Document:

Exhibit 10.1 

 

Amendment
#1

 

Cooperative
Research and Development Agreement # 02734

 

“Cooperative
Research and Development Agreement for the

Development
and Evaluation of the NCI Proprietary Adoptive Cell

Transfer
Immunotherapy Using Tumor Infiltrating Lymphocytes in

Patients
with Metastatic Melanoma, Utilizing Genesis Biopharma’s

Business
Development Expertise in Adoptive Cell Transfer

Immunotherapy”

 

The purpose of this amendment is to change certain terms of
the above-referenced Cooperative Research and Development Agreement (CRADA). These changes are reflected below, and except for
these changes, all other provisions of the original CRADA remain in full force and effect. Two originals of this amendment are
provided for execution; one is to remain with the National Cancer Institute and the other is to remain with the Collaborator.

 

1)     The Collaborator’s name is revised from Genesis
Biopharma, Inc. to Lion Biotechnologies, Inc., with accompanying address corrections; the Collaborator Principal Investigator (PI)
is revised from Anthony J. Cataldo to Elma S. Hawkins, Ph.D., M.B.A.

 

2)     Appendix A - TIL (tumor infiltrating lymphocytes) for
the following cancer indications are added to the Appendix A Research Plan: bladder, lung, triple-negative breast, and HPV-associated
cancers. Appendix A is also amended for the NCI Surgery Branch to send fresh melanoma, bladder, lung, triple-negative breast, and
HPV-associated cancer tumor specimens collected under NCI protocol 03-C-0277 entitled “Cell Harvest and Preparation for Surgery
Branch Adoptive Cell Therapy Protocols” to Lion or its agents for performing studies of improved TIL selection and/or for
studies related to TIL scale-out production and process development.

 

3)     Appendix B the Collaborator’s yearly funding is
increased to $2,000,000.00 per year, with quarterly payments of $500,000.00 (except for the first payment which is $250,000 prorated
from the amendment execution date to 2/4/15). Appendix B is also amended to add the NCI Surgery Branch’s contribution of
melanoma, bladder, lung, triple-negative breast, and HPV-associated cancer specimens to Lion or its agents for studies under this
CRADA.

 

5) Appendix C — Section 8.8 and a definition for “Multi-Party
Data” is added, along with accompanying revisions to Section 7.2 and 7.6 licensing provisions; Section 13.9 is revised to
add language relating to the use of Collaborator’s agents, contractors or consultants.

 

SIGNATURES
BEGIN ON THE NEXT PAGE

 

    	 

    	 

    

 

	ACCEPTED AND AGREED TO:	 	 
	 	 	 
	For the National Cancer Institute	 	 
	 	 	 
	/s/ JAMES H. DOROSHOW	 	1/16/2015
	James H. Doroshow, M.D.	 	Date
	Deputy Director for Clinical and Translational	 	 
	Research, NCI	 	 
	 	 	 
	For Collaborator:	 	 
	 	 	 
	/s/ ELMA S. HAWKINS	 	1/22/2015
	Elma S. Hawkins, Ph.D., M.B.A.	 	Date
	Chief Executive Officer	 	 

 

    	 

    	 

    

 

PUBLIC
HEALTH SERVICE

 

COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-PHS
CLINICAL RESEARCH

 

This Agreement is based on the model Cooperative Research and
Development Agreement (“CRADA”) adopted by the U.S. Public Health Service (“PHS”) Technology Transfer Policy
Board for use by components of the National Institutes of Health (“NIH”), the Centers for Disease Control and Prevention
(“CDC”), and the Food and Drug Administration (“FDA”), which are agencies of the PHS within the Department
of Health and Human Services (“HHS”).

 

This Cover Page identifies the Parties to this CRADA:

 

The U.S. Department of Health and Human
Services, as represented by the

National Cancer Institute

an Institute, Center, or Division (hereinafter
referred to as the “IC”) of the

National Institutes of Health

 

and

 

Lion Biotechnologies, Inc.

hereinafter referred to as the “Collaborator”,

having offices at 21900 Burbank Blvd.,
3rd Floor, Woodland Hills, CA 91367

created and operating under the laws of
Nevada.

 

	PHS ICT-CRADA	CRADA
    Ref. No. 02734	MODEL ADOPTED June 18, 2009
	Page 1 of 15		Confidential

    	 

    	 

    

 

CONTACTS
INFORMATION PAGE

 

CRADA Notices

 

	For ICD:	For Collaborator:
	 	 
	Technology Transfer Center, NCI	Lion Biotechnologies, Inc.
	6120 Executive Blvd., Suite 450 	21900 Burbank Blvd., 3rd Floor
	Rockville, MD  20852	Woodland Hills, CA  91367
	Tel.  301-496-0477	Tel.  818-992-3126
	Fax: 301-402-2117	www.lionbio.com

 

Patenting and Licensing

 

	For ICD:	For Collaborator (if separate from above):
	 	 
	Division Director, Division of Technology	Peter D. Ho, Ph.D., M.B.A.
	Development and Transfer	Director, Business Development
	NIH Office of Technology Transfer	Lion Biotechnologies, Inc.
	6011 Executive Boulevard, Suite 325	21900 Burbank Blvd., 3rd Floor
	Rockville, Maryland 20852-3804	Woodland Hills, CA  91367
	Tel:  301-496-7057	Tel.  818-992-3126
	Fax:  301-402-0220	 

 

Delivery of Materials Identified In Appendix
B (if any)

 

	For ICD:	For Collaborator:
	 	 
	Steven A. Rosenberg, M.D., Ph.D.	Elma S. Hawkins, Ph.D., M.B.A.
	Surgery Branch, NCI	Clinical Development
	10 Center Drive, MSC 1201	Lion Biotechnologies, Inc.
	Bldg. 10, CRC Room 3-3940	21900 Burbank Blvd., 3rd Floor
	Bethesda, MD  20892-1201	Woodland Hills, CA  91367
	Tel. 301-496-4164	Tel.  646-775-4817
	Fax: 301-402-1738	 

 

	PHS ICT-CRADA	CRADA Ref. No. 02734	MODEL ADOPTED June 18, 2009
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SUMMARY PAGE

 

EITHER PARTY MAY, WITHOUT FURTHER CONSULTATION
OR PERMISSION, 

RELEASE THIS SUMMARY PAGE TO THE PUBLIC.

 

TITLE OF CRADA:            Cooperative
Research and Development Agreement for the Development and Evaluation of the NCI Proprietary Adoptive Cell Transfer Immunotherapy
Using Tumor Infiltrating Lymphocytes in Patients with Metastatic Melanoma, Bladder, Lung, Triple-negative Breast, and HPV-associated
Cancers, Utilizing Lion Biotechnologies’ Business Development Expertise in Adoptive Cell Transfer Immunotherapy

 

	PHS [IC] Component:	National Cancer Institute
	 	 
	IC CRADA Principal Investigator:	Steven A. Rosenberg, M.D., Ph.D.
	 	 
