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`
`Novartis Exhibit 2180.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Biocompatib1lity of Materials m Medical Devices
`
`Table la Classification s of medical devices marketed in the uni ted states
`
`Class
`
`Type of dev ice
`
`FDA filing requi red
`
`II
`
`m
`
`Crutches, bedpans, depressors, adhesive
`bandages, hospi tal beds
`Hearing aids, blood pumps, catheters
`con tact lens, electrodes
`Cardiac pacemakers, intrauterine devices,
`intraocular lens, heart valves, orthopedic
`devices
`
`PMN/S I0K
`
`5 1 0(k)
`
`PMA
`
`PMN, premarket notification.
`
`Table lb Classifications of med ical dev ices of the european union
`
`Class
`
`Type of device
`
`Stethoscopes, hospital beds, wheelchairs
`
`Ila
`
`li b
`
`Ill
`
`Heari ng aids, electrographs, ultrasound
`assessmen t equipment
`Surg ical lasers, infusion pumps, ven tilators
`Intensive care moni toring equ ipment
`Ball oon catheters, heart valves
`
`Reg ulatory requirements
`
`Techn ical file, other
`assurances
`Technical file, conformity
`
`Techn ical file, type
`examination
`Aud it of quality assurance,
`examination of des ign
`
`the host. All materials used in devices will elicit a response
`from the host; it could be an immediate response, one that is
`prolonged, or even a de layed reaction that occurs sometime after
`contact with the dev ice. The outcome of the response depends
`on the site of implan tation, the spec ies of the host, the genet ic
`makeup of the host, and the sterility of the implan t. All imp lants
`have a significantly greater rate of infoction when compared
`with the background rate assoc iated with the surgi cal procedure
`performed in the absence of the dev ice. At the very least, an
`implant shou ld not interfere with biological processes that are
`required fo r normal homeostasis of the host.
`
`Biological Systems-Which
`Ones Are Important for Normal
`Homeostasis and Survival?
`
`Devices in contact with the external tissues such as skin typ(cid:173)
`ically are considered separately fro m a biocompatibil ity per(cid:173)
`spective fro m dev ices implanted internally. Implantable dev ices
`affect biological processes that involve blood; therefore, the test(cid:173)
`ing of these devices is somewhat more complicated. Many skin
`contact devices are used short term, and therefore biocompatibil (cid:173)
`ity testi ng is limi ted. However, for permanent internal implants,
`the requ ired testing can be as long as several years and re(cid:173)
`quire analysis of the effects of the device on cells and ti ssues
`as well as on heal ing responses that occur at the interface be(cid:173)
`tween the tissue and the dev ice. For this reason, it is important
`to understand which biological systems may be affected when
`permanen t implants are to be used.
`
`Biological processes involved in host-t issue responses to
`implantabl e medical dev ices reflect the activation of a se(cid:173)
`ries of cascades that require blood proteins or other compo(cid:173)
`nents found in blood. Biological systems activated by implan ts
`include blood clotting, platelet aggregation, complemen t ac(cid:173)
`tivation , kin in formation , fibri nolysis, phagocytosis, imm une
`responses, and wound hea ling ( I) (Table 2). Wound healing
`in volves several biological processes, including blood clott ing,
`in flammat ion, dilat ion of ne ighbori ng blood vessels, accumu la(cid:173)
`tion of blood ce lls and flu id at the point of contact, and fina ll y
`deposition of fibrous ti ssue around an implan t. Vasod il at ion of
`blood vessels and accumu lation of interstitial fl uid arou nd an
`implant can occur through activation of the kinin and com(cid:173)
`plement pathways ( I). Phagocytosis of dead ti ssue occu rs by
`attract ion and migration of inflammatory cells to the site of in(cid:173)
`j ury near an imp lant. The inflammatory ce lls attracted include
`neutrophils and monocytes that are present 10 digest dead tissue
`and implant materials. Once phagocytosis occurs, it may lead
`to di gestion of imp lant remnants and forma tion of fib rous scar
`tiss ue around the implant. If a large blood clot surrounds an
`implant, then fi bri nolysis must proceed to remove the clotted
`blood before the heali ng process can be completed ( I).
