`Hale BioPharma Ventures, LLC
`
`59
`
`EPA-124 519
`02.11.2017
`
`St. Dev.
`
`0.0097
`
`% RSD
`
`7.14
`
`0.0095
`
`6.76
`
`0.8884
`
`8.34
`
`9.0649
`
`8.34
`
`Table 5-10: Solution 02 25°C/60% RH spray content uniformity results
`
`Weight
`
`Weight
`
`Diazepam
`
`% Diazepam
`
`Sample
`
`Collected, g
`
`Actuated, g
`
`Recovered, mg
`
`Recovered
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`0.12280
`
`0.13318
`
`0.13260
`
`0.12064
`
`0.13215
`
`0.13559
`
`0.13158
`
`0.13357
`
`0.12611
`
`0.13549
`
`0.13452
`
`0.12305
`
`0.13582
`
`0.13790
`
`0.13371
`
`0.13495
`
`0.12165
`
`0.12443
`
`8.88043
`
`9.55581
`
`9.71837
`
`9.48123
`
`9.34463
`
`9.48722
`
`9.43613
`
`9.79164
`
`8.84732
`
`Average
`
`0.12931
`
`0.13178
`
`9.394
`
`90.62
`
`97.51
`
`99.17
`
`96.75
`
`95.35
`
`96.81
`
`96.29
`
`99.91
`
`90.28
`
`95.85
`
`3.3701
`
`St. Dev.
`
`0.0058
`
`% RSD
`
`4.52
`
`0.0056
`
`4.25
`
`0.3303
`
`3.52
`
`3.52
`
`Table 5-11: Solution 02 40°C/75% RH spray content uniformity results
`
`Weight
`
`Weight
`
`Diazepam
`
`% Diazepam
`
`Sample
`
`Collected, g
`
`Actuated, g
`
`Recovered, mg
`
`Recovered
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`0.12336
`
`0.12563
`
`0.05723
`
`0.13554
`
`0.13619
`
`0.05792
`
`0.13908
`
`0.13679
`
`0.13227
`
`0.13414
`
`0.13331
`
`0.13455
`
`0.13314
`
`0.13249
`
`0.13515
`
`0.13844
`
`0.13736
`
`0.13387
`
`9.02005
`
`9.43076
`
`9.93829
`
`9.87755
`
`9.64403
`
`9.80808
`
`9.31952
`
`9.28106
`
`9.32935
`
`92.04
`
`96.23
`
`101.41
`
`100.79
`
`98.41
`
`100.08
`
`95.10
`
`94.70
`
`95.20
`
`Average
`
`0.12423
`
`0.12649
`
`9.517
`
`97.11
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0501
`
`page 0501
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`60
`
`EPA-124 519
`02.11.2017
`
`St. Dev.
`
`0.0254
`
`% RSD
`
`20.45
`
`0.0260
`
`20.57
`
`0.3148
`
`3.31
`
`3.2119
`
`3.31
`
`
`
`
`
`4
`
`2:
`
`4
`
`4
`
`:5
`
`4
`
`9
`
`942843
`
`942999
`
`4245366
`
`9.44944
`
`9.44244
`
`4—3—6844;
`
`94441-5
`
`9443154
`
`4499449
`
`94—34%
`
`94—3344
`
`44—4-8415
`
`9445.44
`
`9.44744
`
`444452-94.
`
`944%}
`
`9—749
`
`499—64
`
`494—34
`
`Jr9444
`
`9.43229
`
`91-19441-
`
`448—71854
`
`496—28
`
`9.44441-
`
`944949
`
`44—86—7322
`
`4-9649
`
`We
`
`9.439%
`
`944499
`
`9.9944
`
`44—25%
`
`9-6699
`
`4—94-99
`
`4-7-144-
`
`844994—
`
`979949
`
`
`
`944444
`
`9.44999
`
` 4
`
`49-94449
`
`99-29
`
`'4
`
`9
`
`4
`
`9
`
`9
`
`4
`
`9
`
`9
`
`944999
`
`944454
`
`4494444
`
`9-1-4949
`
`94.4499
`
`43-49499
`
`944694
`
`994949
`
`4499949
`
`944994
`
`944399
`
`4994399
`
`9-4-3494
`
`944299
`
`49-24999
`
`944344
`
`9-4-3594
`
`49-44994
`
`942-999
`
`942599
`
`4444944
`
`944499
`
`944944
`
`4499594
`
`9444
`
`99-44
`
`99-59
`
`99-59
`
`9494
`
`95-99
`
`492-59
`
`9949
`
`44194499
`
`944744
`
`944949
`
`44434
`
`94-94
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0502
`
`page 0502
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`61
`
`EPA-124 519
`02.11.2017
`
`
`
`Jr
`
`3
`
`4
`
`§
`
`~7-
`
`9
`
`943694
`
`94999—75
`
`$593419
`
`92—673
`
`94%2—94
`
`94942—5
`
`394E519
`
`497—34
`
`94497—28
`
`944949
`
`25—18894
`
`94§3§§é
`
`9.4%493
`
`26—69424
`
`9249
`
`9%«93
`
`94§448
`
`9% 98-43494
`
`494—54
`
`94-54-94
`
`9-4—5393»
`
`96—92996
`
`95—82-
`
`W 94494-1-
`
`94—é42—é
`
`94—499
`
`9848
`
`W 3:49
`
`9:59
`
`5—7—5
`
`54-5
`
`
`
`
`
`
`
`
`
`4
`
`3
`
`4
`
`5-
`
`6
`
`$1
`
`9
`
`94—35524
`
`9.434931
`
`2844-588
`
`4996;
`
`944989
`
`944495
`
`96—48985
`
`99—68
`
`94996—2
`
`94—32149 W 493-83
`
`942948
`
`94968.3: W 94—85
`
`94442—3
`
`9.44541-
`
`2%94—3—3
`
`49—149
`
`94—3992
`
`944996 W 9466
`
`94499;;
`
`9.45344 W 91249
`
`Wage
`
`943196
`
`94499;
`
`2-7434
`
`98468
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0503
`
`page 0503
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`62
`
`EPA-124 519
`02.11.2017
`
`Example 6
`
`WIMIM All of the solutions and—suspensions—described in Examples 3 Wand formulated as
`
`described in Examples 3—aHd—4, with the addition of a suitable amount of an alkyl glycoside, as described
`
`herein, such as dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose
`
`distearate, and/or combinations of two or more thereof, or marketed as Intravail® by Aegis Therapeutics, San
`
`l Diego, CA. The solutions WWwith added alkyl glycoside may then be put up on stability as
`described in Example 5, mutatis mutandis.
