RFI_N02CO82598-8.pdf

STATEMENT OF WORK (SOW)

N02CO82598-8

1.0 TITLE

Services to generate high resolution X-ray crystal structures of the extracellular domains of Chimeric Antigen Receptor (CAR) proteins and other immunologically relevant surface receptors and co-receptors, and their interactions with their tumor antigens.

2.0 BACKGROUND

Clinical researchers at the National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research (CCR) have been working for many years to harness the patient’s own immune system to fight their cancer. A central direction for NCI/CCR in this cancer immunotherapy approach has been “Adoptive Cell Transfer” (ACT). New T-cell-based immunotherapies use the patient’s T-cells, enriched with genetically engineered proteins called Chimeric Antigen Receptors (CARs), to target antigens on the surface of tumor cells. These cells are then expanded in large numbers in vitro and infused back into the patient to attack cancer cells. Moreover, as the cells expand and persist in the patient they serve as a long-term drug (a “living drug”) to keep the tumor in check. These therapies have shown great promise and recently, as a result of the success of CAR T-cell clinical trials, the NCI received FDA approval for CAR T-cell therapy to treat large-B-cell lymphoma.

CAR T-cell therapy involves isolating T-cells from the patient’s blood and genetically engineering them to express a surface protein called a chimeric antigen receptor (CAR). This receptor protein is made from different domains of native proteins of the immune system and has the ability to recognize antigens expressed on the surface of tumor cells. As T-cells are the immune system’s natural killing cells, binding of a CAR to the tumor antigen also initiates a cascade of cellular events that results in clearing of tumor cells.

While both CAR T-cell hold great promise in the clinic, the biochemical and biophysical basis for what makes an effective CAR protein remains unexplored. The three-dimensional structure of these CAR molecules that give the genetically engineered T-cells the ability to identify target antigens on the surface of tumor cells, has never been studied. Structural analysis of the CAR proteins either alone or interacting with their target antigens on tumor cells, can enable clinicians to rationally design and improve CAR therapies.

CCR clinicians are also using other genetically engineered receptor proteins as immunotherapeutic molecules for recognition of tumor-specific neoantigen complexes as targets on solid tumors in epithelial cancers.

Comprehensive structural analysis of extracellular domains of individual CAR proteins or other immunologically relevant receptor proteins alone, and bound to the extracellular domains of their specific antigen or neoantigen complex respectively, as well as their co-receptors can help elucidate how receptors on the surface of T-cells engage with antigens or neoantigen complexes to lead to effective T-cell activation. This can enable NCI researchers to rationally design more effective ACT immunotherapies that target multiple types of cancer. Structure determination of immunologically relevant surface receptors (proteins) require considerable expertise, and structural analysis can only be performed once atomic coordinates of the protein structures become available.

2.1 OBJECTIVE

The primary objective is to obtain protein structures of the extracellular domains of CAR proteins and other immunologically relevant receptors proteins, using X-ray crystallography. CCR is interested in procuring services to generate high resolution crystal structures of the extracellular domains of individual CARs or other receptor proteins, either alone or bound to the extracellular domains of their respective antigens. The results from this work will help CCR computational biologists elucidate how the different extracellular structural domains/regions of individual CAR proteins contribute to CAR-surface antigen interactions, and reveal how this contributes to effective T-cell activation.

An additional goal is to generate crystal structures after specific domains of the receptors are altered, to obtain structural information on these new “variant” proteins. This can help determine if these new variants could be more effective receptors within engineered T-cells.

Comprehensive structural determination of CAR proteins or other immunologically relevant surface receptors and co-receptors, and their interactions with their tumor antigens, will enable CCR to help rationalize receptor design and optimize receptor-target antigen or target neoantigen complex interactions. This will lead to development of more effective genetically engineered T-cell based immunotherapy for cancer patients.

