Ann. Rev. Med. 1979. 30:8/�9
`
`
`
`
`Copyright © 1979 by Annual Reviews Inc. All rights reserved
`
`VALIDITY OF THERAPY
`FOR MILD HYPERTENSION
`
`.7307
`
`Edward D. Freis, MD.
`
`Veterans Administration Hospital and Department of Medicine,
`
`
`
`
`
`
`Georgetown University School of Medicine, Washington, DC 20422
`
`
`
`
`Hypertension affects at least one in ten adults in nearly every country in the
`
`
`
`
`world. It ranks third only to atherosclerosis and cancer as a cause of death.
`
`
`
`It is also a leading risk factor in atherosclerotic complications such as
`
`
`
`
`
`myocardial infarction, sudden death, and atherothrombotic stroke. Hyper­
`
`
`
`
`
`tension, therefore, is a double-edged sword. It produces complications spe­
`
`
`
`
`cifically related to hypertension per se, such as hemorrhagic stroke,
`
`
`
`
`
`congestive heart failure, and renal failure, and, in addition, it aggravates and
`
`accelerates atherosclerosis.
`
`RATIONALE OF TREATMENT
`
`are still unknown. hypertension The ultimate cause or causes of essential
`
`
`
`
`
`
`
`Except for rare secondary forms the goal in treating hypertension is not to
`
`
`
`
`cure the disorder but to control the blood pressure and, thereby, prevent
`
`
`
`
`hypertensive complications. This approach is based on the theory, which we
`
`
`can now regard as established from both animal experiments and clinical
`
`
`
`
`trials, that the major cardiovascular complications associated with hyper­
`
`
`
`
`
`tension are the result of damage produced directly by the elevated blood
`
`
`
`
`pressure. It has not been demonstrated, however, that reducing the elevated
`
`
`
`
`blood pressure will retard the development of the atherosclerotic complica­
`
`tions often associated with hypertension.
`The cardiovascular changes that characterize hypertension appear to be
`
`
`
`
`
`
`
`
`
`secondary to elevated blood pressure (1). Fibrinoid necrosis and hyalinosis
`
`
`
`
`
`of the arterioles probably represent adaptations to the increased blood
`
`
`
`
`
`pressure; cerebral microaneurysms, a frequent source of cerebral hemor-
`
`
`
`81
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-1
`IPR2016-00379
`
`

`
`82 FREIS
`
`rhage, may result from yield stresses produced by the hypertension; and left
`
`
`
`
`
`
`
`ventricular hypertrophy and dilatation represent adjustment to an increased
`
`
`
`afterload. The predisposition to atherosclerosis may be due to injury to the
`
`
`
`of antihyper­(2). The rationale arterial intima caused by the hypertension
`
`
`
`tensive treatment, therefore, is to reduce the blood pressure to a level where
`these damaging effects will not occur.
`
`EVIDENCE IN ANIMALS
`
`The complications of hypertension can be completely prevented by antihy­
`
`
`
`
`
`
`
`
`pertensive drug treatment in the spontaneously hypertensive rat (3). The
`
`
`
`Kyoto strain of spontaneously hypertensive rats develop a progressive ele­
`
`
`vation of blood pressure with increasing age; after one year they begin to
`
`
`
`
`die from cardiovascular complications associated with the hypertension. If
`
`antihypertensive agents are added to the drinking water their blood pres­
`sures remain at low levels and they develop none of the cardiovascular
`
`
`
`
`complications associated with hypertension. Furthermore, their life span
`
`
`increases by more than half that of the untreated animals and becomes the
`
`same as that of a normal rat (4). The treated animals tolerated the drugs
`
`and appear as very well; they gain weight normally, bear normal litters,
`
`
`
`active and healthy as normotensive untreated rats.
`The cardiovascular complications occurring in spontaneously hyperten­
`
`
`
`sive rats are in many respects similar to those found in hypertensive patients
`
`
`
`
`and include hemorrhagic stroke, congestive heart failure, and renal damage.
`
`The rat lesions differ from those in man, however, in one important respect.