	Collaborator:	Lion Biotechnologies, Inc.
	 	 
	Collaborator CRADA Principal Investigator:	Elma S. Hawkins, Ph.D., M.B.A.
	 	 
	Term of CRADA:	Five (5) years from the Effective Date

 

ABSTRACT OF THE RESEARCH PLAN:

 

The principal goal of this CRADA is to develop and evaluate
effective adoptive cell transfer-based immunotherapies (ACT) using Tumor Infiltrating Lymphocytes (TIL), where the ACT/TIL therapy
approach is proprietary to the NCI, for the treatment of patients with metastatic melanoma, bladder, lung, triple-negative breast,
and HPV-associated cancers, utilizing the business development expertise and resources of Lion Biotechnologies, Inc., Specifically
this CRADA will (1) support the in vitro development of improved methods for the large scale generation and selection of
TIL with anti-tumor reactivity from patients with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated
cancers, based on ACT therapies developed by and proprietary to the NCI Surgery Branch, to be used for large scale production of
TIL for the ACT treatment of patients with these cancers; (2) develop these approaches for large scale TIL generation that are
in accord with Good Manufacturing Practice (GMP) procedures suitable for use in treating patients with metastatic melanoma, bladder,
lung, triple-negative breast, and HPV-associated cancers; and (3) develop clinical trials using these improved methods of large
scale TIL generation as well as improved patient preparative regimens with the goal of commercializing the ACT/TIL therapy approach
for treating patients with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT
AGREEMENT

 

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX A

 

RESEARCH PLAN

 

Title of CRADA

Cooperative Research and Development Agreement
for the Development and Evaluation of the NCI Proprietary Adoptive Cell Transfer Immunotherapy Using Tumor Infiltrating Lymphocytes
in Patients with Metastatic Melanoma, Bladder, Lung, Triple-negative Breast, and HPV-associated Cancers, Utilizing Lion
Biotechnologies, Inc.’s Business Development Expertise in Adoptive Cell Transfer Immunotherapy

 

 

NCI Principal Investigator

Steven A. Rosenberg, M.D., Ph.D.

Chief, Surgery Branch

Center for Cancer Research (CCR)

National Cancer Institute (NCI)

 

Collaborator Principal Investigator

Elma S. Hawkins, Ph.D., M.B.A.

Chief Operating Officer, Clinical Development

Lion Biotechnologies, Inc.

 

Term of CRADA

Five (5) years from the date of the final
CRADA signature.

_____________________________________________________________________________

 

Goals
of this CRADA

 

The principal goal of this CRADA is to develop and evaluate
effective adoptive cell transfer-based immunotherapies (ACT) using Tumor Infiltrating Lymphocytes (TIL), where the ACT/TIL therapy
approach is proprietary to the NCI, for the treatment of patients with metastatic melanoma, bladder, lung, triple-negative breast,
and HPV (Human Papilloma Virus)-associated cancers, utilizing the business development expertise and resources of Lion Biotechnologies,
Inc., Specifically this CRADA will (1) support the in vitro development of improved methods for the large scale generation
and selection of TIL with anti-tumor reactivity from patients with metastatic melanoma, bladder, lung, triple-negative breast,
and HPV-associated cancers, based on ACT therapies developed by and proprietary to the NCI Surgery Branch, to be used for large
scale production of TIL for the ACT treatment of patients with these cancers; (2) develop these approaches for large scale TIL
generation that are in accord with Good Manufacturing Practice (GMP) procedures suitable for use in treating patients with metastatic
melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers; and (3) develop clinical trials using these improved
methods of large scale TIL generation as well as improved patient preparative regimens with the goal of commercializing the ACT/TIL
therapy approach for treating patients with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers.
The scope of this CRADA, including any in vitro and in vivo testing conducted by Dr. Steven A. Rosenberg and members
of the NCI Surgery Branch within the CCR is strictly limited to the development of TIL as a single agent therapy in conjunction
with commercially available reagents routinely used for ACT therapy (aldesleukin (IL-2), other chemotherapeutic agents) in treating
patients with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers, utilizing Lion’s expertise
in the large scale production of adoptive cell transfer immunotherapies. Additional research or clinical activities involving current
or prospective NCI Surgery Branch adoptive immunotherapy protocols are outside the scope of this CRADA unless and until the Parties
mutually agree to these studies which shall be added by written amendment to this CRADA.

 

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Expertise
of the Parties

 

Dr. Steven A. Rosenberg has extensive experience in the development
and application of his proprietary adoptive cell-based therapies (ACT) for patients with cancer. His laboratory has developed in
vitro techniques for generating anti-tumor T cells obtained from patient tumors (TIL) under conditions suitable for subsequent
infusion. Dr. Rosenberg and his colleagues in the NCI Surgery Branch have extensive experience in the development of cell-based
reagents and the conduct of clinical trials utilizing these cells in immunotherapeutic protocols.

 

Lion Biotechnologies, Inc. has assembled a team of senior level
scientists and clinicians who have experience in the application of cell-based immunotherapies to help guide the commercial development
of ACT therapy for the treatment of metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers, as
specified in “Goals of this CRADA” (“Goals”) based on the NCI Surgery Branch proprietary technologies for
TIL preparation and administration of ACT to patients. Lion is developing GMP facilities to perform this work emphasizing the development
and evaluation of improved techniques for TIL generation that meet GMP standards as well as to conduct clinical trials of ACT/TIL
therapy designed to meet the standards of the FDA to achieve approval for the commercialization of this treatment approach. Thus
the combination of the scientific and clinical expertise of the NCI Surgery Branch with the scientific and clinical expertise of
Lion, and availability of Lion’s GMP production facilities, represents an ideal opportunity that can lead to the commercialization
of the ACT/TIL treatment approach for patients with those cancers as specified in “Goals”, making these treatments
more widely available to patients in need.

 

The NCI Surgery Branch and Lion thus have complementary expertise
and facilities that can develop technologies and clinical treatment approaches that have the potential to improve cell transfer
therapy and make it more widely available to patients through commercialization by Lion.

 

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Experimental
Plan 

 

The experimental details that follow are approximate and may
be changed upon mutual agreement of the NCI and Collaborator. Any change in the scope of this CRADA will be by mutual consent and
written Amendment to the CRADA. 

