| EP 12 801 372.9-1455
`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
`
`

`

`| 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
`
`
`
`+
`
`2
`
`3
`
`4
`
`3
`
`4
`
`9.
`
`012873.
`
`Q-12009
`
`42:85366
`
`0-1-4044
`
`0-44
`
`43.6822
`
`044545
`
`O-A4SF
`
`44.0944
`
`9-43205
`
`043344
`
`MLS
`
`O-14554
`
`G-14743
`
`1448202
`
`94-84
`
`O72.
`
`400.67
`
`410134
`
`103.44
`
`O-13229
`
`O-134-44+
`
`44-87-8653
`
`106-25
`
`O-t4744
`
`O-A4040
`
`1436732
`
`40626
`
`Asverace
`
`Or13005
`
`O-74490
`
`0.0074.
`
`+4252
`
`8.6602
`
`T0486
`
`47154
`
`Bt-Dev
`
`80076
`
`
`
`4
`
`2
`
`3
`
`4
`
`5
`
`6
`
`z
`
`g
`
`9
`
`644444
`
`044869
`
`43.04770
`
`044066
`
`e44454
`
`43.3297
`
`643042
`
`043485
`
`4378126
`
`844667
`
`GA4879
`
`4336970
`
`044294
`
`044338
`
`4254399.
`
`943794
`
`044253
`
`43,25396
`
`043374
`
`043594
`
`4344084
`
`942388
`
`042559.
`
`4434944
`
`043799
`
`0401
`
`43.88564
`
`93.26
`
`94,52
`
`98.44
`
`95.50
`
`$9.59
`
`94.67
`
`95.86
`
`492.50
`
`99:48
`
`Average
`
`043755
`
`044015
`
`43.434
`
`95.94
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0502
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`page 0502
`
`

`

`| EP 12 801 372.9-1455
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`
`61
`
`EPA-124 519
`02.11.2017
`
`Stee
`
`O-O073-
`
`OFS
`
`dads
`
`aeF3-
`
`
`
`Qedeet Bolts Sot ae Seo
`
`
`
`
`
`
`
` +
`
`013604
`
`0-413807
`
`2593445
`
`92.62.
`
`3
`
`4
`
`3
`
`4
`
`9
`
`O-15294
`
`0-15425
`
`39035370
`
`40734
`
`O14728
`
`O-4016
`
`23-78804
`
`9-15352
`
`915493
`
`2660724
`
`92-10
`
`93.03.
`
`O-15148
`
`645254
`
`28-4304
`
`104-34
`
`O-AS107
`
`845393
`
`2632906
`
`95-82.
`
`ALVeEAES
`
`O-14044
`
`O-45425
`
`27-490
`
`De-18
`
`RSD
`
`3-79
`
`3:30
`
`S75
`
`S15
`
`
`
`
`
`
`
`+
`
`3
`
`4
`
`$
`
`6
`
`4
`
`9.
`
`O-135-744
`
`9-13-1079.
`
`28-14388
`
`400.52
`
`O-474082
`
`O74-195.
`
`2678985
`
`O-42962
`
`13249
`
`29-07-1923
`
`O-12548
`
`O-12683.
`
`2ASOTES
`
`O-14423
`
`0-1-4544
`
`28-30433
`
`O-13922
`
`0-1-4096
`
`2434644
`
`95.6%
`
`403-83
`
`DSS
`
`101-79
`
`97-66
`
`O-14902
`
`015344
`
`2720039
`
`9748.
`
`Asverage
`
`043-796
`
`9-1-4002
`
`27-634
`
`98-68
`
`(markup)
`AQUESTIVE EXHIBIT 1040=page 0503
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`AQUESTIVE EXHIBIT 1040 page 0503
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`