`
`
`
`
`The rat is resistant to atherosclerosis and seldom exhibits such lesions even
`
`
`when plasma cholesterol levels are increased by diet. The complete protec­
`
`
`
`tion from cardiovascular lesions provided by treatment in the rat, therefore,
`
`
`
`applies only to hypertensive complications and not to atherosclerotic le­
`
`
`sions, which rarely occur in the spontaneously hypertensive rat.
`
`EARLY CLINICAL TRIALS
`
`The evidence in man is based largely on controlled clinical trials. The first
`
`
`
`
`
`of both trial was carried out by Hamilton and co-workers (5) in 61 patients
`
`
`
`
`sexes with severe essential hypertension. Patients were assigned alternately
`
`
`to either active drugs or to no treatment. Over a follow-up period of two
`
`
`to six years, there were significantly fewer complications in the treated
`
`
`
`patients than in the untreated group. Almost all of the treated patients who
`
`
`
`developed complications failed to achieve a reduction of diastolic blood
`
`
`pressure below 110 mm Hg. Most ofthe complications were of the hyper­
`
`tensive rather than the atherosclerotic type.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-2
`IPR2016-00379
`
`

`
`THERAPY 83
`HYPERTENSION
`
`A controlled trial carried out by Wolff & Lindeman (6) in 87 patients with
`
`
`
`
`
`moderate to severe
`
`indicated that over an average
`follow-up
`hypertension
`
`
`period of two years the incidence of morbid events in the treated patients
`
`
`was one third that observed in the placebo group.
`
`
`
`Carter (7) carried out a prospective randomized trial in 97 hypertensive
`
`stroke survivors. Over a period of three to five years 46% of the control
`
`
`
`
`patients died as compared to 26% of the treated group. Nonfatal strokes
`
`
`
`occurred in 23% of the control group as compared to 14% of the treated
`
`
`
`
`patients. However, in a well-controlled trial in patients with mild hyperten­
`
`
`
`
`
`sion who had survived a single stroke, Hoobler and his associates (8) found
`
`
`
`
`
`no significant protection against subsequent strokes by treatment.
`
`THE VETERANS ADMINISTRATION TRIAL
`
`The largest scale controlled trial was that carried out by the Veterans
`
`
`
`
`
`
`
`Administration Cooperative Study Group (9-11). This randomized, dou­
`
`
`
`
`
`ble-blind study included 523 male hypertensive patients, average age 49
`
`
`
`
`years, whose initial diastolic blood pressure ranged between 90 and 129 mm
`
`
`
`
`
`Hg (average of two clinic visits immediately preceding randomization).
`
`
`
`
`Many of the patients showed evidence of end-organ disease and all main­
`
`
`tained a diastolic blood pressure of 90 mm Hg or higher during a week's
`
`
`
`
`
`
`hospitalization. Patients were randomly assigned, double-blind either to a
`
`
`
`
`combination of hydrochlorothiazide, reserpine, and hydralazine or to place­
`bos of these drugs.
`The trial was terminated early in the subgroup of 143 patients with initial
`
`
`
`
`
`
`
`diastolic blood pressure averaging between 115 and 129 mm Hg (9). Of the
`
`
`
`
`70 patients in the control group 27 developed major cardiovascular compli­
`
`
`
`
`cations over an average follow-up period of only 20 months. Most of these
`
`
`
`
`complications were of the hypertensive rather than the atherosclerotic type.
`
`
`In the treated group of 73 patients there was only one major cardiovascular
`
`
`event, which was an atherothrombotic stroke. Two others were removed
`
`
`from the study because of side effects of the antihypertensive drugs.
`
`
`There remained in the trial 380 patients with mild to moderate elevations
`
`
`
`
`of blood pressure prior to randomization averaging between 90 and 114 mm
`
`
`
`Hg (10). These patients were followed for an average period of 3.3 years and
`
`
`some were followed for more than f ve years. Nineteen of the control
`
`
`
`
`patients died of cardiovascular complications as compared to eight in the
`
`
`treated group, a ratio of more than two to one in favor of treatment. All
`
`
`
`
`of the deaths occurring in the treated group of patients were related to
`
`
`
`
`atherosclerotic complications whereas the deaths in the control group were
`
`
`
`
`due to either hypertensive or atherosclerotic events. Since many of the
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-3
`IPR2016-00379
`
`

`
`84 FREIS
`
`patients had hypertension of long duration, it would be expected that they
`
`
`
`
`
`
`
`already had extensive atherosclerosis at the time of entry.