 

I.           Develop
improved methods for the generation and selection of TIL with anti-tumor reactivity from patients with metastatic melanoma, bladder,
lung, triple-negative breast, and HPV-associated cancers, as specified in “Goals”,  based on adoptive cell transfer
therapies proprietary to and developed by the NCI Surgery Branch, for use in the large scale production of TIL for this ACT treatment
of these cancers.

 

Simplified and better methods
for TIL selection and growth are needed to supplement current NCI Surgery Branch efforts in order to expand ACT/TIL therapy to
greater numbers of patients with those cancers as specified in “Goals”, Studies of improved methods for TIL selection
will be investigated by the NCI Surgery Branch and Lion. This will include use of in vitro assays of specificity that are
based on specific blocking of Class I MHC (Major Histocompatibility Complex) molecules that can provide evidence for the specific
recognition of autologous tumor and use of sensitive assays of the upregulation of molecules such as 4-1-BB or others on the lymphocyte
cell surface. Such studies in the NCI Surgery Branch may also include the separation of phenotypically different lymphocyte subsets
present in TIL such as central memory, effector memory and terminally differentiated effector cells. NCI Surgery Branch studies
in mice have shown that lymphocyte subsets such as central memory cells can be more effective in the adoptive immunotherapy of
experimental tumors and this needs to be studied in humans with those cancers as specified in “Goals.” In addition,
NCI Surgery Branch may send fresh melanoma, bladder, lung, triple-negative breast, and HPV-associated cancer specimens from NCI
protocol 03-C-0277 entitled “Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols” to Lion
or its agents to develop techniques for growing TIL and for performing assays involving criteria which are designed to improve
TIL selection. Assays will be performed on the growing TIL to evaluate their recognition of autologous tumor cells assessed by
gamma interferon release in overnight co-culture with tumor and to evaluate the phenotypic expression of cell surface markers on
TIL such as CD62L, CD45RO, CD45RA and CD127. Such studies would form the basis for TIL selection and generation for use in the
large scale production of TIL for the treatment of patients with those cancers as specified in “Goals.”

 

II.          Develop
approaches to large scale TIL generation that are in accord with Good Manufacturing Practice (GMP) procedures suitable for their
use in treating patients with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers, as specified
in “Goals”

 

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The selection and growth of autologous
TIL from patients with those cancers as specified in “Goals” is a vital part of the successful use of this approach.
Prior NCI Surgery Branch methods for TIL growth involved extensive in vitro testing using multiple cell lines and fresh
tissue samples as well as the growth of cells in up to 40 2-liter culture bags using large amounts of medium to treat each patient.
Under this CRADA, studies will be conducted of improved methods for the generation of the large numbers of TIL necessary for patient
treatment. These studies will explore the use of alternate culture vessels including those that involve the use of gas permeable
membranes. The NCI Surgery Branch has begun some of these studies but extensive additional studies are required to optimize cell
growth including the determination of the best concentrations of feeder cells, timing of media change and concentrations of growth
factors such as IL-2 (commercially available). These studies will be conducted by the NCI Surgery Branch with advice, input and
expertise provided by Lion. In addition, the NCI Surgery Branch may send tumor samples from those cancers as specified in
“Goals” which were collected from NCI protocol 03-C-0277 to Lion or its agents for studies including scale-out for
the methods of expansion of individualized lymphocyte treatments, assays for product and in-process performance, and harmonization
assays for centralized process development and determination of TIL product consistency. Additionally, biological reagents and
materials may be sent to Lion or its agents for the development of qualifying assays and process development related to scale-out
of the TIL expansion process. Techniques thus described will need to be adapted to meet the GMP requirements of the Food and Drug
Administration for infusion into patients. This may require modification of the procedures developed in the NCI Surgery Branch.
Lion and the NCI Surgery Branch will work together to develop Standard Operating Procedures (SOP) for large scale TIL growth, selection
and testing that meet the approval of the FDA. Joint meetings with the FDA will be required to define the exact format and criteria
need to meet FDA approval.

 

III.         Develop
clinical trials using these improved methods of large scale TIL generation as well as improved patient preparative regimens to
treat patients with metastatic melanoma, bladder, lung, triple-negative breast and HPV-associated cancers, as specified
in “Goals”

 

Clinical trials will be designed and implemented to
evaluate the clinical effectiveness of ACT/TIL therapy resulting from large scale techniques in patients with those cancers as
specified in “Goals”, based on the proprietary NCI Surgery Branch technology and approaches developed in the first
two parts of this Experimental Plan. Lion and the NCI Surgery Branch will work together to develop multiinstitutional clinical
trials evaluating the clinical effectiveness of the administration of autologous TIL generated using Lion technology to patients
with those cancers as specified in “Goals” that can potentially be used as licensing trials for FDA approval. The NCI
Surgery Branch does not have a suitable GMP facility that will meet FDA standards for the conduct of such a trial. Exploratory
pilot trials may be necessary prior to beginning a licensing trial and these may be conducted in the Surgery Branch alone or in
conjunction with other multicenter sites associated with Lion. The development and conduct of licensing trials will require the
GMP expertise of Lion and the extensive experience of the NCI Surgery Branch working together. TIL for these trials will be produced
on a large scale by Lion at a central facility for distribution to participating multicenter sites (including the NCI Surgery Branch).
An IND with the FDA will be filed by Lion which will serve as the Coordinating Center for such trials. The goal of such trials
will be to generate data to support the approval by the FDA of this ACT/TIL therapy approach. In vitro testing of patient
samples from such trials will evaluate the activity and persistence level of the transferred cells in the circulation of treated
patients and will be conducted by the NCI Surgery Branch both for any pilot trials that are performed as well as for the large
multiinstitutional trials that are planned.

 

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Description
of the Contributions and Responsibilities of the Parties

 

Surgery Branch, NCI

 

		-	Develop and test new improved and simplified in vitro methods for the selection and growth of TIL with anti-tumor activity
for large scale preparations that can be used in clinical cell transfer studies. As described in the Experimental Plan above, this
will include evaluation of new growth techniques, culture vessels, and tests

 

		-	Perform in vitro studies of the immunologic parameters surrounding the new cell transfer clinical protocol(s) by analyzing
the phenotypic and functional properties of the transferred cells and their persistence in the patient following adoptive transfer
in all clinical trials conducted under this CRADA, as outlined in Section III above.

 

Lion

 

		-	Develop, implement and evaluate GMP procedures for the large scale production of TIL suitable for infusion into patients
with metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated cancers as specified in “Goals.”

 

		-	Conduct studies including scale-out for the methods of expansion of individualized lymphocyte treatments, assays for product
and in-process performance, and harmonization assays for centralized process development and determination of TIL product consistency.
Additional studies may be conducted for the development of qualifying assays and process development related to scale-out of the
TIL expansion process.