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`| EP 12 801 372.9-1455
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`
`Example 6
`
`224410214) All of the solutions and—suspensiens—described in Examples 3 and—+-areand formulated as
`
`described in Examples 3~ead4, 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
`| Diego, CA. The solutions and-saspensiens—with added alkyl glycoside may then be put up onstability as
`described in Example 5, mutatis mutandis.
`
`Example 7
`The solutions and-suspensions-ofExamples 3-4 and 6 are evaluated for pharmacokinetics in a
`| 0222410215]
`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 o#-suspensien—as
`
`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 and-suspensions-administered by the intranasal administration route.
`
`10223410216]
`
`Toxicity is assessed by known means. In particular, histological samples are collected from
`
`the nasal mucosaltissues of the test animals. Other toxological methodsare optionally employedas well.
`
`Example 8
`
`2244/0217
`
`The solutions and-suspensiens-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 amountof a solution e#-suspersien-as described in Examples 3;-4 and
`
`6, with the solution 6t-suspensien-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 saspeasien-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 intravenoussolution containing the drug or imaging agent.
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
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`
`Example 9
`
`The above-described solutions-and/er-suspensiens can be evaluated for pharmacokinetics in
`| 225410218)
`humans. Normal, healthy humantest 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 |
`
`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 ef—suspernsion—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
`
`102264(0219|
`
`
`
`The above-described solutions¢ can be evaluated for efficacy in a suitable
`
`animal model. Briefly, for each dose of suspersten-or-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 begunto seize, a solution et-suspensien-as described herein
`
`is administered intranasally to the animal. The efficacy of the dose of the solution end/ersuspensien—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
`
`O2e-410220| 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 11-1
`
`Ingredient
`
`Concentration
`(% (w/y))
`
`Diazepam
`a-tocopherol”
`Ethanol(dehydrated)
`Intravail A3”"
`Benzyl alcohol
`*Vitamin E, **Dodecyl maltoside
`
`10.00 % (w/v)
`56.47 % (w/v)
`—q.s. ((~18.07) % (w/y))
`0.25 % (wiv)
`10.50 % (w/v)
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
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`
`_A batch of solution ofTable 11-1 was prepared and subjected to stability testing at 25°C/60%
`| 2284/0221)
`R.H. 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
`
`
`mg/mL
`
`
`
`
`
`
`
`
`
`solution|solution sean—3 —5 ——2 —1
`
`
`
`
`
`|Appearance||Paleambertoambersolution|amber to ambersolution|Ambersolution|solution|Amber solution|Ambersolution
`
`Label Claim
`
`2291/0722)
`
`A batch of solution of Table 11-1 was prepared and subjectedto stability testing at 30°C/65%
`
`R.H. (accelerated conditions) for 12 months. The following table provides stability determinations for this
`
`batch at initial, 1 month and 12 month timepoints.
`
`g
`
`
`
`Diazepam % Label|103.3 97.8 99.7
`
`
`
`solution
`
`Claim
`
`A batch of solution of Table 11-1 was prepared and subjectedto stability testing at 40°C/75%
`#0410223)
`102304[0223]
`prep
`J
`y
`
`R.H. (accelerated conditions) for 12 months. The following table provides stability determinations for this
`
`Test Parameter
`
`1 Month
`
`6 Month
`
`Initial % Label
`Claim (100
`mg/mL
`
`
`
`