`
`The incidence of all morbid events both nonfatal as well as fatal was
`
`
`
`
`
`assessed by the life-table method of analysis (Figure 1). This indicated
`that
`
`
`
`over a five-year period the risk of developing a major cardiovascular compli­
`
`
`cation was reduced from 55% in the control group to 18% in the treated
`
`
`
`patients, a ratio of approximately three to one in favor of treatment. In
`
`
`addition to these morbid events there were 20 patients, all in the control
`
`
`
`group, who exhibited progression of their hypertension to above 120 mm
`
`
`Hg diastolic blood pressure and who were removed from the trial before
`
`they developed a major complication.
`The effectiveness of treatment was definitely related to the initial height
`
`
`
`
`
`
`
`
`of the blood pressure (10, 11). The striking effect of treatment in the group
`
`ALL MORBID EVENTS
`
`
`
`
`Estimated cumulative incidence of morbidity over a
`
`
`
`five-year period as calculated by life-table method.
`
`
`
`
`
`
`
`
`
`10%
`
`
`
`1
`
`3
`2
`4
`Years of Observation
`
`5
`
`Figure 1 Graph of estimated five year morbidity in the control vs the treated group of 380
`
`
`
`
`
`male patients with initial diastolic blood pressure in the range of 90- 114 mm Hg inclusive.
`(Data from Ref. 10),
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-4
`IPR2016-00379
`
`

`
`THERAPY 85
`HYPERTENSION
`
`with severe hypertension has already been described. The patients with mild
`
`
`
`
`
`
`
`
`to moderate hypertension were subdivided into two groups,
`those with
`
`
`
`
`initial diastolic levels of 90-104 mm Hg and the group with diastolic blood
`
`
`
`pressures of 105-114 mm Hg at entrance into the study. Treatment was
`considerably
`
`
`more effective in the latter than in the former or mild group.
`
`
`
`
`In the patients with moderate hypertension cardiovascular complications
`
`
`
`were four times higher in the control than in the treated patients. But, in
`
`the mild group the difference was less than two to one in favor of treatment.
`
`
`
`Because of this minor difference in incidence of complications and also
`
`
`
`because of the relatively small size of the mild subsample, the effectiveness
`
`
`of treatment for mild hypertension was left in doubt. It is worth noting,
`
`
`
`however, that progression to a more severe stage of hypertension and the
`
`
`
`
`development ofleft ventricular hypertrophy were not included as assessable
`
`
`
`morbid events. If they had been included the results would have indicated
`
`a greater effectiveness of treatment.
`
`
`US PUBLIC HEALTH SERVICE HOSPITALS TRIAL
`
`There are, as yet, no other controlled trials on mild hypertension in which
`
`
`
`
`
`
`the data have been published in full. The results of the study in the United
`
`
`
`
`States Public Health Service Hospitals conducted by Dr. W. McFate Smith
`
`
`
`have been published only in preliminary form (12). Their patients numbered
`
`
`
`389 and were followed for as long as seven years. In contrast to the Veterans
`
`
`
`
`Administration study, none of their patients exhibited evidence of end­
`
`
`
`they tended Furthermore, organ disease at the time of entry into the study.
`
`
`to be younger with an average age of 44 years as opposed to 49 years in the
`
`
`
`
`
`Veterans trial. The trial also included females as well as male patients.
`
`
`
`
`
`
`While they admitted patients with diastolic levels ranging between 90 and
`
`
`
`115 mm Hg, the majority of the patients had rather mild hypertension as
`
`
`
`
`indicated by the average admission blood pressure of 148/99 mm Hg.
`
`
`
`
`Over the seven-year period of follow-up, hypertensive complications oc­
`
`
`
`curred more than twice as frequently in the control as in the treated group.
