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`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals,Inc.
`Exhibit 2112
`Page 1
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`WhatIs Angiogenesis?
`
`Article
`Published: July 6, 2022
`
`| Sarah Whelan
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals,Inc. Exhibit2112
`Page 2
`
`

`

`2
`
`Stalk cell development
`
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`
`Maturation & stabilization
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`Induction of VEGF signaling
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`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2112
`Page 3
`
`

`

`Read time: 8 minutes
`
`Angiogenesis is the formation of new blood vessels, an essential process that facilitates tissue growth and wound healing in
`living things. However, diseases like cancer can take advantage of angiogenesis and use it to grow and spread. In this
`article, we will describe the different types of angiogenesis, how it goes out of control in cancer and how we can use drugs
`to inhibit angiogenesis and reduce tumor growth.
`Angiogenesis definition
`
`Angiogenesis is defined as the process by which new blood vessels are formed from existing ones. The term angiogenesis
`comes from the words “angio” meaning blood vessels and “genesis” meaning creation.
`
`Angiogenesis begins during embryo development, when the growth of new blood vessels is essential for the development of
`new cells and tissues. The new veins, arteries and capillaries are needed to supply cells with oxygenated blood and nutrients
`and take away deoxygenated blood and waste products. In adult organisms, the endothelial cells that line the inside of blood
`vessels (the lumen) are largely dormant. However, specific signals can reactivate these cells and induce angiogenesis when
`their environment is low in oxygen (hypoxic), after injury or in placenta formation during pregnancy.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 4
`
`

`

`Angiogenesis was first described in 1794, with the observation that pronounced metabolic activity is dependent on the
`extent of the vascular system.1 More recent research investigating how angiogenesis works in cancer began in 1971 with the
`hypothesis that the growth of cancerous tumors is dependent on angiogenesis.2
`Regulation of angiogenesis
`
`Angiogenesis is a tightly regulated process. Strict control is necessary to make sure that new vasculature is only formed
`when and where it is needed, and organisms have several “off” and “on” switches to facilitate this.
`
`If these signals controlling angiogenesis are unbalanced, this can result in the abnormal formation of blood vessels, which
`can play a role in the pathogenesis of many diseases. Increased angiogenesis can lead to diseases such as cancer, arthritis,
`retinopathy and atherosclerosis.3 On the other hand, impaired angiogenesis can lead to heart and limb ischemia and delayed
`wound healing.4
`
`Therefore, it is important to maintain this balance between pro-angiogenic and anti-angiogenic signals, which is known as
`the “angiogenic switch”. This steady equilibrium is maintained through the activity of cellular signaling pathways,
`particularly through the activation of growth factor receptors.
`
`Pro-angiogenic factors include5:
`
`VEGFR – vascular endothelial growth factor receptor
`EGFR – endothelial growth factor receptor
`PDGFR – platelet-derived growth factor receptor
`TIE2 – angiopoietin-1 receptor
`
`Anti-angiogenic factors and endogenous angiogenesis inhibitors include6:
`
`Angiostatin
`Endostatin
`Thrombospondin
`Types of angiogenesis
`
`Angiogenesis is split into two main types: sprouting angiogenesis and intussusceptive angiogenesis. These occur both in
`adult organisms and in utero, taking place in nearly all organs and tissues.
`
`Sprouting angiogenesis
`
`First discovered almost 200 years ago, sprouting angiogenesis is the more well understood of the two types. During
`sprouting angiogenesis, new blood vessels sprout from pre-existing ones following a gradient of growth factor signals
`produced by endothelial cells.1,7 It is initiated and driven by the secretion of pro-angiogenic growth factors such as VEGF.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 5
`
`