 

		-	Consult with the FDA to determine the appropriate clinical trial design necessary to secure approval for the commercial development
of TIL therapy for patients with those cancers as specified in “Goals” and sponsor the IND for these new clinical protocols
Serve as the coordinating center for the multicenter licensing clinical trials.

 

		-	Supply TIL in sufficient quantities to the NCI Surgery Branch and other multicenter sites to complete the planned clinical
trials (including the licensing trial) needed for FDA approval of ACT/TIL. Support the establishment of a central facility for
the processing and provision of TIL for the studies under this CRADA.

 

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Surgery Branch, NCI and Lion

 

	 	-	Develop SOP for large scale TIL growth, selection and testing to support the FDA approval of the ACT/TIL therapy approach.  Attend joint meetings with the FDA to define the exact format and criteria needed in the clinical trial(s) to obtain FDA approval.
	 	 	 
	 	 	Develop, conduct and evaluate multiinstitutional clinical trials (to include the NCI Surgery Branch as a clinical trial site) for patients with metastatic melanoma, bladder, lung, triple-negative breast and HPV-associated cancers (as specified in”Goals”) treated with TIL that can be used as licensing trials required for FDA approval and subsequent commercialization of ACT/TIL.
	 	 	 
	 	-	Conduct assays to be used in the selection of appropriate cells (based on both functional and phenotypic criteria) to optimize the effectiveness of the adoptive transfer. 
	 	 	 
	 	-	Exchange information and expertise to further the successful development of TIL therapy for patients with those cancers as specified in “Goals.”  

 

Related NCI and Collaborator
Agreements: None

 

Related Intellectual
Property and Business/Scientific Expertise of the Parties

 

NCI Surgery Branch

 

1) PCT/US03/27873 entitled “Immunotherapy with
In Vitro-Selected Antigen-specific Lymphocytes After Nonmyeloablative Lymphodepleting Chemotherapy“, filed 9/5/03.
Inventors: Mark E. Dudley, Steven A. Rosenberg, John R. Wunderlich. This is inclusive of all U.S. continuing applications and divisionals,
and foreign applications.

 

2) USSN 12/869,390 entitled “Adoptive Cell Therapy
with Young T Cells”, filed 8/26/10. Inventors: Mark E. Dudley and Steven A. Rosenberg. This is inclusive of all U.S. continuing
applications and divisionals.

 

3)  PCT/US12/02974 entitled “Methods of Growing
Tumor Infiltrating Lymphocytes in Gas-Permeable Containers”, filed 3/20/12. Inventors: Steven A. Rosenberg, Mark E. Dudley,
et al.. This is inclusive of all U.S. continuing applications and divisionals, and foreign applications.

 

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4) PCT/US14/046478 entitled “Methods of Preparing
Anti-human Papillomavirus Antigen T Cells”, filed 7/14/2014. Inventors: Christian S. Hinrichs and Steven A. Rosenberg. This
is inclusive of all U.S. continuing applications and divisionals.

 

Lion Biotechnologies, Inc.

 

Lion has applied to NIH for a license to NIH owned intellectual
property under the license applicationsA-079-2014 and A-286-2014; Lion has a license to NIH-owned intellectual property under license
L-129-2011/0. Collaborator desires to license NIH owned intellectual property that includes the patents describing the NCI proprietary
ACT/TIL therapy approach to be developed under this CRADA.

 

Lion Biotechnologies, Inc. is a publicly traded biotechnology
company developing therapies for the treatment of cancer. Lion’s lead therapeutic candidate will be an autologous cell therapy
product using tumor infiltrating lymphocytes for the treatment of metastatic melanoma, bladder, lung, triple-negative breast and
HPV-associated cancers as specified in”Goals”, to be developed under this CRADA. Lion has a partnership with a major
manufacturer for the provision of TIL for clinical trials to be conducted under this CRADA as well as post-regulatory approval.
The manufacturing facility is cGMP certified and inspected by FDA.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT
AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX B

 

STAFFING, FUNDING AND MATERIALS/EQUIPMENT
CONTRIBUTIONS

OF THE PARTIES

 

Staffing Contributions:

 

IC will provide scientific staff and other support necessary
to conduct the research and other activities described in the Research Plan. IC’s scientific staff will include IC’s
CRADA Principal Investigator and technical staff.

 

IC estimates that     3-5    person-years of effort
per year will be required to complete the CRADA research.

 

Collaborator will provide scientific staff and other support
necessary to conduct the research and other activities described in the Research Plan. Collaborator’s scientific staff will
include Collaborator’s Principal Investigator and technical staff.

 

Collaborator estimates that    3-5    person-years
of effort per year will be required to complete the CRADA research.

 

Funding Contributions:

 

Collaborator agrees to provide funds in the amount of $2,000,000.00
per year of the CRADA for IC to use to acquire technical, statistical, and administrative support for the research activities,
as well as to pay for supplies and travel expenses. Collaborator will provide funds in the amount of $500,000.00 on a quarterly
basis. The first quarterly installment of of a prorated amount of $250,000.00 from the Amendment execution date to February 4,
2015 will be due within thirty (30) days of the Effective Date of the Amendment. Each subsequent installment will be due within
thirty (30) days of each quarterly anniversary of the CRADA Effective Date. Collaborator agrees that IC can allocate the funding
between the various categories in support of the CRADA research as IC’s CRADA PI sees fit.

 

CRADA PAYMENTS:

 

Collaborator will make checks payable to the National Cancer
Institute and will reference the CRADA number 02734 and title “CRADA for the Development and Evaluation of the NCI Proprietary
Adoptive Cell Transfer Immunotherapy Using Tumor Infiltrating Lymphocytes in Patients with Metastatic Melanoma, Bladder, Lung,
Triple-negative Breast and HPV-associated Cancers Utilizing Lion Biotechnologies, Inc.’s Business Development Expertise in
Adoptive Cell Transfer Immunotherapy” on each check, and will send them via trackable mail or courier to:

 

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CRADA Funds Coordinator

Technology Transfer Center, NCI

6120 Executive Blvd., Suite 450

Rockville, MD 20852

 

CRADA Travel Payments:

Travel arrangements for all Government staff will be made in
accordance with the Federal Travel Rules and Regulations, whether arranged by IC and funded using either appropriated funds or
CRADA funds, or arranged and funded directly by Collaborator.

 

Materials/Equipment Contributions:

 

IC will provide the following IC Materials for use under this
CRADA:

 

	 	Test Article:	None
	 	 	 
	 	IC Materials:	Fresh melanoma, bladder cancer, lung cancer, triple- negative breast cancer, and HPV-associated cancer tumor specimens collected under NCI protocol  03-C-0277 entitled “Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols”
	 	 	 
	 	Capital Equipment:	None

 

Collaborator will provide the following Collaborator Materials
and/or capital equipment for use under this CRADA:

 

	 	Test Article:	Autologous Tumor Infiltrating Lymphocytes (TIL) grown
	 	 	and processed under GMP conditions, suitable for use in clinical trials under this CRADA.
	 	 	 