`
`
`
`Most of the preventable complications appeared to be related to electrocar­
`
`
`
`
`
`diographic manifestations ofleft ventricular hypertrophy. The incidence of
`
`
`
`atherosclerotic events, however, including those related to coronary artery
`
`
`
`
`disease, was essentially the same in the treated and control patients.
`
`CORONARY ARTERY DISEASE
`
`Hypertension even of mild degree aggravates and accelerates atherosclero­
`
`
`
`
`
`
`sis (13). Atherosclerosis appears to be a response to injury to the arterial
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-5
`IPR2016-00379
`
`

`
`86 FREIS
`
`endothelium (2) that in many instances could be the result of the hyperten­
`
`
`
`
`
`sion. Hypertension also causes structural changes in the arterial walls such
`
`
`
`
`as disruption of the elastic lamellae and proliferation of fibrous and collage­
`
`
`
`nous connective tissue with resulting loss of distensibility of the arterial
`
`
`
`
`wall. The distention of arteries secondary to hypertension also may stretch
`
`
`the endothelium to make it more permeable to lipids. The question of
`
`
`
`reversibility of these changes with continued reduction of blood pressure
`has not yet been settled.
`In the Veterans Administration trial, treatment was highly effective in
`
`
`
`
`
`
`preventing the complications that are specifically related to the hyperten­
`
`
`
`sion itself as opposed to atherosclerotic complications. Hypertensive com­
`
`
`
`
`
`plications such as cerebral hemorrhage, renal functional deficits, congestive
`
`
`
`heart failure, and dissecting aortic aneurysm occurred exclusively in the
`
`control group. On the other hand, atherosclerotic events such as myocar­
`
`
`dial infarction, atrial fibrillation, and heart blocks appeared with approx­
`
`imately the same frequency in the control and treated patients. Smith
`
`
`
`found essentially the same differential effect of treatment on hypertensive
`
`
`
`as compared to atherosclerotic complications in patients with mild hyper
`tension.
`It might be argued that many of the patients entering the Veterans study
`
`
`
`
`
`were not representative of the general hypertension population because of
`
`age, hypertension oflong standing, and evident target-organ disease. There­
`
`fore, many of them may have had extensive sclerosis of their coronary
`
`
`
`arteries at the time of entry and the risk of myocardial infarction was great
`
`
`regardless of the level of blood pressure. However, as noted above, Smith's
`
`
`
`study in patients with uncomplicated mild hypertension provides similar
`
`
`
`results; the incidence of complications due to coronary artery disease was
`
`not significantly different in the treated and control groups (12).
`
`Neither the Veterans Administration study nor the Public Health Service
`
`
`
`Hospital trial were specifically designed to answer the question of the effect
`
`
`
`
`of treatment in preventing myocardial infarction. Larger scale studies cur­
`rently underway in the United States and other countries should provide
`
`
`
`more definitive evidence. For the present, it seems best to keep an open mind
`
`
`
`on the subject, although the prospects for achieving significant benefit with
`
`blood pressure reduction alone do not appear promising.
`Myocardial infarction is far and away the leading cause of disability and
`
`
`
`
`
`
`death in patients with mild hypertension. Such patients rarely develop the
`
`
`
`hypertensive complications that are so spectacularly benefited by treatment.
`
`
`The usual cause of death in untreated mild hypertension is either myocar­
`
`
`dial infarction or sudden death; if the patients survive to old age they may
`
`also die of atherothrombotic stroke.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-6
`IPR2016-00379
`
`

`
`
`
`HYPERTENSION THERAPY 87
`
`DECISION TO TREAT MILD HYPERTENSION
`
`Mild hypertension is herein defined as a diastolic blood pressure in the range
`
`
`
`
`
`
`
`
`of 90-104 mm Hg inclusive (fifth phase of Korotkoff sounds) over three or
`
`
`
`
`
`more successive office or clinic visits. The reasons for stipulating at least
`
`
`
`
`three visits is that the readings on the initial visit may be misleadingly high
`
`
`
`and also that blood pressure characteristically fluctuates over a wide
`range.