3.0 SCOPE

The CCR requires services to generate high resolution X-ray crystal structures of the extracellular regions of individual CAR proteins, other immunologically relevant surface receptors or co-receptors proteins either alone, or bound to the extracellular domain of their respective surface antigen or neoantigen complex respectively. The CCR shall provide dematerialized information in the form of a sequence of a protein. The Contractor shall then provide all materials and supplies, and all technical services and scientific expertise that will be required to successfully obtain high-resolution crystal structures of these proteins. This includes, proposing a plan for structural determination and performing all of the following: cloning of the specific extracellular domain of the selected proteins, protein expression, protein purification, crystallization screening, crystal optimization, X-ray diffraction studies, structure determination, to deliver dematerialized information as 3D positions of atoms of the protein, with a detailed expert description in of the crystal structure. The Contractor shall provide all required technical and scientific expertise for all aspects of this work, from the planning stages through to interpretation of the results. Expertise will be provided by well-established Ph.D. scientists with a published record in both structural biology and structural analysis of immunologically-relevant receptor proteins.

The Contractor shall provide for each structural study proposed by the NCI Project Officer, a project plan that includes the proposed extracellular regions of the target protein domain and details on their strategies for DNA cloning, protein expression and protein purification. Upon approval of the plan by the NCI Project Officer, the Contractor shall proceed with the implementation of the project plan, which may initially involve some optimization of protein expression and purification, before proceeding to large scale protein purification to enable protein crystallization. Initial protein crystallization shall be conducted using sparse matrix screening to help identify optimal crystallization conditions. Once optimal crystallization conditions are identified, Contractor shall proceed to large scale protein crystallization that can be used for X-ray diffraction studies using synchrotron beamlines and structural determination using conventional crystallographic structure determination and structure refinement software.

As a final product, CCR/NCI requires atomic coordinates for crystal structures to be delivered as electronic files in PDB format, and structure factors corresponding to atomic coordinates delivered as electronic files in MTZ format, to the NCI Project Officer.

The CCR/NCI would like to setup a contract that includes Base year plus Option years, as significant effort will be expended to determine the high-resolution crystal structures of the different immunologically relevant surface receptors and co-receptors, and their interactions with their cognate tumor antigens or neoantigen complexes, that are currently being evaluated for therapy in the clinic or will be evaluated in the next 5 years. CCR may have need to use this contract to evaluate other CAR and other immunologically relevant surface receptors and co-receptors protein structures, as they are being designed and developed by CCR scientists. Thus, it is important that the contract can be renewed in the out years if the CCR is satisfied with the Contractor’s performance and if appropriated funds are available for that fiscal year.

4.0 CONTRACT REQUIREMENTS/ AND PERSONNEL QUALIFICATIONS

The Contractor shall perform the following tasks:

4.1 Generate high-resolution crystal structures of the extracellular domain of a specific CAR or other immunologically relevant surface protein, and if required by the NCI, generate high resolution crystal structures of the specific CAR or other immunologically relevant surface receptors protein interacting with the extracellular domain of its surface antigen or neoantigen complex, respectively.

4.1.1 All work shall be carried out on the Contractor’s site or an affiliated site, using their own resources. These shall include:

a) State of the art facilities to perform cloning, bacterial or eukaryotic protein expression, and protein purification including cold room capabilities to enable optimal protein purification and crystallization.

b) Access to automated chromatography systems to rapidly produce high purity protein on a large scale for crystallization.

c) Facilities equipped with specialized robotic technologies incorporated in an integrated workflow that enables rapid protein crystallization and optimization.

d) In-house X-ray equipment as well as dedicated access to a beamline at an internationally recognized laboratory with a Synchrotron light source.

4.1.2 The Contractor shall provide an experienced senior scientific director and investigator with a Ph.D. in the biological sciences and a track record of published crystal structures of immunologically relevant cell surface proteins, who will develop a detailed plan and oversee the execution of the project. The individual(s) will have extensive experience in recombinant protein production from both prokaryotic and eukaryotic expression systems, and in both planning and execution of x-ray crystallographic studies of membrane proteins, preferably of immune cell receptor proteins. The individuals will also have an extensive publication record in the structural biology field. Experience with structural determination of cancer-related and immune cell receptor proteins will be a plus.

4.1.3 The Contractor shall propose a plan to perform structural determination of an extracellular domain of specific CAR or other immunologically relevant surface receptor proteins. The plan shall include the exact amino acid sequence of the extracellular domain of the specific Chimeric Antigen Receptor (CAR) protein or other immunologically relevant surface receptor protein and if required by the NCI, the amino acid sequence of the extracellular domain of its surface antigen or neoantigen complex.

4.1.4 The project plan proposed by the Contractor shall include a cloning, expression and purification strategy for the extracellular domain of the specific CAR or other immunologically relevant surface receptor protein, and if required by the NCI, a cloning, expression and purification strategy for the extracellular domain of the surface antigen or neoantigen complex.