	 	Collaborator Materials:	None
	 	 	 
	 	Capital Equipment:	None

 

If either Party decides to provide additional Materials for
use under this CRADA, those materials will be transferred under a cover letter that identifies them and states that they are being
provided under the terms of the CRADA.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT
AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX C

 

MODIFICATIONS TO THE MODEL CRADA

 

Add the Definition of “Multi-Party Data” in Article
2 to read as follows:

 

“Multi-Party Data” means
data from studies sponsored by IC pursuant to Clinical Trial Agreements (CTA) or CRADAs, where such data are collected under Protocols
involving combinations of investigational agents supplied from more than one CTA or CRADA collaborator. “Multi-Party Data”
also means data from studies where such data are collected pursuant to research involving combinations of proprietary materials
from more than one collaborator as documented in more than one agreement.

 

Amend Section 7.2 to read as follows:

 

7.2     Collaborator’s License Option to CRADA
Subject Inventions. With respect to Government rights to any CRADA Subject Invention made solely by an IC employee(s) or made
jointly by an IC employee(s) and a Collaborator employee(s) for which a Patent Application was filed, PHS hereby grants to Collaborator
an exclusive option to elect an exclusive or nonexclusive or co-exclusive, if applicable, commercialization license. The option
to elect a co-exclusive license shall apply when a CRADA Subject Invention is also an Invention made under another agreement resulting
from mutually agreed upon studies, as described in Section 8.8 (regarding Multi-Party Data Rights)], and the field of use of this
co-exclusive license shall be limited to the use of the combination of the Test Article with another agent(s) commensurate with
the scope of the Research Plan. The license will be substantially in the form of the appropriate model PHS license agreement and
will fairly reflect the nature of the CRADA Subject Invention, the relative contributions of the Parties to the CRADA Subject Invention
and the CRADA, a plan for the development and marketing of the CRADA Subject Invention, the risks incurred by Collaborator, and
the costs of subsequent research and development needed to bring the CRADA Subject Invention to the marketplace. The field of use
of the license will not exceed the scope of the Research Plan.

 

	PHS ICT-CRADA	Case Ref. No. 02734	MODEL ADOPTED June 18, 2009
	Page 13 of 15	 	Confidential

 

    	 

    	 

    

 

Amend Section 7.6 to read as follows:

 

7.6     Third Party License. Pursuant to 15
U.S.C. § 3710a(b)(1)(B), if PHS grants Collaborator an exclusive license or co-exclusive license to a CRADA Subject Invention
made solely by an IC employee or jointly with a Collaborator employee, the Government will retain the right to require Collaborator
to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the CRADA Subject Invention
in Collaborator’s licensed field of use on terms that are reasonable under the circumstances; or, if Collaborator fails to
grant a license, to grant a license itself. The exercise of these rights by the Government will only be in exceptional circumstances
and only if the Government determines (i) the action is necessary to meet health or safety needs that are not reasonably satisfied
by Collaborator, (ii) the action is necessary to meet requirements for public use specified by federal regulations, and such requirements
are not reasonably satisfied by Collaborator; or (iii) Collaborator has failed to comply with an agreement containing provisions
described in 15 U.S.C. § 3710a(c)(4)(B). The

determination made by the Government under this Paragraph
is subject to administrative

appeal and judicial review under 35 U.S.C. §
203(b).

 

Section 7.8 “Joint CRADA Subject
Inventions Not Exclusively Licensed by Collaborator” is deleted in its entirety.

 

Add Section 8.8 as follows:

 

8.8     Multi-Party Data Rights.
For mutually agreed upon clinical Protocol(s) where Test Article is used in combination with another investigational agent supplied
to IC pursuant to a CTA or CRADA between IC and an entity not a Party to this CRADA (hereinafter referred to as “Third Party”),
or for non-clinical study(ies) where research involving combinations of proprietary materials from more than one collaborator as
documented in more than one agreement, the access and use of Multi-Party Data by the Collaborator and Third Party shall be co-exclusive
as follows:

 

		8.8.1	IC will provide both Collaborator and Third Party with notice regarding the existence and nature of the agreements governing
the use of the Test Article and Third Party’s investigational agent, the design of the proposed combination Protocol(s) or
non-clinical study(ies), and the existence of any obligations that might restrict IC’s participation in the proposed combination
Protocols or non-clinical study(ies).

 

		8.8.2	Collaborator shall agree to permit use of the Multi-Party Data from these trials by Third Party
to the extent necessary to allow Third Party to develop, obtain regulatory approval for, or commercialize its own investigational
agent(s). However, this provision will not apply unless Third Party also agrees to Collaborator’s reciprocal use of Multi-Party
Data.

 

		8.8.3	Collaborator and Third Party must agree in writing prior to the commencement of the combination
Protocol(s) or non-clinical study(ies) that each will use the Multi-Party Data solely for the development, regulatory approval,
and commercialization of its own investigational agent(s).

 

	PHS ICT-CRADA	Case Ref. No. 02734	MODEL ADOPTED June 18, 2009
	Page 14 of 15	 	Confidential

 

    	 

    	 

    

 

		8.84	The sharing of Multi-Party Data does not alter the ownership of the Multi-Party Data or obligations
of IC, Collaborator and Third Party to keep Confidential Information owned by any other Party or Parties confidential.

 

Amend the Definition of “Independent Contractors”
in Article 13.9 to read as follows:

 

13.9     Independent Contractors. The relationship of
the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners. Each
Party shall maintain sole and exclusive control over its personnel and operations. If Collaborator elects to perform any portion
of the Research Plan through an agent, contractor or consultant, Collaborator agrees to incorporate into such contracts all provisions
necessary to ensure that the work of such agents, contractors or consultants is governed by the terms of the CRADA, including,
but not limited to a provision for the assignment of inventions of the agent, contractor or consultant to the Collaborator.

 

	PHS ICT-CRADA	Case Ref. No. 02734	MODEL ADOPTED June 18, 2009
	Page 15 of 15	 	ConfidentialEX-4.1

 Exhibit 4.1 

Execution Version 

FIRST SUPPLEMENTAL INDENTURE, dated as of January 26, 2015, among Medtronic, Inc., a Minnesota corporation (the
“Company”), Medtronic plc (“New Medtronic”), a public limited company incorporated under the laws of Ireland and the parent of the Company, Medtronic Global Holdings, S.C.A. (“Medtronic Luxco” and,
together with New Medtronic, the “Guarantors”), a corporate partnership limited by shares (société en commandite par actions) organized under the laws of the Grand Duchy of Luxembourg and an
affiliate of the Company, and Wells Fargo Bank, National Association, a national banking association duly organized under the laws of the United States, as trustee (the “Trustee”). 