`It must be admitted at the outset that our knowledge of the value of
`
`
`
`
`
`treatment in mild hypertension is fragmentary. Yet, it is far and away the
`
`
`
`
`most frequently encountered form of hypertension in clinical practice. Ac­
`
`
`Health Survey, the prevalence of mild hypertension
`
`cording to the National
`
`
`is approximately five times higher than all other forms combined (14). The
`
`
`
`problem is ever with us and we must, therefore, make as prudent decisions
`
`
`
`
`as possible. To decide to treat all individuals with diastolic levels of 90 mm
`
`
`
`Hg or above would involve about 20 million patients in the United States
`
`
`
`
`(estimated number with such average levels over three visits), who would
`
`
`
`
`be receiving antihypertensive agents on a life-long basis. The cost and risks
`
`
`
`of such an undertaking are staggering. Before doing so we must be certain
`
`
`
`that the therapeutic program is justified. If drug therapy is of only question­
`
`
`
`
`able value we should ask whether its benefits justify the expense, inconve­
`
`
`
`
`nience, and possible toxic side effects associated with treatment. The
`
`
`
`
`common thread that ties together the results of the various therapeutic trials
`
`
`
`
`
`is that treatment is highly effective against hypertensive complications but
`
`
`
`
`is only questionably effective against atherosclerotic complications.
`
`
`
`
`
`Treatment, therefore, is definitely indicated whenever the risk of hyper­
`
`
`
`
`
`
`tensive complications is present. Also, the several controlled trials indicated
`
`
`
`that approximately 1-2% per year of mild hypertensives progress to a more
`
`
`
`
`
`severe stage. In the Veterans Administration trial this progression occurred
`
`
`mostly in younger patients. Also, the evidence is clear that electrocardio­
`
`
`
`
`
`graphic changes indicative of left ventricular hypertrophy are favorably
`
`influenced by treatment.
`Patients with mild hypertension who are at greatest risk of developing
`
`
`
`
`
`
`
`
`hypertensive complications or progression of hypertension are those with
`
`
`
`
`the following characteristics: (a) presence of target-orgaQ disease such as
`
`
`
`L VH, Group II fundi, etc; (b) age below 45 years; (c) black race; (d) males;
`
`
`
`(e) diastolic pressure above 95 mm Hg on each of three pretreatment visits;
`
`
`and if) family history of severe hypertensive disease.
`
`
`
`The more of these hypertensive risk factors that are present, the greater
`
`
`
`
`is the indication for treatment. Also, the more closely the average diastolic
`
`
`
`blood pressure approaches 105 mm Hg, the more likely it is that treatment
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-7
`IPR2016-00379
`
`

`
`88 FREIS
`
`will be undertaken. Both the height of the blood pressure and the number
`
`
`
`
`of other risk factors present are essential components in the therapeutic
`formula.
`The remaining individuals with mild hypertension are mostly those above
`
`
`
`
`
`the age of 45 who are without symptoms. This represents the largest group
`of the hypertensive
`
`
`population and their chief risk is the development of
`
`
`
`atherosclerotic complications. Although there is no proven effective preven­
`
`
`
`tive treatment for these patients it would seem prudent to utilize whatever
`knowledge we have short of exposing them to drugs. Such "hygienic"
`
`
`measures would include low-sodium and low-saturated-fat diets, regular
`
`
`
`exercise, weight reduction of the obese, and discontinuation of cigarette
`smoking.
`if future therapeu­
`
`A more aggressive approach will, of course, be justified
`
`
`
`tic trials produce evidence that antihypertensive drug treatment protects
`
`
`against the complications of coronary artery disease. Several recent con­
`
`trolled trials have indicated that beta-adrenergic-blocking drugs reduce the
`
`risk of myocardial infarction or sudden death (15, 16). While these studies
`
`
`
`
`need confirmation, they suggest that reducing the adrenergic drive to the
`
`
`
`heart may have protective effects independent of, or in addition to, simple
`
`reduction of blood pressure.
`
`SUMMARY
`
`Hypertensive patients are candidates for drug therapy when they are at risk
`
`
`
`
`
`
`
`of developing hypertensive complications. There is at present no evidence
`
`that drug therapy is effective when the risk is limited only to atherosclerotic
`
`
`complications. However, the question must be left open because of insuffi­
`cient data.