`Blood proteins are invo lved in the lysis of fore ign cells via the
`complement pathway ( I). Thi s mechani sm involves activation
`of comp lement proteins in the presence of an ant ibody-antigen
`complex attached to the surface of a foreign cell. Components
`of the complement pathway are sometimes com promised by
`act ivation and/or adsorption onto the surface of a medical de(cid:173)
`vice. Thi s action leads 10 comple men t co mponent depletion that
`causes the patient to be at ri sk fo r bacterial in fection and makes
`evaluation of complement depletion an important aspect of the
`
`2
`
`WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY © 200B, John Wiley & Sons, Inc.
`
`Novartis Exhibit 2180.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Biocompat1bility of Materials m Medical Devices
`
`Table 2 Biological systems affected by medi cal devices ( I)
`
`System
`
`Funct ion
`
`Dev ice effect
`
`Blood clotting
`
`Maintains blood fl uidi ty
`
`Complement
`Fibrinolys is
`
`Prevent s bacterial invasion
`Degrades blood clots
`
`Immune responses
`
`Limits infec tion
`
`Kin in forma tion
`
`Causes vasodilati on
`
`Pl atelet aggregat ion
`Phagocytosis
`
`Lim its bleeding
`Limits infection
`
`Wound healing
`
`Repairs ti ssue defects
`
`Clot fo rmation-
`occl usion
`Depletes complement
`Degrades tiss ue
`grafts
`Prolongs
`infl ammation
`Prolongs
`infl am mation
`Shortens platelet life
`Prolongs
`Inflammation
`Promotes fibrous scar
`Tissue
`
`design of cardiovascular devices. Act ivated complemen t com(cid:173)
`ponents also pro long infl ammati on by generating CJa and C5a,
`which are agent s that cau se vasod il ation. Complement activation
`is associated with and contributes to who le-body infl ammation ,
`wh ich is observed as a complication to cardi opulmon ary bypass.
`Compl ement activat io n is responsible fo r hyperac ute rejection
`of anim al tissue grafts (2) and is important in reactions to im(cid:173)
`plants (3-5).
`Most foreig n surfaces cause blood to clot as a result of di(cid:173)
`rect con tact with a fo re ign surface. Thi s cl otting occu rs via the
`intrinsic cl ottin g cascade or from injury to tissue that develops
`during im plantat ion as result of act ivation of Hageman factor
`and fac tor IX, whi ch are two prote ins fou nd in blood (Table 2).
`Pl atelets, which are enucleated cell s, are also found in blood;
`they re lease factors that contribute to formation of blood cl ots.
`Devices used in the card iovascul ar syste m normall y are de(cid:173)
`signed to li mit the ir propensity to clot blood. In the case of
`card iovascul ar dev ices, excessive blood clotting will cause the
`device to occlude; in these applications, blood clotti ng is min(cid:173)
`imized. Because fo reign materials ty pi ca ll y cause blood clot s,
`they are onl y used to replace large and medium-sized vessels.
`Host vessels are used to rep lace the func tion of small -diameter
`vesse ls. Several tests are used to measure blood clott ing and
`platelet aggregation caused by contact with a medical device
`(6-8).
`In add ition to act ivating blood clotting (9), act ivated Hage(cid:173)
`man factor activates prekalli krein of the kin in system, whi ch
`leads to bradyk in in that cau ses vasc ular vasodi lation. Acti va(cid:173)
`tion of Hageman fac tor and blood clotti ng also leads to the
`conversion of plasmi nogen 10 plasmin which in it iates the degra(cid:173)
`dation of fibrin for med duri ng clotting by a process termed
`fibrinolys is (I).
`Phagocytic cells including neutro phil s and mac rophages, coat
`med ical dev ices either from direct blood contact or via inflam(cid:173)
`mation and ex travascular movement of these ce ll s in to the ti ssue
`fluids that surround a device. In either situation, first neu trophi ls
`and then monocy tes arrive in the area arou nd the dev ice and at(cid:173)
`tempt to degrade the implant. If the implant is biodegradable,
`then these cell s remain unt il the dev ice is totall y removed. If
`
`the dev ice is nondegradabl e, then the number of ce ll s surround(cid:173)
`ing an implant will depend on the how react ive the implant is.
`For example, although Dacron vascular grafts are permanent de(cid:173)
`vices, monocytes can be observed surround ing the implant fo r
`months and years. In some pat ients, cont in ued reacti vity can
`cause peri- im plant fl uid accumu lat ion, whi ch if left uncorrected
`can require impl ant remova l. In other cases where contact of tis(cid:173)
`sue with the im plant causes a prolonged in flammatory respo nse,
`other white blood cells incl udin g eosinophils, B cell s, and T
`cells can be observed in the vici nity of the device. These cell s
`are an indi cat ion of ei ther an allergic react ion or the fo rmation
`of ant ibodies that st imu late prolonged infl ammati on. Measure(cid:173)
`ment of in fl amm atory ce ll s surroundi ng an impl ant is usuall y
`accom pli shed by direct hi stological evalu ation ( 10- 12).
