrosis. The other dog was irradiated on June 11, 1991
and sacrificed at the end of August. In this dog, the probe had been inserted at
one site 2 cm from a hepatic artery, and sequentially at a second site as well.
Each irradiation was for 1 hour. Blood samples were taken every two days to
monitor liver function. No abnormalities were observed. Pathological examination
showed well defined cell changes within a 7-9 mm diameter area of tissue. The
fifth dog
irradiated in mid July was sacrificed after three months. Little necrosis was
observed.
Recent measurements have provided thermal profiles, along radii outward from the
probe tip, in three acute dog brains. One chronic dog liver was irradiated and
another will be done to determine if there are any long term damaging effects
due to the observed minor hyperthermia. A few additional tests, radiative and
thermal, may be performed in rats, rabbits, or dogs, as necessary.
Briefly, under anesthesia, the animal tissue is exposed according to accepted
protocols. The x-ray source is positioned with the tip either between lobes of
the liver or within liver or brain tissue and activated for various periods of
time (one to three hours). The animal is sacrificed either immediately, or
surgically closed and allowed to recover for up to three months. The effects of
irradiation are evaluated both grossly and histologically. No pain or
additional distress is expected to the animal. Animals are sacrificed with an
anesthetic overdose.