The cloning, expression and purification strategies will take into consideration whether the domains are best expressed in eukaryotic or bacterial expression systems and the appropriate leader sequence(s) that can enable effective expression, secretion and purification. All protein purification shall proceed under optimal conditions, (4-degree C), to ensure optimal native folding of the protein.

4.1.5 Upon approval of the plan by the NCI Project Officer, the Contractor shall proceed to cloning and small-scale expression and purification of the domains of the CAR or other immunologically relevant surface receptor protein, and if required by the NCI, cloning, small scale expression and purification of the surface antigen or neoantigen complex protein constructs. The results of the small-scale protein purification(s) shall be shared with the NCI Project Officer to ensure that optimal protein isolation can be obtained before this production is scaled up. Results will be communicated electronically to the NCI Project Officer as a brief written report. In the event of a less than optimal protein purification, the Contractor shall devise other strategies to improve optimal protein expression and purification and implement them on a small scale to test them out.

4.1.6 Upon approval by the NCI Project Officer, the Contractor shall commence on a larger scale expression and purification of the CAR or other immunologically relevant surface Receptor protein domains and if required by the NCI, surface antigen or neoantigen complex protein constructs, in order to proceed to protein crystallization.

4.1.7 Initial protein crystallization shall be conducted using sparse matrix screening to help identify optimal crystallization conditions. This will ensure that multiple formulations can be tried, using different salts, polymers, organics, buffers, pH, to identify the best conditions for protein crystallization. X-ray diffraction of these crystals from the matrix screen shall help identify the appropriate conditions for optimal crystal growth.

4.1.8 Once initial crystallization conditions are identified, the Contractor shall proceed to optimization of crystallization for high resolution structure determination. The protein crystals shall be used for X-ray diffraction studies using a micro-diffraction undulator synchrotron beamline that can obtain high resolution data from even small or weakly-diffracting crystals.

4.1.9 A progress report on the project that includes any intermediary result shall be delivered as electronic files to the NCI Project Officer.

4.1.10 Once x-ray diffraction data has been collected, the Contractor shall determine structures using molecular replacement methods with appropriate search models available in the PDB, or through de novo phasing methods. All structural analyses shall be performed by Ph.D.

scientists and will identify and describe in detail important intramolecular and intermolecular interactions, hydrogen bond patterns, salt bridges, intra and intermolecular cysteine bridges, as well as ordered crystallographic waters. Regions of poor electron density will receive special attention in the case of disordered regions if they happen in critical regions of interest and could benefit from a new structure determination strategy.

4.1.11 A final project report that includes the atomic coordinates for crystal structures shall be delivered as electronic files in PDB format, and structure factors corresponding to atomic coordinates shall be delivered as electronic files in MTZ format, to the NCI Project Officer.

4.2 Generate high-resolution crystal structures of the extracellular domain of a CAR or other immunologically relevant surface Receptor protein in which a specific part of a domain or linker, or sequence of a domain has been modified (insertion, deletion or change of amino acids), to become a “variant” (modified) protein, as specified by the NCI Project Officer.

And if required by the NCI, generate high resolution crystal structure of this variant CAR or other immunologically relevant surface Receptor protein interacting with the extracellular domain of its surface antigen or neoantigen complex.

4.2.1 All work shall be carried out on the Contractor’s site, or an affiliated site, using their own resources. These shall include:

a) State-of-the-art facilities to perform cloning, bacterial or eukaryotic protein expression, and protein purification, including cold room capabilities to enable optimal protein purification and crystallization.

b) Access to automated chromatography systems to rapidly produce on a large scale, high purity protein.

c) Facilities with specialized robotic technologies in an integrated pipeline to perform rapid protein crystallization and optimization.

d) In-house X-ray equipment as well as dedicated access to a beamline at an internationally recognized laboratory with a Synchrotron light source.

4.2.2 The Contractor shall provide an experienced senior scientific director and investigator with a Ph.D. in the biological sciences and a track record of published crystal structures of immunologically relevant cell surface proteins, who will develop a detailed plan and oversee the execution of the project. The individual(s) shall have extensive experience in recombinant protein production from both prokaryotic and eukaryotic expression systems, and in both planning and execution of x-ray crystallographic studies of membrane proteins, preferably of immune cell receptor proteins, as well as an extensive publication record in the structural biology field. Experience with structural determination of cancer-related and immune cell receptor proteins is preferred.