`As phagocyt ic cells acc umulate near the implant, they elab(cid:173)
`orate hydrolytic enzy mes that degrade both the implant and the
`surround ing ti ssues; fibro blasts and endothel ial cell s are also mi(cid:173)
`gratin g into the area aro und the device and begin to lay dow n
`new ex tracell ular matrix with capi ll aries and coll agen fibrils
`( I). Thu s, the wound healing process invo lves inflammat io n,
`re moval of the implant and tissue components, as well as the
`deposi tion of new extracellu lar matrix. If the implant is no n(cid:173)
`degradable and nonporous, then a fi brous capsule fo rms arou nd
`it. The thickness of the fibro us capsule depends on the degree
`of inflammation caused by the dev ice. If the implant is porous,
`the dev ice may biodegrade and lead to the formation of a small
`amount of fibrous scar ti ssue in the defect when the imp lant is
`removed. In some cases, however, after the impl ant bi odegrades,
`an abundance of scar tissue can be deposi ted where the implant
`was prev iously observed. The thickness of the fibrous capsule
`formed around an implant is usuall y measu red hi stologically.
`Wear part icles generated by a moving dev ice can lead to
`prolo nged in fla mmation and even im pl ant fa il ure in the case of
`hip and knee impl an ts. Small polymeric or metall ic part icl es,
`which are about I µ m in diameter, are ingested by neutrophils
`and monocytes and may lead to necrosis of these cells and the
`re lease of infl ammatory med iators into the wound area. Large
`particles arc surro unded by mo nocytes, which fo rm multin ucle(cid:173)
`ated giant cells that can in many cases be tolerated by ti ssues
`
`WI LEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY © 2008, John Wiley & Sons, lnc.
`
`Novartis Exhibit 2180.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Biocompatib1lity of Materials m Medical Devices
`
`without lead ing to imp lant failu re. However, once wear part icles
`are released fro m the implant , they can migrate to other ti ssues
`or even to local lymph nodes causing swelling and systemic
`problems. Impl ant wear particl es are quantitati vely determ ined
`from hi stolog ical and electron-microscopic stud ies ( 13- 15).
`
`Types of Tests-What Types
`of Tests Are Used?
`
`Two types of regul atory approval s ex ist for medical dev ices in
`the United States, 5 10(k) notifi cation and premarket approva l
`(PM A). The types of tests requi red fo r approval depend on the
`classifi cation of the medical dev ice. 510(k) noti ficati on in volves
`marketing a dev ice that is substanti all y equi valent to a dev ice
`on the market prior to 1976. All dev ices introduced after 1976
`that are not substant iall y equivalent to devices on the market
`before 1976 are automaticall y class ified as Class 3 dev ices and
`require PMA ( 16). For a dev ice to be considered substanti all y
`equi valent to a dev ice on the market before I 976, it must have
`the same intended use, no new tec hnological characteristics,
`and have the same performance as one or more dev ices on the
`market prior to 1976. In addit ion, all medi cal dev ices mu st be
`sterili zed either by end-sterili zation or by some other accept(cid:173)
`able means that can be validated, which means that any test
`done in cell culture or in an animal model must be conducted
`on a dev ice that has been validated to be sterile. Sterility vali(cid:173)
`dation is conducted on all medical dev ices as described in the
`literature ( 17).
`The testing conducted on biomaterials intended for use in
`medi cal dev ices mu st address safety and effecti veness criteri a
`th at depend on the intended use as described above as disc ussed
`in depth the literature ( 18, 19). The spec ifi c tests required vary
`with the type of device and application; however, some general
`testing is usually recommended. Norm all y, an imal testing is
`conducted 10 demonstrate that a medical dev ice is safe, and
`when implanted in humans that the dev ice will reduce, all ev iate,
`or eliminate the possib il ity of adverse medi cal reactions or
`conditions ( 17).
`According to the American Society of Testi ng Materials
`(ASTM ) Medical Dev ices Standards (A nnual Book of ASTM
`Standards, Section 13, Medical Devices, ASTM 1916 Race
`Street, Phi ladelphia, PA 19103; availab le at ww1v.ast111. 01:g), the
`type of generic biological 1esl methods fo r material s and dev ices
`depend s on the end-use appli cation. The ASTM as well as the
`International Organi zation for Standard ization (ISO) publishes
`standards fo r testing medical dev ices as listed in Tables 3 and 4.