`

`Figure 1: The stages of sprouting angiogenesis.
`
`The main stages of sprouting angiogenesis are:
`
`1. Induction of VEGF signaling – Cells near blood vessels produce VEGF, which forms a gradient of high to low
`intensity.
`2. Formation of tip cells – The endothelial cell exposed to the strongest VEGF signals becomes a “tip” cell. Tip cells
`have thin cellular processes called filopodia, which secrete enzymes designed to degrade the extracellular matrix and
`guide the extension of the developing vessel across the VEGF signal gradient.
`3. Stalk cell development – The tip cell stimulates NOTCH signaling in adjacent cells, transforming them into “stalk”
`cells as the tip cell follows the VEGF gradient.
`4. Vessel outgrowth – Stalk cells proliferate and drive the outgrowth of the new vessel.
`5. Anastomosis and perfusion – As stalk cells proliferate, opposing tip cells are guided together, fusing the new vessels
`in a process called anastomosis. A continuous lumen is created that allows blood to flow between the pre-existing
`vessels.
`6. Maturation and stabilization – Finally, recruitment of pericytes and deposition of extracellular matrix along the
`walls of the vessel result in maturation and stabilization.
`
`Intussusceptive angiogenesis
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 6
`
`

`

`Figure 2: The stages of intussusceptive (splitting) angiogenesis.
`
`Intussusceptive angiogenesis was first discovered in 1986 and is less well understood than sprouting angiogenesis.7 Also
`known as “splitting” angiogenesis, pre-existing vessels are effectively split in two. Small hollow pillars form within the pre-
`existing vessel, eventually expanding to create two parallel capillaries. This is thought to be quicker and more efficient than
`sprouting angiogenesis, initially only requiring the reorganization of existing endothelial cells and not the growth or
`proliferation of new cells.1
`
`Intussusceptive angiogenesis occurs throughout life, taking place in the eye, intestine, kidney, ovary and uterus. It is also
`particularly important in embryo development; a situation where fast growth is needed without being too energetically
`demanding.
`Angiogenesis in cancer
`
`Cancer and angiogenesis were first linked in 1971 with the observation that malignant tumors have extensive vascular
`networks while benign tumors do not.2
`
`Sustained angiogenesis is one of the fundamental hallmarks of cancer.8 Tumor cells gain the ability to flip the “angiogenic
`switch”, resulting in an overabundance of pro-angiogenic signals and a lack of endogenous anti-angiogenic signals. This
`promotes their growth and spread to other parts of the body in a process known as metastasis. During metastasis, blood
`vessels carry tumor cells to establish themselves in distant sites, typically in the liver, lungs and skeletal system.9
`
`In this way, angiogenesis and cancer go hand-in-hand, as tumors cannot grow more than 2–3 mm3 in diameter without
`support from the growth of additional blood vessels. To do this, tumors use both sprouting and intussusceptive angiogenesis
`to secure extra blood supply and provide themselves with oxygen and nutrients.7
`
`Without an adequate blood supply, rapidly growing tumor cells suffer from a lack of oxygen and become hypoxic. Hypoxia
`is a key part of angiogenesis in tumors as it upregulates many pro-angiogenic signals, often through hypoxia-inducible
`factors (HIFs). HIFs are transcription factors that activate and upregulate the transcription of various genes in response to
`low oxygen availability. HIFs bind to areas of DNA within target genes known as hypoxia response elements (HREs). Once
`bound, HIFs activate the transcription of genes such as VEGF, thereby increasing angiogenesis.10
`Angiogenesis inhibitors
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 7
`
`