4.2.3 The Contractor shall propose a plan to perform structural determination of the extracellular domain of a specific variant of a CAR or other immunologically relevant surface receptor protein, and if required by the NCI, the Contractor will also include the amino acid sequence of its surface antigen or neoantigen complex. The plan shall include how the amino acid sequence of the extracellular domain of the CAR or other immunologically relevant surface receptor protein is being modified in the variant.

4.2.4 The plan shall include a cloning, expression and purification strategy for the extracellular domain of the variant CAR or other immunologically relevant surface receptor protein, and if required by the NCI, a cloning, expression and purification strategy for the extracellular domain of the surface antigen or neoantigen complex. The cloning, expression and purification strategies will take into consideration whether the domains are best expressed in eukaryotic or bacterial expression systems and the appropriate leader sequence(s) that can enable effective expression, secretion and purification. All protein purification shall proceed under optimal conditions, to ensure optimal native folding of the protein domains and peptide complexes.

4.2.5 Upon approval of the plan by the NCI Project Officer, the Contractor shall proceed to cloning and small-scale expression and purification of the domains of the variant CAR or other immunologically relevant surface Receptor protein, and if required by the NCI, surface antigen or neoantigen complex constructs. The results of the small-scale protein purification(s) shall be shared with the NCI Project Officer to ensure that optimal protein isolation can be obtained before this production is scaled

up. In the event of a less than optimal protein purification, the Contractor shall devise other strategies to improve optimal protein expression and purification and implement them on a small scale to test them out.

Results will be communicated to the NCI Project Officer as a written report.

4.2.6 Upon approval by the NCI Project Officer, the Contractor shall commence on a larger scale expression and purification of the variant CAR or variant receptor protein domains and if required by the NCI, surface antigen or neoantigen complex protein constructs, in order to proceed to protein crystallization.

4.2.7 Initial protein crystallization shall be conducted using sparse matrix screening to help identify optimal crystallization conditions. This will ensure that multiple formulations can be tried, using different salts, polymers, organics, buffers, pH, to identify the best conditions for protein crystallization. X-ray diffraction of these crystals from the matrix screen shall help identify the appropriate conditions for optimal crystal growth.

4.2.8 Once initial crystallization conditions are identified, the Contractor shall proceed to optimization of crystallization for high resolution structure determination. These protein crystals shall be used for X-ray diffraction studies using a micro-diffraction undulator synchrotron beamline that can obtain high resolution data from even small or weakly-diffracting crystals.

4.2.9 A progress report on the project that includes any intermediary result shall be delivered as electronic files to the NCI Project Officer.

4.2.10 Once X-ray diffraction data have been collected, the Contractor shall determine structures using molecular replacement methods with appropriate search models available in the PDB, or through de novo phasing methods. All structural analyses shall be performed by Ph.D.

scientists and will identify and describe in detail important intramolecular and intermolecular interactions, hydrogen bond patterns, salt bridges, intra and intermolecular cysteine bridges, as well as ordered crystallographic waters. Regions of poor electron density will receive special attention in the case of disordered regions if they happen in critical regions of interest and could benefit from a new structure determination strategy.

4.2.11 A final project report that includes the atomic coordinates for crystal structures shall be delivered as electronic files in PDB format, and structural factors corresponding to atomic coordinates shall be delivered as electronic files in MTZ format, to the NCI Project Officer.

5.0 PERIOD OF PERFORMANCE

The anticipated period of performance shall consist of a 12-month base period, plus four 12-month option periods, from the date of award. See Appendix I for Base Period Task List.

• See Appendix I for Base Period Task List

6.0 PLACE OF PERFORMANCE

All work and analysis shall be conducted at the Contractor’s site.