`
`Example 7
`
`The solutions and—suspensions—of Examples 3,—4 and 6 are evaluated for pharmacokinetics in a
`l WIMWI
`suitable animal model, such as in mice, rats, rabbits or dogs. First each animal (e. g. rabbit) is administered an
`
`amount of a benzodiazepine drug intravenously. The amount of intravenously dosed benzodiazepine drug is
`
`selected to be less, e.g. roughly half, of what is considered an effective dose administered nasally. For
`
`example, the intravenous dose of diazepam administered to rabbits is about 0.05 to about 0.2 mg/kg, e. g. about
`
`0.1 mg/kg. Blood is collected immediately before administration and at specific time points post-
`
`administration. Plasma blood levels of the drug are assayed for each of the blood samples. After at least a one
`
`day washout period, each animal is administered, intranasally, an amount of a solution Was
`
`described in Examples 3,—4 and 6. Blood is collected immediately before administration and at substantially
`
`the same specific time points as the IV dose post-administration. Pharmacokinetic curves (blood plasma
`
`concentration of drug versus time) are constructed for the intravenous route of administration and for each of
`
`the solutions andsu—spensions—administered by the intranasal administration route.
`
`WJMWI
`
`Toxicity is assessed by known means. In particular, histological samples are collected from
`
`the nasal mucosal tissues of the test animals. Other toxological methods are optionally employed as well.
`
`Example 8
`
`WIMWI
`
`The solutions and—suspensiefis—of Examples 3,—4 and 6 are evaluated for their ability to deliver
`
`drug across the blood brain barrier in a suitable animal model, such as in mice, rats, rabbits or dogs. Each
`
`animal is administered, intranasally, an amount of a solution eF—suspen—sien-as described in Examples 3:4 and
`
`6, with the solution ersuspens—ien—optionally containing an imaging agent, such as a dye, that may be used as a
`
`proxy for determining the ability of the drug to cross the blood brain barrier. The drug or imaging agent is
`
`detected at selected time points after administration of the suspension—or solution to determine how well the
`
`drug or imaging agent crosses the blood brain barrier. These results may be compared with analogous result
`
`obtained with an intravenous solution containing the drug or imaging agent.
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0504
`
`page 0504
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`63
`
`EPA-124 519
`02.11.2017
`
`Example 9
`
`The above-described solutions—andler—suspens-iens can be evaluated for pharmacokinetics in
`l Wlwml
`humans. Normal, healthy human test subjects are administered an amount of the drug intravenously. The
`
`amount chosen for intravenous administration may be any amount, but is conveniently a dose that is
`
`considered effective in treating seizure in humans. For example, an IV dose of diazepam administered to
`
`humans may be in the range of 1
`
`to 15 mg, e.g. about 7.5 mg. Blood is collected immediately before
`
`administration and at selected time points after administration. Plasma blood levels of the drug are assayed for
`
`each of the blood samples. After at least a one day washout period, each subject is administered, intranasally,
`
`an amount of a solution m—suspension—as described herein. Blood is collected immediately before
`
`administration and at substantially the same time points after administration as the intravenous time points.
`
`Pharmacokinetic curves (blood plasma concentration of drug versus time) are constructed for the intravenous
`
`and intranasal administration routes.
`
`Example 10
`
`WIMWI
`
`The above-described solutions ' can be evaluated for efficacy in a suitable
`
`animal model. Briefly, for each dose of suspeiasiefi—er—solution to be tested, a test animal is stimulated with a
`
`seizure inducing stimulus. The stimulus may be light, sound, chemical or other stimulus effective to induce
`
`seizure in the model animal. Once the animal has begun to seize, a solution mansion—as described herein
`
`is administered intranasally to the animal. The efficacy of the dose of the solution andyier—s-aspension—is
`
`evaluated based upon the animal’s response to the test dose. This procedure is repeated through sufficient
`
`iterations, and at sufficient numbers of doses, to identify a dose that is considered effective to treat seizure by
`
`intranasal administration of the drug.