`Biological reactions that are detrimental to the successful use
`of a materi al in one dev ice app li cation may not be applicable
`to the success of a material in a different end use. A list of
`potenti all y applicable bi ocompatibi lity tests that are related to
`the end use of a materi al and/or a device is given in Table 3 as
`a start ing point. These tests are as follows:
`
`Cell culture cytotoxicity
`
`This test is used 10 evalu ate the toxicity of a material i11
`vitro or an ex tract of a materi al used in a device. Several
`
`Table 3 Biolog ical tests used to evaluate bi ocompat ibilily
`based on ASTM medical device standards, sect ion 13
`
`Test
`
`ASTM standard
`
`Cell culture cytotox icity
`Skin irritation
`Intramu scular and subcutaneous implant
`Blood compatibility
`Hemo lysis
`Carcinogenesis
`Long-term implantation
`Mucous membrane irritation
`Systemic injection acute toxicity
`ln1racu1aneous injection
`Sensitization
`Mutagenicity
`Pyrogeni city
`
`F748
`F7 19
`F748
`F748
`F756
`F748
`F748
`F748
`F750
`F749
`F720
`F748
`F748
`
`di ffe rent tests have been used and have produced a spectrum
`of biocompatibili1 y assessments on the same material (20-22).
`The tests used measure the viability of cells in contact with a
`material or an extract of a material. A variety of cell lines can
`be used; however, a modified fib roblast line is usuall y 1he go ld
`standard. Some tests used incl ude I) direct cell culture, 2) agar
`di ffusion testing, 3) filter di ffusion testing, and 4) barrier testing
`(22).
`As pointed out by Learmonth (23), although the in1ac1 im plant
`may not be cytotoxic to ce lls, an y material and mechani cal
`flex ural mismatch may lead to release of wear part icles that can
`exc ite a cywchemical reaction that culm inates in inflammation
`and cell cytotoxicity. The generation of wear particles and their
`size is of part icular importance to the failure of joint implant s
`through a process termed os1eolysis (23 ).
`
`Skin irritation assay
`
`This 1es1 in volves applying a patch of the materi al (or an extract
`of the materi al) to an area of an animal th at has been shaved;
`in some cases 1he skin is abraded before the test material is
`app lied. After 24 hours of contact, the patch is removed, and
`the skin is graded fo r redness and swel ling. The grading scale
`can vary from Oto 4: 0 means no redness and/or swelling and 4
`means ex tensive redness and/or swe ll ing. Standard test material s
`are used to evaluate skin irritation (24).
`
`Short-term intramuscular implantation
`
`This test is designed to evalu ate the reaction of ti ssue to a
`device for peri ods of 7 to 30 days. This test can be cond ucted
`in 1he mu scle below the skin in rabbits or rodent s including
`mi ce, rats, and guinea pi gs. At the concl usion of the test period,
`the samples are graded both visuall y and based on analysis
`of hi stol og ical sections. A test described in the United States
`Pharmacopia (USP) is widely used. The purpose of thi s test is to
`evaluate the in flammatory potent ial (e.g., redness and swelling)
`grossly. In some cases, hi stological evalu ation of the ti ssue is
`performed at the li ght and electron microscopic levels 10 look
`fo r phagocytic and immu ne cells. Some in vestigators use an
`
`4
`
`WILEY ENCYCLOPEDIA OF CHEMI CAL BIOLOGY © 200B, John Wiley & Sons, Inc.
`
`Novartis Exhibit 2180.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Biocompat1bility of Materials m Medical Devices
`
`Table 4 Biological evaluati on of med ical devices based on ISO standards
`
`Test
`
`Part I: Evaluation and testing
`Part 2: An imal welfare requi rements
`Part 3: Tests fo r genotox icity, carcinogenici ty and
`reproductive toxicity
`Part 4: Selection of tests for interactions wi th blood
`Part 5: Tests for in vitro cytotox ici ty
`Part 6: Tests fo r local effects after implantation
`Part 10:Tests fo r irritation and delayed-type hypersensiti vity
`Part 11 :Tests fo r syste mi c toxic ity
`
`ISO standard
`
`I 0993- 1 :2003
`I 0993-2:2006
`10993-3:2003
`
`I 0993-4:2002
`10993-5:1999
`I 0993-6:2007
`10993- 10:2002
`I 0993- 11 :2006
`
`intram uscu lar implantat ion site because the blood suppl y and
`hence the inflammatory poten ti al may be easil y eval uated. In
`addit ion, the res ults of short-term implantation tests may not
`reflect material-mediated inflammatory responses that may al so
`occur (25).