`Appearance Pale amber to amber|Ambersolution Ambersolution
`
`batch at initial, 3 month, 6 month and 12 month timepoints.
`
`Test Parameter
`
`Appearance
`
`Initial % Label
`Claim (100
`mg/mL)
`Pale amberto
`
`1 Month
`
`3 Month
`
`6 Month
`
`Ambersolution
`
`Ambersolution
`
`Ambersolution
`
`ambersolution Diazepam
`
`
`
`%|103.3 97.9 100.0 99.4
`
`
`
`
`
`Label Claim
`
`| 1023440224)
`
`The suspension formulation is set forth in Table 11-2(notclaimed), below
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0506
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`| EP 12 801 372.9-1455
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`65
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`
`
`
`Concentration (mg/mL)
`Function
`Component
`Diazepam—st—“‘(‘iéO;O*;*CACtiVe:*®!O!O!}©—CUO™~CONSC!C!O!O!!CO™
`Methyl Paraben
`Preservative
`2A)
`Propyl Paraben
`Preservative
`0.5
`Intravail AS
`Absorption aid
`2:5
`Vitamin E TPGS
`Dispersant
`10.0
`Propylene Glycol
`Dispersant
`100.0
`Povidone
`Suspending agent
`3.0
`
`CarrierWater ges. to 1.0 mL.
`
`
`| Hg321/0225| A batch of suspension of Table 11-2 was prepared and subjected to stability testing at
`25°C/60% R.H. for 3 months. The following table provides stability determinations for this batchat initial and
`
`3 month time points.
`
`Test Parameter
`
`Appearance
`
`Initial % Label Claim (100
`mg/mL)
`Opaque white liquid
`
`3 Month
`
`Opaque white liquid
`
`
`
`Diazepam % Label Claim
`104.4
`102.1
`| 233110226] 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
`
`Appearance
`
`Initial % Label Claim (100
`mg/mL)
`Opaquewhite liquid
`
`1 Month
`
`Opaque white liquid
`
`
`
`Diazepam % Label Claim
`104.4
`102.9
`| 123440227) 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 atinitial, 1 month and 3 month timepoints.
`
`Test Parameter
`
`Appearance
`
`Initial % Label
`Claim (100 mg/mL)
`Opaque white liquid
`
`1 Month
`
`3 Month
`
`104.4
`
`102.7
`
`108.7
`
`Opaque white liquid|White liquid Diazepam % Label Claim
`
`_A three-period, three-treatment, six-sequence, randomized cross-over study was conducted in
`| 1023540228)
`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 wL 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 wL 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
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`EP 12 801 372.9-1455
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`66
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`
`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.
`
`40236+(0229|
`
`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®).
`
`1023540230)
`
`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 (0.15-0.3 % (w/v)), vitamin E (50-60 % (w/v)), ethanol (17-20 % (w/v)) and benzyl alcohol
`
`(10-12 % (w/v)).
`
`4023840231)
`
`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 methodsoftreating a patient with a disorder which maybetreatable with a benzodiazepine drug, such
`
`as seizure, epileptic seizure and/or breakthrough seizure. In some embodiments, solutions described herein
`maybeusedto treat a disorder such asis treated with Diastat® diazepam gel.
`
`102391023) 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 of Pharmacokinetic Parameters for intranasal
`(10 mg)and IV (5 mg) Diazepam
`-Disgzepam Nasal Spray(0mg/l00pL) DiazepamInjection
`
`NRE-LA Suspension
`SELLESolution
`SniginlL TV
`
`Parameter”
`Un Mean ($b)* Mean (Sp)"in Mean($D)*
`
`
`Cy (ea)
`ae
`2278.6)
`a4
`a2 Cy
`a
`S23 (300)
`
`
`24
`LOG Ob, 2A
`
`24
`
`bS0 (008,400)
`
`24 DS (OS OO)
`
`
`
` $299 (1463) 4 34 3832 C1IS0Y
`
`
`
`(he nen)
`
`
`
`a Miewnvaloes are presented as anilmelic means:
`be Median(man, mas) reported fot cw
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0508
`
`page 0508
`
`