`
`Example 11
`
`Wlflwfll A pharmaceutical composition comprising diazepam was prepared as a composition
`
`formulated as a solution to be delivered via a nasal delivery device. The solution was prepared according to
`
`the procedure outlined in the flow diagram of Figure 4. The ingredients used in the 100 mg/mL diazepam
`
`solution are set forth in Table 11-1, below:
`
`Table 1 1-1
`
`Ingredient
`
`Concentration
`1% gw/vn
`
`Diazepam
`(x-tocopherol*
`Ethanol(dehydrated)
`Intravail A3“
`Benzyl alcohol
`*Vitamin E, **Dodecyl maltoside
`
`10.00 % (w/v)
`56.47 % (w/v)
`q.s. ((~18.07) % (w/v))
`0.25 % (w/v)
`10.50 % (w/v)
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0505
`
`page 0505
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`64
`
`EPA-124 519
`02.11.2017
`
`I Wlflfll [ A batch of solution of Table 11-1 was prepared and subjected to stability testing at 25°C/60%
`RH. for 12 months. The following table provides stability determinations for this batch at initial, 3 month, 6
`
`month and 12 month time points.
`
`Test Parameter
`
`Initial % Label Claim (100
`
`1 Month
`
`3 Month
`
`6 Month
`
`m_/mL Diazepam
`
`% 103.3
`
`99.5
`
`99.2
`
`99.1
`
`Label Claim
`
`l
`
`A batch of solution of Table 11-1 was prepared and subjected to stability testing at 30°C/65%
`{04.119191110111101
`R.H. (accelerated conditions) for 12 months. The following table provides stability determinations for this
`
`batch at initial, 1 month and 12 month time points.
`
`Test Parameter
`
`Initial % Label
`
`1 Month
`
`6 Month
`
`Claim (100
`m_/mL
`
`Appearance
`
`Pale amber to amber Amber solution
`
`Amber solution
`
`solution
`
`Diazepam % Label
`
`103.3
`
`97.8
`
`99.7
`
`Claim
`
`g
`
`A batch of solution of Table 11-1 was
`02.17.13
`7....
`WWW.
`
`re ared and sub'ected to stabilit
`p p
`J
`
`y
`
`testin at 40°C/75%
`
`R.H. (accelerated conditions) for 12 months. The following table provides stability determinations for this
`
`batch at initial, 3 month, 6 month and 12 month time points.
`
`Test Parameter
`
`Initial % Label
`
`1 Month
`
`3 Month
`
`6 Month
`
`Claim (100
`111 _/mL)
`
`Appearance
`
`Pale amber to
`
`Amber solution
`
`Amber solution
`
`Amber solution
`
`amber solution Diazepam
`
`% 103.3
`
`97.9
`
`100.0
`
`99.4
`
`Label Claim
`
`l W102?“ The suspension formulation is set forth in Table 11-2£13133}; claimed}, below
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0506
`
`page 0506
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`65
`
`EPA-124 519
`02.11.2017
`
`
`
`{Tnmpfllent
`
`1.)iazepmn
`
`311113111351 Parabep
`
`Prupyl Pamper],
`
`‘Intravaiél r913
`
`Vitamin E ‘T’PGS
`
`Propylene (31wa
`
`Pavidunp
`
`Function
`
`Active:
`
`Emmet-M
`
`Preservatiw
`
`Absmpfinn aid
`
`Disspersam
`
`firspmraant
`
`Sttspmdiag agent
`
`fiancentmfian (mgmejj
`
`1 (10.1.1
`
`2.0
`
`11.3
`
`3.5
`
`10.13
`
`11311.0
`
`5.0
`
`
`
`Water as 11:21 1311111.. Gamer
`
`
`
`l 102321110223] A batch of suspension of Table 11-2 was prepared and subjected to stability testing at
`25°C/60% RH. for 3 months. The following table provides stability determinations for this batch at initial and
`
`3 month time points.
`
`Test Parameter
`
`Initial % Label Claim (100
`m_/mL)
`
`3 Month
`
`Appearance
`
`Opaque white liquid
`
`Opaque white liquid
`
`
`
`Diazepam % Label Claim
`
`104.4
`
`102.1
`
`I
`
`{013—3311011361 A batch of suspension of Table 11-2 was prepared and subjected to stability testing at
`30°C/65% R.H. (accelerated conditions) for 1 month. The following table provides stability determinations for
`
`this batch at initial and 1 month time points.
`
`Test Parameter
`
`Initial % Label Claim (100
`m_/mL)
`
`1 Month
`
`Appearance
`
`Opaque white liquid
`
`Opaque white liquid
`
`
`
`Diazepam % Label Claim
`
`104.4
`
`102.9
`
`I 1024341011127] A batch of suspension of Table 11-2 was prepared and subjected to stability testing at
`40°C/75% R.H. (accelerated conditions) for 3 months. The following table provides stability determinations
`
`for this batch at initial, 1 month and 3 month time points.