`Potential benefits of drug therapy must be weighed against potential risks,
`
`
`
`
`
`
`expense, and inconvenience. Patients at high risk of hypertensive complica­
`tions such as young black males probably should be treated even if the
`
`
`hypertension is mild. On the other hand, in patients with mild hypertension
`
`who are not at such risk it would seem prudent to utilize dietary and
`
`
`hygienic measures that may reduce atherosclerotic changes and that are not
`
`
`harmful in themselves. Whatever decision is made regarding drug treatment
`
`
`the patients must be followed at regular intervals because of the tendency
`for some to progress to a more severe stage.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-8
`IPR2016-00379
`
`

`
`Literature Cited
`
`
`
`HYPERTENSION THERAPY 89
`
`2. Ross, R., Glomset, J. A. 1976. Ther.a­
`
`1. Pickering, G. W. 1968. High Blood
`
`P7�ure, pp. 310-13, 351-52. �ew
`
`York: Grone & Stratton. 717 pp.
`2nd ed.
`
`morbidity: Results in patients with dias­
`
`tolic blood pressures averaging 11 5
`through 129 mm Hg. J. Am. Med. As­
`soc. 202:1028-34
`10. Ibid 1970. II. Results in patients with
`
`N. Eng. J.
`
`diastolic blood pressure
` 90
`thogenesis of atherosclerosis.
`
`through 114 mm Hg. J. Am. As­
`Med. 295:369-77
`soc. 213:1143-52
`3. Freis, E. D., Ragan, D., Pillsbury, H.,
`
`11. Ibid 1972. III. Influence of age, diastolic
`Mathews, M. 1972. Alteration in the
`
`
`pressure and prior cardiovascular dis­
`
`course of hypertension in the spontane­
`
`ously hypertensive rat. Cire. Res.
`
`ease; further analysis of side effects. Cir­
`culation 45:991-1004
`41:1-7
`4. Freis, E. D., Ragan, D. 1976. Treat­
` Co­
`12. US Public Health Service
`Study Group. w. M.
`operative
`
`ment and longevity in spontaneously
`
`(Chairman). 1977. Treatment of mild
`
`hypertensive rats (SHR). Clin. Exp.
`Pharmacol Physiol Suppl. 3, pp. 75-78
`
`
`hypertension. Results of a ten-year in­
`
`tervention trial. Cire. Res. 40: Suppl. I,
`
`5. Hamilton, M., Thompson, E. �., Wis­
`pp.98-105
`
`neiwski, T. K. M. 1964. The role of
`
`blood pressure control in preventing
`13. Freis, E. D. 1969. Hypertension and
`
`
`atherosclerosis. Am. J. Med. 46:735-40
`
`
`complications in hypertension. Lancet
`1:235-38
`14. �ational Health Survey. 1966. Hyper­
`6. Woltf, F. W., Lindeman, R. D. 1966.
`
`tension and hypertensive heart disease
`Effects of treatment in hypertension:
`in adults. 1960-62, US Dept. Health,
`
`Results of a controlled study. J. Chronic
`
`Educat. Welfare, Vital Health Stat. Ser.
`Dis. 19:227-40
`
`II, �o. 13. Washington, DC: GPO
`7. Carter, A. B. 1970. Hypotensive
`
`15. Wilhelmsson, C., Vedin, J. A., Wil­
`helmsen, L., Tibblin, G., Werko, L.
`
` in stroke survivors. Lancet 1:
`
`1974. Reduction of sudden deaths after
`8. Hypertension-Stroke
`
`Cooperative Study
`
`myocardial infarction by treatment
`Group. 1973. Stroke recurrence after
`
`
`with alprenolol. Preliminary results.
`
`antihypertensive therapy. Circulation
`Lancet 20:1157-60
`48: Suppl. IV-84 (Abstr.)
`16. Ahlmark, G., Saetre, H., Korsgren, M.
`
`
`
`9. Veterans Administration Cooperative
`
`1974. Reduction of sudden deaths after
`Study Group on Antihypertensive
`
`myocardial infarction. Letter to the edi­
`
`Agents. 1967. Effects of treatment on
`tor. Lancet 2:1563
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1028-9
`IPR2016-00379