W I T N E S S E T H 

WHEREAS, the Company has heretofore executed and delivered to the Trustee an Indenture, dated as of September 15, 2005 (the
“Base Indenture”), providing for the initial issuance of up to $1,000,000,000 aggregate principal amount of the Company’s $400,000,000 4.37% Senior Notes due 2010 and $600,00,000 4.75% Senior Notes Due due 2015 (herein and
therein collectively called the “Notes”);  
 WHEREAS, Section 9.01(11) of the Base Indenture permits the
Company and the Trustee, without the consent of any Noteholder, to enter into an indenture supplemental to the Base Indenture to make any changes that do not materially and adversely affect the rights of any Holder; and 

WHEREAS, pursuant to Section 9.01 of the Base Indenture, the Trustee is authorized to execute and deliver this First Supplemental
Indenture. 
 NOW, THEREFORE, in consideration of the foregoing and for other good and valuable consideration, the receipt of which is
hereby acknowledged, the parties mutually covenant and agree for the equal and ratable benefit of the Holders as follows: 
 SECTION 1.
Capitalized Terms. Capitalized terms used herein without definition shall have the meanings assigned to them in the Base Indenture and the rules of construction contained in the Base Indenture will apply equally to this First Supplemental
Indenture. 
 SECTION 2. Amendments to the Base Indenture. 

(a) The following definitions are added to Section 1.01 of the Base Indenture in alphabetical order: 

(i) “Guarantor” means any Affiliate of the Company that Guarantees the Notes in accordance with the terms of
this Indenture. 
 (ii) “Medtronic Luxco” means Medtronic Global Holding SCA, a corporate partnership
limited by shares (société en commandite par actions) organized under the laws of the Grand Duchy of Luxembourg. 

(iii) “New Medtronic” means Medtronic plc, an Irish public limited company. 

(iv) “Note Guarantee” means any Guarantee of the Notes that may from time to time be entered into by an
Affiliate of the Company. 
 (b) The following definitions in Section 1.01 of the Base Indenture are amended and restated to read as
follows: 

 (i) “Board of Directors” means, with respect to the Company,
either the board of directors of the Company, any duly authorized committee of that board or any other equivalent governing entity of the Company and, with respect to any Guarantor, the board of directors of such Guarantor, any duly authorized
committee of that board or any other equivalent governing entity of such Guarantor. 
 (ii) “Board
Resolution” means a resolution duly adopted by the Board of Directors which is certified by the Secretary or an Assistant Secretary, or any other authorized officer, manager or signatory, of the Company or any Guarantor, as the case may be,
and remains in full force and effect as of the date of its certification. 
 (iii) “Officers’
Certificate” means a certificate signed in the name of the Company or any Guarantor (i) by the chairman of the Board of Directors, the president or chief executive officer or a vice president, or any other authorized officer, manager
or signatory of the Company or any Guarantor and (ii) by the chief financial officer, the treasurer or any assistant treasurer or the secretary or any assistant secretary or any other authorized officer, manager or signatory, of the Company or
any Guarantor. 
 (iv) “Opinion of Counsel” means a written opinion signed by legal counsel, who may be an
employee of or counsel to the Company or any Guarantor, satisfactory to the Trustee. 
 (c) Section 6.11 of the Base Indenture is
amended to add “, any Guarantor” after each appearance of the word “Company”. 
 (d) Section 6.15 of the Base
Indenture is amended to add “and each Guarantor” after each appearance of the word “Company”. 
 (e) Section 9.01(8)
of the Base Indenture is amended to add “or any Guarantor” after each appearance of the word “Company”. 
 (f)
Section 9.01 of the Base Indenture is amended: 
 (i) to add “ or any Guarantor (with respect to a Guarantee or
this Indenture)” after the word “Company” in the first sentence thereof; 
 (ii) remove the “or” at
the end of clause 9.01(10); and 
 (iii) add the following immediately after clause 9.01(11): 

      “or 

(12) to add or release a Guarantor as required or permitted by this Indenture.” 

(g) The Base Indenture is amended to add the following immediately after Article 10: 

“ARTICLE 11 

GUARANTEES 

Section 11.01. Note Guarantee. 

(a) Subject to this Article 11, each of the Guarantors hereby, jointly and severally, irrevocably and unconditionally guarantees, on a senior
basis, to each Holder and to the Trustee and its successors and assigns, irrespective of the validity and enforceability of this 

 
Indenture, the Notes or the obligations of the Company hereunder or thereunder, that: (1) the principal of and premium, if any, and interest on the Notes shall be promptly paid in full when
due, whether at maturity, by acceleration, redemption or otherwise, and interest on the overdue principal of and interest on the Notes, if any, if lawful, and all other obligations of the Company to the Holders or the Trustee hereunder or thereunder
shall be promptly paid in full or performed, all in accordance with the terms hereof and thereof; and (2) in case of any extension of time of payment or renewal of any Notes or any of such other obligations, that same shall be promptly paid in
full when due or performed in accordance with the terms of the extension or renewal, whether at stated maturity, by acceleration or otherwise. Failing payment by the Company when due of any amount so guaranteed or any performance so guaranteed for
whatever reason, the Guarantors shall be jointly and severally obligated to pay the same immediately. Each Guarantor agrees that this is a guarantee of payment and not a guarantee of collection. 