`

`Several angiogenesis inhibitors, also known as anti-angiogenics, have been developed and approved by regulatory
`authorities such as the U.S. Food and Drug Administration (FDA) to treat cancer. These prevent tumors from growing new
`blood vessels, cutting off the incredibly resource-hungry cancer cells from much-needed nutrients and oxygen. In this way,
`angiogenesis inhibitors “starve” tumors with the goal of preventing them from growing and metastasizing, or even helping
`to shrink them.
`
`Anti-angiogenic drugs have been approved for several cancers such as kidney, colorectal and lung cancer. However, the
`success of angiogenesis inhibitors has been limited as they are often effective only for short periods before the cancer cells
`become resistant. Resistance is common and is often acquired through tumor cells activating alternative cellular pathways
`that induce blood vessel growth.11
`
`Anti-angiogenic therapy is given either as a pill or through a vein (intravenously). These inhibitors can be used on their own
`(i.e., as monotherapy) or in combination with other treatments such as chemotherapy or radiotherapy. Using angiogenesis
`inhibitors as a combination therapy can help increase the efficacy of the drug(s) they are paired with and reduce the
`likelihood of developing drug resistance.9
`
`Examples of angiogenesis inhibitors and their targets are summarized in the table below, along with examples of some of
`the cancer types they are approved to treat (this is not an exhaustive list).11,12
`
`Drug name
`
`Target(s)
`
`Approved cancer type(s)
`
`Axitinib (Inlyta)
`
`VEGFR, PDGFR
`
`Kidney
`
`Bevacizumab (Avastin)
`
`VEGF-A
`
`Cervical, colorectal,
`glioblastoma, kidney, liver,
`non-squamous small-cell lung
`cancer (NSCLC)
`
`Cabozantinib (Cometriq, Cabometyx) VEGFR
`
`Kidney, liver, thyroid
`
`Lenvatinib (Lenvima)
`
`VEGFR1–3, PDGFR
`
`Ramucirumab (Cyramza)
`
`VEGFR2
`
`Regorafenib (Stivarga)
`
`VEGFR1–3, TIE2
`
`Endometrial, kidney, liver,
`thyroid
`
`Colorectal, liver, NSCLC,
`stomach
`
`Colorectal, gastrointestinal,
`liver
`
`Sorafenib (Nexavar)
`
`VEGFR, PDGFR
`
`Kidney, liver, thyroid
`
`Sunitinib (Sutent)
`
`VEGFR, PDGFR
`
`GI, kidney, pancreatic
`neuroendocrine
`
`References:
`
`
`
`However, there are many
`possible side effects of anti-
`angiogenics.12 This is
`because angiogenesis is still
`needed to create new blood
`vessels in non-cancerous,
`healthy tissue.
`
`Relatively common side
`effects include:
`
`High blood pressure
`(hypertension)
`Dry, itchy, rash-prone skin
`Diarrhea
`Fatigue
`Impaired wound healing
`
`More serious side effects
`can also occur with anti-
`angiogenesis inhibitors, such
`as bleeding, blood clots and
`holes in the intestine (bowel
`perforations) – although
`these are very rare.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 8
`
`

`

`1. Adair TH, Montani JP. Overview of Angiogenesis. Morgan & Claypool Life Sciences; 2010. Accessed June 17, 2022.
`https://www.ncbi.nlm.nih.gov/books/NBK53238/
`2. Folkman J. Tumor Angiogenesis: Therapeutic Implications. N. Engl. J. Med. 1971;285(21):1182-1186. doi:
`10.1056/NEJM197111182852108
`3. Fallah A, Sadeghinia A, Kahroba H, et al. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-
`dependent diseases. Biomed. Pharmacother. 2019;110:775-785. doi: 10.1016/j.biopha.2018.12.022
`4. Moriya J, Minamino T. Angiogenesis, cancer, and vascular aging. Front. Cardiovasc. Med. 2017;4. doi:
`10.3389/fcvm.2017.00065
`5. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities.
`Cell Mol. Life Sci. 2020;77(9):1745-1770. doi: 10.1007/s00018-019-03351-7
`6. Folkman J. Endogenous angiogenesis inhibitors. APMIS. 2004;112(7-8):496-507. doi: 10.1111/j.1600-
`0463.2004.apm11207-0809.x
`7. Udan RS, Culver JC, Dickinson ME. Understanding vascular development. Wiley Interdiscip. Rev. Dev. Biol.
`2013;2(3):327-346. doi: 10.1002/wdev.91
`8. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674. doi:
`10.1016/j.cell.2011.02.013
`9. Riihimäki M, Thomsen H, Sundquist K, Sundquist J, Hemminki K. Clinical landscape of cancer metastases. Cancer
`Med. 2018;7(11):5534-5542. doi: 10.1002/cam4.1697
`10. Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J. Clin. Invest.
`2022;132(11). doi: 10.1172/JCI159839
`11. Haibe Y, Kreidieh M, El Hajj H, et al. Resistance mechanisms to anti-angiogenic therapies in cancer. Front. Oncol.
`2020;10. doi: 10.3389/fonc.2020.00221
`12. Angiogenesis and Angiogenesis Inhibitors to Treat Cancer. Cancer.Net. Published November 1, 2018. Accessed June
`23, 2022. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/personalized-and-targeted-
`therapies/angiogenesis-and-angiogenesis-inhibitors-treat-cancer
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 9
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`IPR2023-00884
`Samsungetal. v. Regeneron
`Exhibit 2112
`Regeneron Pharmaceuticals,Inc.
`Page 10
`
`

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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2112 Page 11
`
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