`
`Test Parameter
`
`Initial % Label
`
`1 Month
`
`3 Month
`
`108.7
`
`Appearance
`
`Opaque white liquid
`
`Opaque white liquid White liquid
`
`Claim (100 m_/mL)
`
`Diazepam % Label Claim
`
`104.4
`
`102.7
`
`l WIMMI A three-period, three-treatment, six-sequence, randomized cross-over study was conducted in
`healthy volunteers. For each dose, each volunteer was domiciled for at least 12 hours prior to each dose and
`
`until after a 24 hour pharmacokinetic sample was collected. Single doses of 100 uL of the pharmaceutical
`
`compositions described in Tables 11-1 and 11-2 were administered to each volunteer as one spray to the left
`
`nostril of 100 uL per spray. Pharmacokinetic samples were collected at 22 time points over 10 days. (PK time
`
`points: 2.5, 5, 10, 15, 20, 30 and 45 minutes, 1, 1.5, 2, 4, 12, 24, 36, 48, 72, 96, 144, 192 and 240 hours after
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0507
`
`page 0507
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`66
`
`EPA-124 519
`02.11.2017
`
`each dose.) No serious adverse events were noted. PK data were compared with those obtained with 5 mg of
`
`diazepam administered intravenously. The PK data are summarized in Table 11-3 and Figures 1-3.
`
`11152431111111.1211]
`
`The solution of Table 11-1 and the suspension of Table 11-2 were found to be well-tolerated
`
`with only mild adverse events reported. The solution of Table 11-1 was further found to have similar
`
`bioavailability to intravenous administration of diazepam (96% of iv.) The intranasal formulation of Table
`
`11-1 exhibited a TmaX of 1.5 hours, a CmaX of approximately 272 ng/mL. These results are comparable to
`
`those reported in the literature for commercially available diazepam gel (Diastat®).
`
`11111411111111.1311]
`
`Solutions similar to those set forth in Table 11-1 can be prepared consisting of: diazepam (5-
`
`15 % (w/v)), dodecyl maltoside (0.01-1 % (w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 % (w/v)) and
`
`benzyl alcohol (5-15 % (w/v)); diazepam (9-11 % (w/v)), dodecyl maltoside (0.1-0.5 % (w/v)), vitamin E (50-
`
`60 % (w/v)), ethanol (15-22.5 % (w/v)) and benzyl alcohol (7.5-12.5 % (w/v)); or diazepam (10 % (w/v)),
`
`dodecyl maltoside (O.15-O.3 % (w/v)), vitamin E (50-60 % (w/v)), ethanol (17-20 % (w/v)) and benzyl alcohol
`
`(10-12 % (w/v)).
`
`11111311111112.1311
`
`Solutions similar to those set forth in Table 11-1 achieve bioavailability that is from about 80-
`
`125% of that achieved with the same benzodiazepine administered intravenously, e. g. bioavailability that is
`
`from about 90-110% of that achieved with the same benzodiazepine administered intravenously or about 92.5
`
`to 107.5% that obtained with the same benzodiazepine administered intravenously. Such solutions may be
`
`used in methods of treating a patient with a disorder which may be treatable with a benzodiazepine drug, such
`
`as seizure, epileptic seizure and/or breakthrough seizure. In some embodiments, solutions described herein
`
`may be used to treat a disorder such as is treated with Diastat® diazepam gel.
`
`{11117211111111.1311 A summary of pharmacokinetic data obtained for the solution and a suspension form of
`
`diazepam is shown below in Table 11-3:
`
`Table 11-3
`
`Summary Hf Pharmacukinefim Parameters for lntmnasal
`(11) mg} and W (5 mg} mazepam
`
`'1 T ET", .1:1:11 TT T 111.1
`
`mmfiifiwifimk Sufipnnsmu
`NRLJ.M Saluflmx
`5 mgfmh IV
`11
`7
`7
`7’
`11111111 1311‘“ 7
`,. 7 M“ M1111”
`’WW-i
`MW ,
`
`limM 111
`11:11:11
`24
`3221. 11711.51
`:14
`33.13 111111111
`24
`
`555* 11311111
`
`
`
`
`3:1
`1.1271111111112111
`:4
`1.5131131516111131
`.34
`11115 11711131.: 11511}
`
`
`33-313 (.1 115111-
`34
`"1341.1 11 $1,912}
`3,4
`532121 1141331
`:14
`
`~ 3.111193111111231
`
`1111 1131131225; 31m pmgamwfl 291:1; 11111111111411: 121113111135.
`1'»
`1a:
`1:, :' 11111111111311 1 131,111.11, 111111361 1911121111111 171% ’1",,,.,,,,m
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0508
`
`page 0508
`
`
`
`I EP 12 801 372.9-1455
`Hale BioPharma Ventures, LLC
`
`67
`
`EPA-124 519
`02.11.2017
`
`The data collected in the study are further illustrated in Figures 1-3. Figure l is a linear scale
`I Wlflfifiifil
`plot of the arithmetic mean of the plasma concentration of diazepam after intranasal (IN) administration of 10
`
`mg of diazepam as the suspension of Table 11-2 and after IN administration of 10 mg of diazepam as a
`
`solution of Table 11-] compared to intravenous (IV) administration of 5 mg of diazepam. Figure 2 is a semi-
`
`logarithmic scale plot of the same data shown in Figure 1. Figure 3 shows the first 24 hours of data from
`
`Figure l on a linear scale.