`

`| 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 1 is a linear scale
`| 40246110233)
`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 11-1 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 showsthe first 24 hours of data from
`
`Figure 1 onalinearscale.
`
`{024-11—\W-hile-preferred-emboduments-of-the-present-invention-hayve-been-shows-and-deseribed-herein-tt-avl
`
`be-obsieus-to-these-skitted-im-the-an-that-such-embediments-are-provided-by-wany-of-example-onb.-Numerous
`
`verations,-changes.and-substitutions-w4lnoew-oecur-to-those-siited-in-the-art-without-departine—rom-the
`
`teenon-l-chould-be-uaderstood-Lhat-verious-aiiersaives-to-the-ombuduments-ol-ihe-ivention-ceseriped
`
`herein-may-be-employed-in-practemetheinvention--t-is-intendedthat-the-fellowine-claims-define-the-scope
`
`of-the-invention-and-—that-metheds-and-structures-withi-the-seope-of-these-claims-and-theu-equivealents-be
`
`eoverse-thereny:
`
`(markup)
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0509
`
`page 0509
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-l-
`
`EPA-124 519
`02.11.2017
`
`Auxiliary Request 2
`Claims
`
`1. A pharmaceutical solution for use in a method oftreating 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);andand
`(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,
`clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
`flumazenil,
`flurazepam,
`halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
`lorazepam,
`prazepam, quazepam, triazolam, temazepam,
`loprazolam, 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.
`
`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: a-
`tocopherol, B-tocopherol, y-tocopherol, 6-tocopherol,
`a-tocotrienol, B-
`tocotrienol, y-
`tocotrienol, d- tocotrienol,
`tocophersolan, any isomers thereof, any esters thereof, any
`analogs thereof, and any combinations thereof.
`
`10
`
`15
`
`20
`
`25
`
`6-—Fhe-pharmaceutical-selutienfor-tse-accerding-_te-—claim—+.—centaining10-22.596—GWA
`ethanc-and5-12-506-t0h-benzytaleshok
`
`76. 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).
`
`
`and515%tev)benzy!alcohol
`
`97. 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.
`
`30
`
`35
`
`AR2, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0510
`
`page 0510
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-2-
`
`EPA-124 519
`02.11.2017
`
`according to claim +87, wherein the
`for use
`solution
`4908. The pharmaceutical
`pharmaceutically-acceptable formulation comprises 0.01% to 1% (w/w) of dodecyl
`maltoside.
`
`449. The pharmaceutical solution for use according to claim 1, consisting of diazepam,
`vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.
`
`feTHepharmacedtcatSeelution—fer-iuse-according—te—ciaim—tcensisting-oF-5-159¢-twh
`
`
`
`i-thA}-dedecy-mattesige-
`
`SEER SHSMpcavlbaralatiyLA Yastothenole SLahhateberealeaaland
`
`4+5--Fre—pharmaceutical-selution—fer—tuse—accerdingto—claimn—_1.,—censisting-oF-10%--wA
`
`10
`
`and-O-25Se-bwA-dadeey-matesicde:
`
`AR2, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0511
`
`page 0511
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-l-
`
`EPA-124 519
`02.11.2017
`
`Main Request
`Claims
`
`10
`
`15
`
`20
`
`25
`
`1. A pharmaceutical solution for use in a method oftreating 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,
`from 10% to 50%(w/w); and
`
`in a combined amount
`
`oO anow siyoseane
`
`wherein the benzodiazepine drug is selectedfrom theotgroup» consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
`flumazenil,
`flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam,
`oxazepam,
`lorazepam, prazepam, quazepam,
`triazolam,
`temazepam,
`loprazolam, any
`pharmaceutically-acceptable salts thereof, and any combinations thereof.
`
`Former Claim 3: deleted:
`
`3. The wse-efse—pharmaceutical solution ef-for_use according toclaim +~—2im—treating
`seizures, containing 1 to 20%(w/v) of benzodiazepine.
`
`4. The wse-ettse—pharmaceutical solution ef~for_use according toclaim 4~3in—treating
`seizures, containing 1 to 20%(w/v) of diazepam.
`
`5. The se-oFthe-pharmaceutical solution effor use accordingto_claim 1-#-treating-seizures
`
`wherein the one or more natural or synthetic tocopherols or tocotrienols are selected from
`the group consisting of:
`a-tocopherol, §-tocopherol, y-tocopherol, 6-tocopherol,
`a-
`tocotrienol, B- tocotrienol, y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof,
`any esters thereof, any analogs thereof, and any combinations thereof.
`
`6. The wse-eFthe-pharmaceutical solution eforuse according toclaim 1+"-treating-seizures,
`containing 10-22.5%(w/v) ethanol and 7.5-12.5%(w/v) benzyl alcohol.
`
`wherein the one or more natural or
`
`synthetic vocopherols or
`
`tocotrienols, or any
`
`combinations thereof, is in an amount from 45% to 85%(w/w).
`
`
`
`consisting of 5-15% (w/v) diazepam, 0.01-1% (w/v)alkyl¢alkyl ‘alycoside, 45-65% (w/v) vvitamin
`
`35
`
`E, 10-25% (w/v) ethanol and 5-15%(w/v) benzyl alcohol.
`
`MR, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0512
`
`page 0512
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-2-
`
`EPA-124 519
`02.11.2017
`
`wherein the pharmaceutically-acceptable formulation comprises at least 0.01% (w/w) of an
`alkyl glycoside.
`
`10. The use~oFtse-pharmaceutical solution efor useaccordingtoclaim 9+0-in-treating
`seizures, wherein the pharmaceutically-acceptable formulation comprises0.01% to 1%
`(w/w) of dodecyl maltoside.
`
`11. The use-eF-tse—pharmaceutical solution ef~for_useaccording toclaim 1—R—treating
`seizures, consisting of diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.
`
`12. The use-ef-tse-pharmaceutical solution ef-for_useaccording to claim 1~inA—treating
`seizures, 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 use-oF-tse—pharmaceutical solution ef~for use according to claim 1~A—treating
`seizures, 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.
`
`10
`
`15
`
`MR, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0513
`
`page 0513
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-l-
`
`EPA-124 519
`02.11.2017
`
`Auxiliary Request 1
`Claims
`
`1. A pharmaceutical solution for use in a method oftreating 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,
`from 10% to 50%(w/w); and
`(d) an alkyl glycoside
`
`in a combined amount
`
`2. The pharmaceutical solution for use according to claim 1, wherein the benzodiazepine
`drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide,
`clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
`flumazenil,
`flurazepam,
`halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
`lorazepam,
`prazepam, quazepam, triazolam, temazepam,
`loprazolam, 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.
`
`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: a-
`tocopherol, B-tocopherol, y-tocopherol, 6-tocopherol,
`a-tocotrienol, B-
`tocotrienol, y-
`tocotrienol, d- 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
`
`AR1, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0514
`
`page 0514
`
`