7.0 REPORT(S)/DELIVERABLES AND DELIVERY SCHEDULE

DELIVERABLE DELIVERABLE DESCRIPTION / FORMAT

REQUIREMENTS DUE DATE

#1 Task 4.1.3 and Task 4.1.4

Task 4.2.3 and Task

Scientific project proposal in Word or PDF format outlining step-by-step plan to perform structural determination of an extracellular domain of a specific CAR or other immunologically relevant

30 days after award

4.2.4 surface Receptor protein. Proposal shall be submitted to the NCI Project Officer. Plan shall include the exact amino acid sequence of the extracellular domain of the specific Chimeric Antigen Receptor (CAR) protein or other immunologically relevant surface receptor protein and if required by the NCI, the amino acid sequence of the extracellular domain of its surface antigen or neoantigen complex. Plan shall also include a cloning, expression and purification strategy for the extracellular domain of the specific CAR or other immunologically relevant surface Receptor protein, and if required by the NCI, a cloning, expression and purification strategy for the extracellular domain of the surface antigen or neoantigen complex.

#2 Task 4.1.5 and Task 4.2.5

Electronically transmitted brief written report summarizing results of the small-scale protein purification(s) of the extracellular domains for CAR or other immunologically relevant surface receptor protein and/or the tumor antigens and recommendation to proceed or plan for trouble-shooting if unsuccessful.

90 days after award

#3 Task 4.1.9 (Task 4.2.9)

A progress report on the project that includes any intermediary result shall be delivered as an electronic file to the NCI Project Officer.

180 days after award

#4 Task 4.1.11 and Task 4.2.11

A final project report shall be delivered to the Project Officer. Final report shall include the atomic coordinates for crystal structures delivered as electronic files in PDB format, structure factors corresponding to atomic coordinates shall be delivered as electronic files in MTZ format, as well as a structural analysis as defined in 4.1.10

30 days after completion of Task 4.1.10, not to exceed 12 months from date of award.

8.0 PAYMENT

Payment shall be made at the completion of each milestone within the Task order, once the deliverable has been given to the Project Officer and they have indicated their satisfaction to the COR. Payment authorization requires submission and approval of invoices to the COR and NIH OFM, in accordance with the attached payment provisions listed below:

The following clause is applicable to all Purchase Orders, Task or Delivery Orders, and Blanket Purchase Agreement (BPA) Calls: PROMPT PAYMENT (JUL 2013) FAR 52.232-25.

Highlights of this clause and NIH implementation requirements follow:

I INVOICE REQUIREMENTS

A. An invoice is the Contractor's bill or written request for payment under the contract for supplies delivered or services performed. A proper invoice is an "Original" which must include the items listed in subdivisions 1 through 12, below, in addition to the requirements of FAR 32.9. If the invoice does not comply with these requirements, the Contractor will be notified of the defect within 7 days after the date the designated billing office received the invoice (3 days for meat, meat food products, or fish, and 5 days for perishable agricultural commodities, dairy products, edible fats or oils) with a statement of the reasons why it is not a proper invoice. (See exceptions under II., below.) Untimely notification will be taken into account in the computation of any interest penalty owed the Contractor.

1. Vendor/Contractor: Name, Address, Point of Contact for the invoice (Name, title, telephone number, e-mail and mailing address of point of contact).

2. Remit-to address (Name and complete mailing address to send payment).

3. Remittance name must match exactly with name on original order/contract. If the

Remittance name differs from the Legal Business Name, then both names must appear on the invoice.

4. Invoice date.

5. Unique invoice #s for all invoices per vendor regardless of site.

6. NBS document number formats must be included for awards created in the NBS:

Contract Number; Purchase Order Number; Task or Delivery Order Number and Source Award Number (e.g., Indefinite Delivery Contract number; General Services Administration number); or, BPA Call Number and BPA Parent Award Number.

7. Data Universal Numbering System (DUNS) or DUNS + 4 as registered in the Central Contractor Registration (CCR).

8. Federal Taxpayer Identification Number (TIN). In those exceptional cases where a Contractor does not have a DUNS number or TIN, a Vendor Identification Number (VIN) must be referenced on the invoice. The VIN is the number that appears after the Contractor’s name on the face page of the award document.

9. Identify that payment is to be made using a three-way match.

10. Description of supplies/services that match the description on the award, by line billed.*

11. Freight or delivery charge must be billed as shown on the award. If it is included in the item price do not bill it separately. If identified in the award as a separate line item, it must be billed separately.

12. Quantity, Unit of Measure, Unit Price, Extended Price of supplies delivered or services performed, as applicable, and that match the line items specified in the award.*

* NOTE: If your invoice must differ from the line items on the award, please contact the Contracting Officer before submitting the invoice. A modification to the order or contract may be needed before the invoice can be submitted and paid.