`
`W4l-l----W-hilraprete-HMMmlami-imems“not:-«themprawn«Wemirmwe--«heeWownandmdemrihedmheremritmwm
`
`IbemWW1}uMo"1'4hohawk:MaliawtlwwWWI-”rat-sueh--«eWmlmns"are«prawided-layway%filegéeample-unlvawtmmrouu
`
`WWm--~ehang%ranéwwhmtutlo2%"Milairwa---oecur"--t{av-thoaemslost-iMW-~13;hemar-t--wiHams:t—«lrspar-rlmgg-«lrommfi—w
`
`mantion:~~-It0hr»ildwhaw-uHderstwl-“that~39;air-iotagmahemalt-WeiMiwthewemlflflliaiemwalltha—hmntiowlesarihml
`
`herein--maywlae"amplowd—in—«waetieing—«t—lwirwnfion:---llwiat:-inter}ded-that--the"folltwifignalaimawdeflne-Wweww
`
`or?“the-4Wenlilon---{Md~thatwe»?hmlee;namlmslrwaww-Whhwhemmower?wthew-elainwwmdn-lheir—efiuWalentwbe
`
`eawered—therehyr
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0509
`
`page 0509
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 1 -
`
`EPA-124 519
`02.11.2017
`
`Auxiliam Reguest 2
`
`Claims
`
`1. A pharmaceutical solution for use in a method of treating seizures by nasal administration
`
`of said pharmaceutical solution which consists of:
`
`(a) a benzodiazepine drug;
`
`(b) one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from 30% to 95% (w/w);
`
`combined amount from 10% to 50% (w/w);andW
`(d) an alkyl glycoside.
`
`2. The pharmaceutical solution for use according to claim 1, wherein the benzodiazepine
`
`drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide,
`
`c|obazam, clonazepam, clorazepam, demoxazepam, diazepam,
`
`flumazenil,
`
`flurazepam,
`
`halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
`
`Iorazepam,
`
`prazepam, quazepam, triazolam, temazepam, Ioprazolam, any pharmaceutically-acceptable
`
`salts thereof, and any combinations thereof.
`
`3. The pharmaceutical solution for use according to claim 2, containing 1 to 20% (w/v) of
`
`benzodiazepine.
`
`10
`
`15
`
`4. The pharmaceutical solution for use according to claim 3, containing 1 to 20% (w/v) of
`
`20
`
`diazepam.
`
`5. The pharmaceutical solution for use according to claim 1, wherein the one or more natural
`
`or synthetic tocopherols or tocotrienols are selected from the group consisting of: Cl-
`
`tocopherol, B-tocopherol, y-tocopherol, o-tocopherol, d-tocotrienol, B-
`
`tocotrienol, y-
`
`tocotrienol, 6- tocotrienol,
`
`tocophersolan, any isomers thereof, any esters thereof, any
`
`analogs thereof, and any combinations thereof.
`
`fiWfoWWfiWWWgWEWWWWfiQMHW
`
`ethahelaWMB—MWWWMW
`
`«2:63,. The pharmaceutical solution for use according to claim 1, wherein the one or more
`
`natural or synthetic tocopherols or tocotrienols, or any combinations thereof, is in an amount
`
`from 45% to 85% (w/w).
`
`WHWfifiMfiWWWWWW
`
`
`
` w
`
`
`
`
`
`aMQQaWWfiWfiWW
`
`02;. The pharmaceutical solution for use according to claim 1, wherein the pharmaceutically-
`
`acceptable formulation comprises at least 0.01% (w/w) of an alkyl glycoside.
`
`25
`
`30
`
`35
`
`ARZ, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0510
`
`page 0510
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 2 -
`
`EPA-124 519
`02.11.2017
`
`hog". The pharmaceutical
`
`solution
`
`for use
`
`according to claim 102, wherein the
`
`pharmaceutically-acceptable formulation comprises 0.01% to 1% (w/w) of dodecyl
`maltoside.
`
`‘ 119;. The pharmaceutical solution for use according to claim 1, consisting of diazepam,
`
`vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.
`
`Hw—i‘llhempharmaeeuheatreWWWMWWWWWWWWWW
`
`r
`
`. WWM£W¥VWWWWMWM€HWWWWMMWW
`
`:
`
`‘ 1.. ¥w}~elodec~yl~maltewl%
`
`WWWWWMQWWWWWWWM§
`
`10
`
`WTQLWWWWMWWM
`
`ARZ, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0511
`
`page 0511
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 1 -
`
`EPA-124 519
`02.11.2017
`
`Main Reguest
`
`Claims
`
`1. A pharmaceutical solution for use in a method of treating seizures by nasal administration
`
`of said pharmaceutical solution which consists of:
`
`(a) a benzodiazepine drug;
`
`(b) one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`
`thereof, in an amount from 30% to 95% (w/w);
`
`(c) 1-25% (w/v) ethanol and 1-25% (w/v) benzyl alcohol,
`
`in a combined amount
`
`from 10% to 50% (w/w); and
`
`(d) antalkyl glycosidegmand
`
`wherein the benzodiazepine drug is selected from the groupCconsisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, c|obazam, clonazepam, clorazepam, demoxazepam, diazepam,
`
`flumazenil,
`
`flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam,
`
`oxazepam,
`
`Iorazepam, prazepam, quazepam,
`
`triazolam,
`
`temazepam,
`
`Ioprazolam, any
`
`pharmaceutically—acceptable salts thereof, and any combinations thereof.
`
`
`Formgrfilaim 3: deleted:
`
`3. The WWtharmaceutical solution ofafor use: amfding ‘lzgmclaim {II—IggIII—MIIIIIIIIIIII
`
`WW3, containing 1 to 20% (w/v) of benzodiazepine.