`

`Hale BioPharma Ventures, LLC
`12 801 372.9-1455
`
`-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,
`and 0.25%(w/v) dodecyl maltoside.
`
`10
`
`AR1, markup
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0515
`
`page 0515
`
`

`

`des brevets
`
`Europdisches
`Patentamt
`European
`Patent Office
`
`Office européen
`
`Acknowledgementofreceipt
`
`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
`
`All applicants as onfile
`
`Applicant
`
`Documents submitted
`
`Submitted by
`
`Method of submission
`
`Date and time
`
`df (9 p.)
`
`package-data.xml
`
`ep-sfd-request.xml
`
`epf1038.pdf (1 p.)
`
`DESC-1.pdf\EPA-124519_specificatio
`n (clean). pdf (55 p.)
`
`DESC-HWA-1.pdf\EPA-124519_specif
`ication (markup).pdf (67 p.)
`
`CLMS-1.pdf\EPA-124519_claims MR
`(clean).pdf (2 p.)
`
`CLMS-HWA-1.pdf\EPA-124519_claim
`s MR (markup).pdf (2 p.)
`
`CLMS-2.pdf\IEPA-124519_claims
`AR1(clean).pdf (2 p.)
`
`CLMS-HWA-2.pdf\EPA-124519_claim
`s AR1(markup).pdf (2 p.)
`
`CLMS-3.pdf\IEPA-124519_claims AR2
`(clean).pdf (1 p.)
`
`CLMS-HWA-3.pdfIEPA-124519_claim
`s AR2(markup).pdf (2 p.)
`
`ORAL-1.pdf\EPA-124519_response.p
`
`receipt generated
`
`Message Digest
`
`
`AQUESTIVE EXHIBIT 1040 page 0516
`Acknowledgementof receipt - application number EP12801372.9
`Page 1 of 2
`
`

`

`Correction by the EPOof 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 ff ADA, Supplement to OJ EPO 10/2007).
`
`/European Patent Office/
`
`AQUESTIVE EXHIBIT 1040
`Acknowledgementof receipt - application number EP12801372.9
`
`AQUESTIVE EXHIBIT 1040 page 0517
`
`page 0517
`Page 2 of 2
`
`