B. Shipping costs will be reimbursed only if authorized by the Contract/Purchase Order. If authorized, shipping costs must be itemized. Where shipping costs exceed $100, the invoice must be supported by a bill of lading or a paid carrier's receipt.

C. Mail an original and 1 copy of the itemized invoice to:

National Institutes of Health Office of Financial Management, Commercial Accounts

2115 East Jefferson Street, Room 4B-432, MSC 8500 Bethesda, MD 20892-8500

For inquiries regarding payment call: (301) 496-6088

In order to facilitate the prompt payment of invoices, it is recommended that the vendor submit a photocopy of the invoice to the “Consignee” designated for the acquisition in blocks 6A – 6E of the face page of the Order/Award document.

II. INVOICE PAYMENT

A. Except as indicated in paragraph B., below, the due date for making invoice payments by the designated payment office shall be the later of the following two events:

1. The 30th day after the designated billing office has received a proper invoice.

2. The 30th day after Government acceptance of supplies delivered or services performed.

B. The due date for making invoice payments for meat and meat food products, perishable agricultural commodities, dairy products, and edible fats or oils, shall be in accordance with the Prompt Payment Act, as amended.

III. INTEREST PENALTIES

A. An interest penalty shall be paid automatically, if payment is not made by the due date and the conditions listed below are met, if applicable.

1. A proper invoice was received by the designated billing office.

2. A receiving report or other Government documentation authorizing payment was processed and there was no disagreement over quantity, quality, or Contractor compliance with a term or condition.

3. In the case of a final invoice for any balance of funds due the Contractor for supplies delivered or services performed, the amount was not subject to further settlement actions between the Government and the Contractor.

B. Determination of interest and penalties due will be made in accordance with the provisions of the Prompt Payment Act, as amended, the Contract Disputes Act, and regulations issued by the Office of Management and Budget.

IV. PROVIDING ACCELERATED PAYMENT TO SMALL BUSINESS

SUBCONTRACTORS, FAR 52.232-40 (DEC 2013)

a) Upon receipt of accelerated payments from the Government, the Contractor shall make accelerated payments to its small business subContractors under this contract, to the maximum extent practicable and prior to when such payment is otherwise required under the applicable contract or subcontract, after receipt of a proper invoice and all other required documentation from the small business subContractor.

b) The acceleration of payments under this clause does not provide any new rights under the prompt Payment Act.

Include the substance of this clause, include this paragraph c, in all subcontracts with small business concerns, including subcontracts with small business concerns for the acquisition of commercial items.

APPENDIX I – Tasks for the Base Period

NCI Contract: Perform services to generate high-resolution X-ray crystal structures of extracellular domains of Chimeric Antigen Receptor (CAR) proteins and other immunologically relevant surface receptors and co-receptors, and their interactions with their tumor antigens.

Task 4.1:

The NCI requires services to generate high resolution X-ray crystal structures of the extracellular regions of two different CAR molecules in the base year.

a) The NCI requires generated high resolution X-ray crystal structures of the extracellular domain of anti-B-cell maturation antigen (BCMA) CAR both alone and in complex with the extracellular domain of BCMA. The details for the anti-BCMA CAR molecule (11D5-3- CD828Z) are referenced in Ali SA, et al. 2016: Blood 128:1688-1700.

b) The NCI requires generated high-resolution X-ray crystal structures of the extracellular domain of the anti-CD19 CAR (47G4-CD828Z, referenced in Patent CA2951045A1).High resolution crystal structures of these CAR domains can reveal key structural determinants that can be used to rationally design more effective CAR molecules for cancer therapy.

Task 4.2:

The NCI requires services to generate high resolution X-ray crystal structures of a variant of the extracellular domain of the anti-BCMA CAR. The specific variation in the sequence of anti-BCMA CAR will partly depend on initial results of anti-BCMA CAR Task 4.1. It will either involve analysis of only the scFv portion of anti-BCMA or a variant of the anti-BCMA CAR containing a three residue AAA insertion between the last strand of the scFv and the beginning of the hinge.

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0ahUKEwjPlqWtoLDaAhXKT98KHcNYADwQFggnMAA&url=https%3A%2F%2Fwww.google.com%2Fpatents%2FCA2951045A1%3Fcl%3Den&usg=AOvVaw1GKrxTn8iv6Jtst7A1fOlE