(b) The Guarantors hereby agree that their obligations hereunder shall be unconditional, irrespective of the validity, regularity or
enforceability of the Notes or this Indenture, the absence of any action to enforce the same, any waiver or consent by any Holder with respect to any provisions hereof or thereof, the recovery of any judgment against the Company, any action to
enforce the same or any other circumstance which might otherwise constitute a legal or equitable discharge or defense of a guarantor. Each Guarantor hereby waives diligence, presentment, demand of payment, filing of claims with a court in the event
of insolvency or bankruptcy of the Company, any right to require a proceeding first against the Company, protest, notice and all demands whatsoever and covenants that this Note Guarantee shall not be discharged except by complete performance of the
obligations contained in the Notes and this Indenture, or pursuant to Section 11.06. 
 (c) If any Holder or the Trustee is required by
any court or otherwise to return to the Company, the Guarantors or any custodian, trustee, liquidator or other similar official acting in relation to the Company or the Guarantors, any amount paid either to the Trustee or such Holder, this Note
Guarantee, to the extent theretofore discharged, shall be reinstated in full force and effect. 
 (d) Each Guarantor agrees that it shall not
be entitled to any right of subrogation in relation to the Holders in respect of any obligations guaranteed hereby until payment in full of all obligations guaranteed hereby. Each Guarantor further agrees that, as between the Guarantors, on the one
hand, and the Holders and the Trustee, on the other hand, (1) the maturity of the obligations guaranteed hereby may be accelerated as provided in Section 5.02 for the purposes of this Note Guarantee, notwithstanding any stay, injunction or
other prohibition preventing such acceleration in respect of the obligations guaranteed hereby, and (2) in the event of any declaration of acceleration of such obligations as provided in Section 5.02 such obligations (whether or not due
and payable) shall forthwith become due and payable by the Guarantors for the purpose of this Note Guarantee. The Guarantors shall have the right to seek contribution from any non-paying Guarantor so long as
the exercise of such right does not impair the rights of the Holders under the Note Guarantees. 
 (e) Each Note Guarantee shall remain in
full force and effect and continue to be effective should any petition be filed by or against the Company for liquidation, reorganization, should the Company become insolvent or make an assignment for the benefit of creditors or should a receiver or
trustee be appointed for all or any significant part of the Company’s assets, and shall, to the fullest extent permitted by law, continue to be effective or be reinstated, as the case may be, if at any time payment and performance of the Notes
are, pursuant to applicable law, rescinded or reduced in amount, or must otherwise be restored or returned by any obligee on the Notes or the Note Guarantees, whether as a “voidable 

 
preference,” “fraudulent transfer” or otherwise, all as though such payment or performance had not been made. In the event that any payment or any part thereof, is rescinded,
reduced, restored or returned, the Notes shall, to the fullest extent permitted by law, be reinstated and deemed reduced only by such amount paid and not so rescinded, reduced, restored or returned. 

(f) In case any provision of any Note Guarantee shall be invalid, illegal or unenforceable, the validity, legality and enforceability of the
remaining provisions shall not in any way be affected or impaired thereby. 
 (g) Each payment to be made by a Guarantor in respect of its
Note Guarantee shall be made without set-off, counterclaim, reduction or diminution of any kind or nature. 

Section 11.02. Limitation on Guarantor Liability. 

Each Guarantor, and by its acceptance of Notes, each Holder, hereby confirms that it is the intention of all such parties that the Note
Guarantee of such Guarantor not constitute a fraudulent transfer or conveyance for purposes of Debtor Relief Law, the Uniform Fraudulent Conveyance Act, the Uniform Fraudulent Transfer Act or any similar U.S. federal or state law or law of such
Guarantor’s jurisdiction of organization (which shall be Irish law, in the case of New Medtronic, and Luxembourg law, in the case of Medtronic Luxco) to the extent applicable to any Note Guarantee. To effectuate the foregoing intention, the
Trustee, the Holders and the Guarantors hereby irrevocably agree that the obligations of each Guarantor shall be limited to the maximum amount as will, after giving effect to such maximum amount and all other contingent and fixed liabilities of such
Guarantor that are relevant under such laws and after giving effect to any collections from, rights to receive contribution from or payments made by or on behalf of any other Guarantor in respect of the obligations of such other Guarantor under this
Article 11, result in the obligations of such Guarantor under its Note Guarantee not constituting a fraudulent conveyance or fraudulent transfer under applicable law. Each Guarantor that makes a payment under its Note Guarantee shall be entitled
upon payment in full of all Note Guarantee obligations under this Indenture to a contribution from each other Guarantor in an amount equal to such other Guarantor’s pro rata portion of such payment based on the respective net assets of all the
Guarantors at the time of such payment determined in accordance with GAAP. 
 Section 11.03. Execution and Delivery. 

(a) To evidence its Note Guarantee set forth in each Guarantor shall execute a supplemental indenture. 

(b) Each Guarantor that provides a Note Guarantee agrees that its Note Guarantee set forth in Section 11.01 shall remain in full force and
effect notwithstanding the absence of the endorsement of any notation of such Note Guarantee on the Notes. 
 (c) If an officer whose
signature is on this Indenture or a supplemental indenture no longer holds that office at the time the Trustee authenticates the Security, the Note Guarantees shall be valid nevertheless. 

(d) The delivery of any Security by the Trustee, after the authentication thereof hereunder, shall constitute due delivery of the Note
Guarantee set forth in this Indenture on behalf of the Guarantors. 

 Section 11.04. Subrogation. 

Each Guarantor shall be subrogated to all rights of Holders against the Company in respect of any amounts paid by any Guarantor pursuant to
the provisions of Section 11.01; provided that, if an Event of Default has occurred and is continuing, no Guarantor shall be entitled to enforce or receive any payments arising out of, or based upon, such right of subrogation until all amounts
then due and payable by the Company under this Indenture or the Notes shall have been paid in full. 
 Section 11.05. Benefits
Acknowledged. 
 Each Guarantor acknowledges that it will receive direct and indirect benefits from the financing arrangements
contemplated by this Indenture and that the guarantee and waivers made by it pursuant to its Note Guarantee are knowingly made in contemplation of such benefits. 

Section 11.06. Release of Note Guarantees. 

(a) A Note Guarantee by a Guarantor shall be automatically and unconditionally released and discharged, and such Note Guarantee shall thereupon
terminate and be discharged and of no further force and effect, and no further action by such Guarantor, the Company or the Trustee shall be required for the release of such Guarantor’s Note Guarantee: 

(1) (A) upon the merger or consolidation of such Guarantor with and into either the Company or any other Guarantor that is the
surviving person in such merger or consolidation, or upon the liquidation of such Guarantor following or concurrently with the transfer of all or substantially all of its assets to either the Company or another Guarantor (and, if applicable, any
minority stockholders of such Guarantor on a pro rata basis according to their ownership interests in such Guarantor); or 

(B) upon the Company exercising its legal defeasance or covenant defeasance options in accordance with Article 8 or the
Company’s obligations under this Indenture being discharged in accordance with the terms of this Indenture and the Notes; and 

(2) such Guarantor delivering to the Trustee an Officers’ Certificate and an Opinion of Counsel, each stating that all
conditions precedent provided for in this Indenture relating to such transaction have been complied with. 
 (b) At the written request and
expense of the Company or the relevant Guarantor, the Trustee shall execute and deliver such documents prepared by the Company or such Guarantor and reasonably required in order to acknowledge such release, discharge and termination in respect of
the applicable Note Guarantee. Neither the Company nor any Guarantor shall be required to make a notation on the Notes to reflect any Note Guarantee or any such release, termination or discharge.” 