`
`Short-term subcutaneous implantation
`
`Thi s test is an alternative for studying the reaction of tissue to a
`device for a period of days to weeks. In this test, a tissue pocket
`is made in the ski n above the muscle layer, the dev ice is inserted
`into the pocket, and the pocket is su tu red or stapled closed.
`Normall y the device is placed deep into the pocket away from
`the site of insertion of the device so that reactions at the suture
`or cl ip site do not affect the eva luation of biocompatibility.
`Although short-term implantation studies do give an analys is of
`the bioco mpatibil ity of a material at a local site; systemic effects
`can also be observed from corros ion prod ucts that develop from
`vasc ular imp lant s that migrate to other sites (26).
`
`minutes at 37°C (3 1). The amou nt of hemoglobi n re leased into
`solution after lys is of the red cells in contact with the device is
`measured. When red cells undergo \ysis, hemoglobin is released
`from the ce lls, and the absorbance from released hemog lobin
`is proportional to the amount of cell lys is. Extensive red-cell
`lysis is not des irable for devices that are to be imp lanted in the
`card iovascular syste m. The measurement of hemolysis and its
`relevance is a question that shou ld be addressed it each device
`application.
`
`Carcinogenicity
`
`Carcinogenicity test ing in volves long-term implantation (up to
`2 years) in an animal model usually under the ski n to look
`fo r tumor fo rmat ion (32). This test is req ui red for dev ices
`that emp loy materials that have not been ex tensively tested.
`Typicall y these tests are conducted in rodents, although rodents
`do form tumors to most solid implants (I).
`
`Blood coagulation
`
`Long-term implantation tests
`
`Blood coagulat ion is normally assessed by determi nation of
`clotti ng times and extent of platelet aggregation ini ti ated by
`the device surface in either static or dy nami c systems. In a
`dynam ic test, blood flo ws through the device or over a test
`surface made of the materials used in the dev ice. This test
`is normally conducted on blood-contacting devices to ensure
`that the blood-coagulation and platelet-aggregation pathways
`are not modified . The tests are conducted in vitro us ing human
`or an imal blood, ex-vivo in a flow chamber using anim al blood,
`or in vivo in an animal model. It has been noted that variability
`in the resu lts using standard materials is noted in ex-vivo tests
`of blood compat ibility; thi s finding is attributed to the type of
`anima l model used, the flow velocity, the time of exposure, and
`the method used to measure blood cell ad hesion (27). Studies
`of stents used in the cardiovascular system illustrate that clot
`or thrombus formation is depende nt on the type and des ign of
`the device (28, 29) and may be influenced by the corrosion of
`metalli c implants (30).
`
`Hemolysis
`
`Hemolys is is determined by placi ng powder, rods, or extracts of
`a materi al in contact with human or an imal plasma for about 90
`
`These tests are covered by ASTM specifica tions F36 \ and
`F469 for muscle and bone, respective ly. Implant materials are
`placed in the muscle as a soft-tiss ue mode l and in bone as a
`hard-tissue model. T he implan tation site is eva luated gross ly and
`histolog icall y for inflammation, giant cell formatio n, signs of
`implant movement, and for tissue necrosis. Although long-term
`implantation gives so me indication of biocompatibility, it does
`not consider issues such as biofilm for mation, infection, and
`encrustation associated with use of devices such as urologic
`implants (33). It is recommended that long-term imp lantation
`tests be conducted on a model relevant to the intended end
`use. In addition , the effect of wear particles is an important
`considerat ion with long-term implantation (23).
`
`Mucous membrane irritation
`
`Mucous membrane irri tation is eva luated by placing a mate(cid:173)
`ri al in close prox imity to a mucous membrane such as the oral
`mucosa. The test eval uates the amou nt of irritation and infl am(cid:173)
`mat ion from gross and hi stological measurements. The hamster
`cheek pouch or oral mucosa is a model freque ntly used for this
`test (34).
`
`WI LEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY © 2008, John Wiley & Sons, lnc.
`
`s
`
`Novartis Exhibit 2180.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`    
`    
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