`
`4. The IIIIL—IIf—Ihewpharmaceutical solution Wfor use: according tomclaim 4M3I~I~I-II¢IIa~IIIIg~
`
`W, containing 1 to 20% (w/v) of diazepam.
`
`5. The tharmaceutical solution @36be use accordill’jfljflclaim lIIIm I
`.
`s
`I
`
`wherein the one or more natural or synthetic tocopherols or tocotrienols are selected from
`the group consisting of: d-tocopherol, B-tocopherol, y-tocopherol, o-tocopherol,
`Cl-
`
`tocotrienol, B- tocotrienol, y- tocotrienol, 6- tocotrienol, tocophersolan, any isomers thereof,
`
`any esters thereof, any analogs thereof, and any combinations thereof.
`
`6. The wwf—Iahapharmaceutical solution IIMIIIusggflggogirdmg to claim lInIIeaIiIIgIwe?»
`
`containing 10- 22.5% (w/v) ethanol and 7.5- 12.5% (w/v) benzyl alcohol.
`
`10
`
`15
`
`20
`
`25
`
`synthetic tocopherols or
`wherein the one or more natural or
`combinations thereof, is in an amount from 45% to 85% (w/w).
`
`tocotrienols, or any
`
`
`consisting of 5-15% (w/v) diazepam, 0.01-1% (w/v) alkyl glycoside, 45-65% (w/y)vitamin
`E, 10- 25% (w/v) ethanol and 5-15% (w/v) benzyl alcohol.
`
`35
`
`MR, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0512
`
`page 0512
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 2 -
`
`EPA-124 519
`02.11.2017
`
`9. The IIIIIIIIIl-wpharmaceutical solution IIMQI IISI-I aIQQIdiIIIg III claim lwiIIIIeaIIIIIweIIIIIeII,
`
`wherein the pharmaceutically-acceptable formulation comprises at least 0.01% (w/w) of an
`
`alkyl glycoside.
`
`10. The HfiflLfilelfimpharmaceutical solution III—IorusmflgwrdhIwgmoclaim QWWIIII—IeaIiIIII
`
`domed, wherein the pharmaceutically-acceptable formulation “(”2nglQl’l 9.53....0.01% to 1%
`
`(w/w) of dodecyl maltoside.
`
`10
`
`15
`
`Wfifi, consisting of 5-15% (w/v) diazepam, 45-65% (w/v) vitamin E, 10-25% (w/v)
`
`ethanol, 5-15% (w/v) benzyl alcohol, and 0.01%-1% (w/v) dodecyl maltoside.
`
`13. The IIIIILIIIeIlIcI—«pharmaceutical solution WfQE IIIIII according Io claim lmwmmam
`
`IIIIIIIIIIIIII, consisting of 10% (w/v) diazepam, 56.47% (w/v) vitamin E, q.s. dehydrated
`
`ethanol, 10.5% (w/v) benzyl alcohol, and 0.25% (w/v) dodecyl maltoside.
`
`MR, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0513
`
`page 0513
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 1 -
`
`EPA-124 519
`02.11.2017
`
`Auxiliam Reguest 1
`
`Claims
`
`1. A pharmaceutical solution for use in a method of treating seizures by nasal administration
`
`of said pharmaceutical solution which consists of:
`
`(a) a benzodiazepine drug;
`
`(b) one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`
`thereof, in an amount from 30% to 95% (w/w);
`
`(c) 1-25% (w/v) ethanol and 1-25% (w/v) benzyl alcohol,
`
`in a combined amount
`
`from 10% to 50% (w/w); and
`
`(d) an alkyl glycoside
`
`2. The pharmaceutical solution for use according to claim 1, wherein the benzodiazepine
`
`drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide,
`
`c|obazam, clonazepam, clorazepam, demoxazepam, diazepam,
`
`flumazenil,
`
`flurazepam,
`
`halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
`
`lorazepam,
`
`prazepam, quazepam, triazolam, temazepam, Ioprazolam, any pharmaceutical|y-acceptab|e
`
`salts thereof, and any combinations thereof.
`
`3. The pharmaceutical solution for use according to claim 2, containing 1 to 20% (w/v) of
`
`benzodiazepine.
`
`4. The pharmaceutical solution for use according to claim 3, containing 1 to 20% (w/v) of
`
`diazepam.
`
`5. The pharmaceutical solution for use according to claim 1, wherein the one or more natural
`
`or synthetic tocopherols or tocotrienols are selected from the group consisting of: Cl-
`
`tocopherol, B-tocopherol, y-tocopherol, o-tocopherol, d-tocotrienol, B-
`
`tocotrienol, y-
`
`tocotrienol, 6- tocotrienol,
`
`tocophersolan, any isomers thereof, any esters thereof, any
`
`analogs thereof, and any combinations thereof.
`
`6. The pharmaceutical solution for use according to claim 1, containing 10-22.5% (w/v)
`
`ethanol and 7.5-12.5% (w/v) benzyl alcohol.
`
`7. The pharmaceutical solution for use according to claim 1, wherein the one or more natural
`
`or synthetic tocopherols or tocotrienols, or any combinations thereof, is in an amount from
`
`45% to 85% (w/w).