`

`Europaisches
`
`Patentamt
`European
`PatentOffice
`Office européen
`des brevets
`
`European Patent Office
`Postbus 5818 .
`2280 HV Rijswijk
`NETHERLANDS
`Tel: +31 70 340 2040
`Fax: +31 70 340 3016
`
`Application No. :
`
`12 801 372.9
`
`Consultation by telephone with the applicant / representative
`
`Despatchfor information
`
`Participants
`
`Applicant:
`
`Hale BioPharma Ventures, LLG
`
`Representative:
`
`Sonnenhauser, Thomas
`
`Member(s) of the
`Examining Division:
`
`Gomez Gallardo, S
`
`Result of consultation
`
`See Separate Sheet
`
`3
`. pret Patenten,
`
`.
`
`%eSares
`22d”
`
`‘
`a
`
`spcovels+geGy¥Yo,
`9»&8,
`
`a,
`
`203 aay
`
`06.11.2017
`
`sae
`
`Enclosure(s):
`
`Gdmez Gallardo, S
`
`meets
`
`EPO Form 2036 12.07TRI
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0518
`
`page 0518
`
`

`

`Europdisches
`Patentamt
`European
`Patent Office
`Office européen
`des brevets
`
`
`/
`
` ll | ll
`
`
`
`
`
`
`
`| ll ll|ll ll |ll
`
`Wichmann, Hendrik
`Wuesthoff & Wuesthoff
`Patentanwalte PartG mbB
`SchweigerstraBe 2
`81541 Munchen
`ALLEMAGNE
`
`L
`
`/
`
`a
`
`European Patent Office
`Postbus 5818 _
`2280 HV Rijswijk
`NETHERLANDS
`Tel: +31 70 340 2040
`Fax: +31 70 340 3016
`
`PREName: HUbner, Werner
`
`Tel: +31 70 340 - 2665
`or call
`+31 (0)70 340 45 00
`.
`.
`NoneGamerGalarde, 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 copyof the result of consultation of 06.11.2017 is enclosed for your information.
`
`es Patenya ae
`osx
`ae.
`: 02o
`
`>a
`
`“n
`% ‘3,
`a
`tng aoipO
`
`>2Uer04
`uead™x~
`
`a
`
`.
`
`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 Main
`is possible to grant
`it
`The examiner informed the representative that
`Requestfiled 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,
`is already
`on file.
`
`EPO Form 2906 01.91TRI
`
`AQUESTIVE EXHIBIT 1040
`
`AQUESTIVE EXHIBIT 1040 page 0520
`
`page 0520
`
`

`

`
`
`i
`Patentamt
`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
`
`13.11.2017
`
`Reference
`EPA-124 519
`
`Application No./Patent No.
`12801372.9 - 1455 / 2720699
`
`
`
`Applicant/Proprietor
`Hale BioPharma Ventures, LLC
`
`BRIEF COMMUNICATION
`
`Oral Proceedings on 01.12.17 at 09:00 hours
`
`Subject:
`
`nef Your letter of .92-11.2017
`(1 Cancellation / postponementat theinstigation of the division
`
`
`
`Communication: [1] The date/time fixed for oral proceedings is maintained.1.
`(J Thereasonsare indicated on enclosed EPO Form 2906.
`
`
`
`2. 0 The requestfor the oral proceedings to be held as a videoconferenceis
`rejected. The reasonsare indicated on enclosed EPO Form 2906.
`
`3.
`
`[0 The above-mentioned oral proceedings will start at... hours.
`
`4. w The summonsto attend oral proceedings on the above-mentioned date is
`cancelled.
`
`OoOFOOO
`
`4.1
`
`4.2
`
`4.3
`
`The reasons are indicated on enclosed EPO Form 2906.
`
`The procedure will be continued in writing.
`A new date will be set later.
`
`New summons will follow.
`
`Due to administrative reasonsthe oral proceedings have to be postponed
`to a later date. New summons will follow.
`
`The application is deemed to be withdrawn. Theright to oral proceedings
`only persists as long as proceedings are pending.
`
`Please take note.
`
`Registered letter
`AQUESTIVE EXHIBIT 1040
`page 0521
`AQUESTIVE EXHIBIT 1040 page 0521
`page1o
`EPO Form 2008A 03.16
`(07/11/17)
`
`

`

`Date
`
`Ap