SECTION 3. Note Guarantee. Each of New Medtronic and Medtronic Luxco, severally and not jointly, hereby agrees to be a Guarantor under
the Base Indenture, as amended and supplemented by this First Supplemental Indenture, and to be bound by the terms of the Base Indenture and the Notes applicable to Guarantors, including, but not limited to, Article 11 of the Base Indenture, as
amended and supplemented by this First Supplemental Indenture, and each Guarantor further agrees that this First Supplemental Indenture is the legal, valid and binding obligation of such Guarantor, enforceable against it in accordance with its
terms. 

 SECTION 4. Notice to Guarantors. Any request, demand, authorization, direction, notice,
consent waiver or Act of Holders or other document provided or permitted by this First Supplemental Indenture to be made upon, given or furnished to, or filed with: 

(a) the Trustee by any Holder or by the Guarantor shall be sufficient for every purpose hereunder if made, given, furnished or filed in writing
to or with the Trustee at its Corporate Trust Office, Attention: Corporate Trust Division; 
 (b) New Medtronic by the Trustee or by an
Holder shall be sufficient for every purpose hereunder (unless otherwise expressly provided) if in writing and mailed, first-class postage pre-paid, to New Medtronic addressed to it at the following address: 

Medtronic plc 
 20 Lower Hatch
Street 
 Dublin 2 
 Ireland

 Attention: General Counsel 

with a copy to (which shall not constitute notice to New Medtronic): 

Medtronic, Inc. 
 710 Medtronic
Parkway 
 Minneapolis, Minnesota 55432 

Attention: General Counsel 
 (b)
Medtronic Luxco by the Trustee or by an Holder shall be sufficient for every purpose hereunder (unless otherwise expressly provided) if in writing and mailed, first-class postage pre-paid, to Medtronic Luxco addressed to it at the following address:

 Medtronic Global Holdings SCA 

1, rue du Potager 
 L-2347
Luxembourg 
 Luxembourg 

Attention: General Partner 

with a copy to (which shall not constitute notice to Medtronic Luxco): 

Medtronic, Inc. 
 710 Medtronic
Parkway 
 Minneapolis, Minnesota 55432 

Attention: General Counsel 

SECTION 5. Relationship to Existing Base Indenture. This First Supplemental Indenture is a supplemental indenture within the meaning of
the Base Indenture. The Base Indenture, as amended and supplemented by this First Supplemental Indenture, is in all respects ratified, confirmed and approved and, with respect to the Notes, the Base Indenture, as amended and supplemented by this
First Supplemental Indenture, shall be read, taken and construed as one and the same instrument. 
 SECTION 6. Foreign Account Tax
Compliance Act. This Seventh Supplemental Indenture has not resulted in a material modification of the Indenture and the Securities, including the Notes, for purposes of the Foreign Account Tax Compliance Act provisions of the Internal Revenue
Code. 

 SECTION 7. Governing Law. THIS FIRST SUPPLEMENTAL INDENTURE WILL BE GOVERNED BY AND
CONSTRUED IN ACCORDANCE WITH THE LAWS OF THE STATE OF NEW YORK AND OF THE UNITED STATES. 
 SECTION 8. Headings. The headings of the
Sections of this First Supplemental Indenture have been inserted for convenience of reference only, are not to be considered a part of this First Supplemental Indenture and shall in no way modify or restrict any of the terms or provisions
hereof. 
 SECTION 9. Counterparts. The parties may sign any number of copies of this First Supplemental Indenture. Each signed copy
shall be an original, but all of them together represent the same agreement. The exchange of copies of this First Supplemental Indenture and of signature pages by facsimile or .pdf transmission shall constitute effective execution and delivery of
this First Supplemental Indenture as to the parties hereto and may be used in lieu of the original First Supplemental Indenture for all purposes. Signatures of the parties hereto transmitted by facsimile or .pdf shall be deemed to be their original
signatures for all purposes. 
 SECTION 10. Trustee. The Trustee shall not be responsible in any manner whatsoever for or in the
respect of the validity or sufficiency of this First Supplemental Indenture or for or in respect of the recitals contained herein, all of which recitals are made solely by the Company and the Guarantors, as the case may be. 

SECTION 11. Successors. All agreements of each of the Guarantors in this First Supplemental Indenture shall bind each of their
respective successors, except as otherwise provided in Section 11.01(f) of the Base Indenture, as amended and supplemented by this First Supplemental Indenture, or elsewhere in the Base Indenture or this First Supplemental Indenture. All
agreements of the Trustee in this First Supplemental Indenture shall bind its successors. 
 [Signature Page Follows] 

 IN WITNESS WHEREOF, the parties hereto have caused this Supplemental Indenture to be duly executed, all as of the
date first above written. 
  

			
	MEDTRONIC, INC.,
		
	By:	 	 /s/ Gary L. Ellis

		 	Name: Gary L. Ellis
		 	Title: Executive Vice President,
		 	          Chief Financial Officer
		
	By:	 	 /s/ Linda Harty

		 	Name: Linda Harty
		 	Title: Vice President and Treasurer

 IN WITNESS WHEREOF, the parties hereto have caused this Supplemental Indenture to be duly executed, all as of the
date first above written. 
  

					
	SIGNED AND DELIVERED as a Deed	  		  	
	 for and on behalf of 
 MEDTRONIC
PLC
 by its lawfully appointed attorney
 GARY L.
ELLIS
 in the presence of:
	  		  	
			
		  		  	 /s/ Gary L. Ellis

		  		  	Signature of Attorney
			
	 /s/ Althea Laska
	  		  	
	 (Witness’ Signature)
  

Althea Laska
	  		  	
	 (Witness’ Name)
  

710 Medtronic Parkway, Minneapolis, Minnesota
	  		  	
	 (Witness’ Address)
  

Exec. Assistant
	  		  	
	(Witness’ Occupation)	  		  	

 IN WITNESS WHEREOF, the parties hereto have caused this Supplemental Indenture to be duly executed, all as of the
date first above written. 
 MEDTRONIC GLOBAL HOLDINGS S.C.A., 

as Guarantor 
 a Luxembourg corporate partnership limited by
shares (société en commandite par actions) 
 represented by 

Medtronic Global Holdings GP S.à r.l. 
 Its General
Partner, in turn acting by 
  

			
	By:	 	 /s/ Andrej Grossmann

	Name: Andrej Grossmann
	Title: Class A Manager
	
	AND
		
	By:	 	 /s/ Linda Harty

	Name: Linda Harty
	Title: Class B Manager

 IN WITNESS WHEREOF, the parties hereto have caused this Supplemental Indenture to be duly executed, all as of the
date first above written. 
  

			
	WELLS FARGO BANK, NATIONAL ASSOCIATION, as Trustee
		
	By:	 	 /s/ Raymond Delli Colli

	Name: Raymond Delli Colli
	Title: Vice President

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