`
`8. The pharmaceutical solution for use according to claim 1, consisting of 5-15% (w/v)
`
`diazepam, 0.01-1% (w/v) alkyl glycoside, 45-65% (w/v) vitamin E, 10-25% (w/v) ethanol
`
`and 5-15% (w/v) benzyl alcohol.
`
`9. The pharmaceutical solution for use according to claim 1, wherein the pharmaceutically-
`
`acceptable formulation comprises at least 0.01% (w/w) of an alkyl glycoside.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`ARI, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0514
`
`page 0514
`
`
`
`Hale BioPharma Ventures, LLC
`12 801 3729-1455
`
`- 2 -
`
`EPA-124 519
`02.11.2017
`
`10. The pharmaceutical solution for use according to claim 9, wherein the pharmaceutically-
`
`acceptable formulation comprises 0.01% to 1% (w/w) of dodecyl maltoside.
`
`11. The pharmaceutical solution for use according to claim 1, consisting of diazepam,
`
`vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.
`
`12. The pharmaceutical solution for use according to claim 1, consisting of 5-15% (w/v)
`
`diazepam, 45-65% (w/v) vitamin E, 10-25% (w/v) ethanol, 5-15% (w/v) benzyl alcohol, and
`
`0.01%-1% (w/v) dodecyl maltoside.
`
`13. The pharmaceutical solution for use according to claim 1, consisting of 10% (w/v)
`
`diazepam, 56.47% (w/v) vitamin E, q.s. dehydrated ethanol, 10.5% (w/v) benzyl alcohol,
`
`10
`
`and 0.25% (w/v) dodecyl maltoside.
`
`ARI, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0515
`
`page 0515
`
`
`
`Europfiisches
`Pateflta mt
`European
`Patent Office
`
`dES brevets
`
`Office auropéen
`
`Acknowledgement of receipt
`
`We hereby acknowledge receipt of the following subsequently filed document(s):
`
`Submission number
`
`5752715
`
`Application number
`
`EP12801372.9
`
`Date of receipt
`
`02 November 2017
`
`Receiving Office
`
`European Patent Office, The Hague
`
`Your reference
`
`EPA-124 519
`
`Applicant
`
`All applicants as on file
`
`Documents submitted
`
`package-data.xm|
`
`ep-sfd-request.xm|
`
`epf1038.pdf (1 p.)
`
`DESC-1.pdf\EPA—124519_specificatio
`n (clean).pdf (55 p.)
`
`DESC—HWA—1.pdf\EPA—124519_specif
`
`CLMS—1.pdf\EPA—124519_claims MR
`
`ication (markup).pdf (67 p.)
`
`(clean).pdf (2 p.)
`
`CLMS—HWA—1.pdf\EPA—124519_claim
`
`CLMS—2.pdf\EPA—124519_claims
`
`3 MR (markup).pdf (2 p.)
`
`AR1(cIean).pdf (2 p.)
`
`
`
`CLMS—HWA—2.pdf\EPA—124519_c|aim
`s AR1(markup).pdf (2 p.)
`
`CLMS—3.pdf\EPA—124519_claims AR2
`(clean).pdf (1 p.)
`
`CLMS—HWA—3.pdf\EPA—124519_c|aim
`
`ORAL-1.pdf\EPA—124519_response.p
`
`s AR2(markup).pdf (2 p.)
`
`df (9 p.)
`
`Submitted by
`
`CN=Petra Baudrexel 24738
`
`Date and time
`receipt generated
`
`Message DigeSt
`
`02 November 2017, 14:53 (CET)
`
`Acknowledgement of receipt - application number EP12801372.9
`
`37:35:AB:DC:2B:2B:65:DB:70:49:ED:2A:E7:F5:B2:6B:64:8D:5F:16
`AQUESTIVE EXHIBIT 1040 page 0516
`
`Pge 1 of 2
`
`
`
`Correction by the EPO of errors in debit instructions filed by eOLF
`Errors in debit instructions filed by eOLF that are caused by the editing of Form 1038E entries or the continued use of outdated
`software (all forms) may be corrected automatically by the EPO, leaving the payment date unchanged (see decision T 152/82,
`OJ EPO 1984, 301 and point 6.3 ffADA, Supplement to OJ EPO10/2007).
`
`/European Patent Office/
`
`AQUESTIVE EXHIBIT 1040
`Acknowledgement of receipt - application number EP12801372.9
`
`AQUESTIVE EXHIBIT 1040 page 0517
`
`page 0517
`Page 2 of 2
`
`
`
`Europfiisches
`Patentamt
`European
`Patent Office
`
`des brevets
`
`Office européen
`
`European Patent Office
`Postbus 58'l8 ..
`2280 HV Ruswuk
`NETHERLANDS
`
`Tel: +31 70 340 2040
`Fax: +31 70 340 3016
`
`Application No.
`
`:
`
`12 801 372.9
`
`Consultation by telephone with the applicant /representative
`
`Despatch for information
`
`Participants
`
`Applicant:
`
`Hale BioPharma Ventures, LLC
`
`Representative:
`
`Sonnenhauser, Thomas
`
`Member(s) of the
`Examining Division:
`
`Result of consultation
`
`See Separate Sheet
`
`GOmez Gallardo, S
`
`06.11.2017
`
`bété ...............
`
`Enclosure(s):
`
`GOmez Gallardo, S
`
`Eiairfiihér .............
`
`
`EPO Form 2036 12-07TRI
`AQUESTIVE EXHIBIT 1040
`page 0518
`
`AQUESTIVE EXHIBIT 1040 page 0518
`
`
`
`Europfiisches
`Patentamt
`European
`Patent Office
`
`des brevets
`
`Office européen
`
`
`
`
`
`
`
`
`
`
`
`
`
`Wichmann Hendrik
`Wuesthoff & Wuesthoff
`Patentanwélte PartG mbB
`SchweigerstraBe 2
`81541 MUnchen
`ALLEMAGNE
`
`r
`
`L
`
`7
`
`A
`
`European Patent Office
`Postbus 58.18 ..
`2280 HV leswuk
`NETHERLANDS
`
`Tel: +31 70 340 2040
`Fax: +31 70 340 3016
`
`Formalities Officer
`Name: HUbner, Werner
`or call
`
`+31 (0)70 340 45 00
`.
`.
`32:15:]3259;551:335, s
`Tel: +31 70 340 - 9546
`
`
`Application No.
`Ref.
`Date
`12 801 372.9 - 1455
`EPA-124 519
`08.11.2017
`
`
`
`
`
`
`
`
`Applicant
`Hale BioPharma Ventures, LLC
`
`Result of consultation
`
`A copy of the result of consultation of 06.11.2017 is enclosed for your information.
`
`s
`.2;
`$3
`4&1
`'
`+3
`E
`9
`‘9"
`’00
`‘95
`
`1‘
`
`A
`‘2
`a
`‘3
`3'U
`2:
`S"
`6‘
`2383
`a
`
`ana 331)“)
`
`GOmez Gallardo, S
`For the Examining Division
`
`Enclosure(s):
`
`Copy of result of consultation (Form 2036)
`
`
`EPO Form 2049A 12-07TRI
`AQUESTIVE EXHIBIT 1040
`page 0519
`
`AQUESTIVE EXHIBIT 1040 page 0519
`
`
`
`Datum
`
`Date
`Date
`
`08.11.2017
`
`Blatt
`
`Sheet
`Feuille
`
`1
`
`Anmelde-Nr:
`
`ApplicationNo:
`Demande n°:
`
`12 801 372.9
`
`The examiner informed the representative that
`
`it
`
`is possible to grant
`
`the Main
`
`Request filed on 02.11.2017, and that the Oral Proceedings scheduled for 01.12.2017
`
`will be cancelled.
`
`It was noted that an amended description was also submitted on
`
`02.11.2017 together with the claims of the Main Request, and, therefore,
`on file.
`
`is already
`
`EPO Form 2906 01.91TRI
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0520
`
`page 0520
`
`
`
`
`
`532333;?“
`European
`Patent Office
`Office européen
`des brevets
`
`
`
`
`
`
`
`
`
`
`
`Wichmann, Hendrik
`Wuesthoff & Wuesthoff
`Patentanwalte PartG mbB
`
`SchweigerstraBe 2
`81541 MUnchen
`ALLEMAGNE
`
`European Patent Office
`80298 MUNICH
`GERMANY
`
`Questions about this communication ?
`Contact Customer Services at www.epo.org/contact
`
`Date
`
`1 3 . 1 1.2 0 1 7
`
`Reference
`EPA-124 519
`
`Applicant/Proprietor
`
`Application No./Patent No.
`128013729 - 1455/2720699
`
`
`
`Hale BioPharma Ventures, LLC
`
`BRIEF COMMUNICATION
`
`Oral Proceedings on 01.12.17 at 09:00 hours
`
`Subject:
`
`M Your letter of 02112017
`El Cancellation / postponement at the instigation of the division
`
`Communication:
`
`1. CI The date /time fixed for oral proceedings is maintained.
`El The reasons are indicated on enclosed EPO Form 2906.
`
`2. CI The request for the oral proceedings to be held as a videoconference is
`rejected. The reasons are indicated on enclosed EPO Form 2906.
`
`3. CI The above-mentioned oral proceedings will start at ............................ hours.
`
`4. M The summons to attend oral proceedings on the above-mentioned date is
`cancelled.
`
`4.1
`
`The reasons are indicated on enclosed EPO Form 2906.
`
`ElElEIEIE'EI
`
`4.2
`
`4.3
`
`The procedure will be continued in writing.
`A new date will be set later.
`
`New summons will follow.
`
`Due to administrative reasons the oral proceedings have to be postponed
`to a later date. New summons will follow.
`
`The application is deemed to be withdrawn. The right to oral proceedings
`only persists as long as proceedings are pending.
`
`Please take note.
`
`Registered letter
`EPO Form 2008A 03.16
`
`(07/11/17)
`
`AQUESTIVE EXHIBIT 1040 page 0521
`
`AQUESTIVE EXHIBIT 1040
`page 1 of 2
`
`page 0521
`
`
`
`Date
`
`Application No. 128013729
`
`For the Examining Division
`
`Q?»
`3°
`I
`w
`
`+3
`5
`:5
`“2»
`’00
`(9557a
`04/78 aauiO
`
`I)” .
`
`‘2
`(0
`a
`
`g.0
`£2
`m
`g”
`50}
`'5
`
`El Enclosure : EPO Form 2906
`
`EPO Form 2008A 03.16
`
`(07/11/17)
`
`AQUESTIVE EXHIBIT 1040 pa