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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________________
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`AQUESTIVE THERAPEUTICS, INC.
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`Petitioner
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`v.
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`NEURELIS, INC.
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`Patent Owner
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`_______________________
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`IPR2019-00451
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`U.S. Patent No. 9,763,876
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`______________________
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`DECLARATION OF DANIEL P. WERMELING, Pharm.D.
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`AQUESTIVE EXHIBIT 1150
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`U.S. Patent No. 9,763,876
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`TABLE OF CONTENTS
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`I.
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`II.
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`A.
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`1.
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`BASIS FOR OPINION .................................................................................. 2
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`RELEVANT CONSIDERATIONS .............................................................13
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`POSA ...........................................................................................................18
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`Ethanol Versus Dehydrated Ethanol ............................................................20
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`III.
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`QUALIFICATIONS AND BACKGROUND .............................................22
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`IV.
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`GROUNDS FOR INVALIDATING THE ‘876 PATENT CLAIMS .........26
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`V.
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`A.
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`B.
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`C.
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`THE HISTORY OF INTRANASAL BENZODIAZEPINE DELIVERY ..29
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`Summary ......................................................................................................29
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`Introduction ..................................................................................................30
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`Nasal Anatomy As Related to Intranasal Drug Delivery ............................32
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`VI.
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`COMMERCIAL SUCCESS AND LONG-FELT NEED IN THE DESIGN
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`OF NASAL PRODUCTS FOR SYSTEMIC DRUG ADMINISTRATION
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`INCLUDES TECHNICAL CONSIDERATIONS AS WELL AS MARKETING
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`CONSIDERATIONS ...............................................................................................36
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`A.
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`Exclusion of Market Considerations ............................................................36
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`B.
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`Patent Owner’s Expert Testified That he was Unaware of the Composition
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`of Patent Owner’s Intranasal Diazepam Spray, Valtoco, and He Could Not Answer
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`Whether Valtoco Satisfied any Long-Felt Need ......................................................37
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`C.
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`Commercial Success Factors – Formulation and Commercial
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`Considerations ..........................................................................................................40
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`1.
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`2.
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`Product Design Considerations ....................................................................42
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`Pharmacokinetics And Pharmacodynamics Of Nasal Benzodiazepines In
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`Healthy Volunteers ..................................................................................................49
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`D.
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`Prior Art Experience With Intranasal Delivery Of Benzodiazepines For
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`Treatment Of Seizures Prior To 2009 ......................................................................53
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`VII. THE PATHWAY TO FORMULATING THE SOLUTION ......................58
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`1.
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`There Were Many Nasal Delivery Systems And Many Non-Technical
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`Problems To Their Commercialization ....................................................................61
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`2.
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`Background In The Intranasal Art ...............................................................72
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`VIII. GWOZDZ, MEEZAN’962 and CARTT‘784 MAKE ALL THE CLAIMS
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`OF THE ‘876 PATENT OBVIOUS. .......................................................................84
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`A.
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`Gwozdz (Exhibit 1014) ................................................................................85
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`1.
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`A POSA Would Have Used Gwozdz’ Disclosure of Ternary Co-Solvent
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`Systems Such as Tocopherol+ Ethanol+Benzyl Alcohol, and Gwozdz’ Disclosure
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`is Not Limited to Administration to One Nostril .....................................................86
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`(a) A POSA Would Expect that a Ternary Co-Solvent System
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`(Tocopherol+Ethanol+Benzyl Alcohol) Could Solubilize More Diazepam
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`Than a Binary Co-Solvent System (Tocopherol+Ethanol) ..........................86
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`(b) Gwozdz’ Ternary Co-Solvent Diazepam Solution in a Reduced
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`Concentration Can be Administered to Both Nostrils to Deliver the Same
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`Amount of Diazepam and Avoid Possibility of Precipitating Out ..............91
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`2.
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`The Combination of Ethanol and Benzyl Alcohol and Diazepam for Use in
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`Treating Seizures in Humans was Well Known ......................................................92
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`B.
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`A POSA HAD THE MOTIVATION TO COMBINE THE TEACHINGS
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`OF GWOZDZ, MEEZAN’962 AND CARTT‘784 .................................................98
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`1.
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`Contrary to Patent Owner’s argument, a POSA would not be deterred from
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`applying Meezan’962’s teaching of the use of alkyl glycosides in connection with
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`non-aqueous solutions. .............................................................................................99
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`2.
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`Contrary to Patent Owner’s argument, a POSA would not be deterred from
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`applying the teachings of Cartt’784 to the disclosures of Gwozdz. Rather, the
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`POSA would be motivated to combine the two references. ..................................100
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`IX.
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`The ‘558 Provisional Application’s (Exhibit 1008) incorporation by
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`reference of the Sigma Catalogue (Exhibit 2006) does not convey to a POSA either
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`a directed disclosure of alkyl glycosides as absorption enhancer or even that the
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`inventors knew that alkyl glycosides would necessarily work as such. ................103
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`X.
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`THERE ARE NO UNEXPECTED RESULTS OR CRITICALITY
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`ASSOCIATED WITH ANY OF THE RECITED ALCOHOL RANGES OR
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`AMOUNTS ............................................................................................................108
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`A.
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`A POSA Would Have Known that Tocopherols Contribute to Increased
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`Bioavailability. .......................................................................................................111
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`B.
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`A POSA Would Have Expected Solutions to Have Higher Bioavailabilities
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`Than Suspensions ...................................................................................................112
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`C.
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`D.
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`Diazepam is 100% Bioavailable For Nasal and Oral Absorption .............113
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`The Table 11-3 data for the solution is not evidence of any criticality
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`associated with the recited claim ranges for ethanol and benzyl alcohol. .............117
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`1.
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`2.
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`Nasally-Administered Diazepam’s 100% Nas-Oral Bioavailability .........120
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`No Data Regarding Bioavailability of Solutions Having Benzyl Alcohol
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`and Ethanol Other Than in Table 11-3 (10.5% benzyl alcohol and 18.07% ethanol
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`(dehydrated)) ..........................................................................................................121
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`XI.
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`A POSA WOULD INCLUDE BENZYL ALCOHOL IN AN
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`INTRANASAL SPRAY FOR ADDRESSING ACUTE LIFE THREATENING
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`HEALTH SITUATIONS, NOTWITHSTANDING ANY IRRITATION THE
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`BENZYL ALCOHOL MIGHT CAUSE ...............................................................121
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`XII. CONCLUSION ..........................................................................................124
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`DECLARATION OF DANIEL P. WERMELING, Pharm.D.
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`I, Daniel P. Wermeling, do hereby make the following declaration:
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`I have been retained by Hoffmann & Baron, LLP counsel for Petitioner,
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`
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`1.
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`Aquestive Therapeutics, Inc., to provide my expert opinion in connection with the
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`Petition for Inter Partes Review of U.S. Patent No. 9,763,876 (“the ‘876 Patent”)
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`in IPR2019-00451. My Curriculum Vitae is attached hereto as Appendix A.
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`2. My opinions in this expert declaration support Petitioner’s Reply to Patent
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`Owner’s Response to the Petition (Paper No. 16), based on the Petition, that all the
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`challenged claims of the ‘876 Patent are obvious in view of the combination of
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`Gwozdz (Exhibit 1014) and Meezan’962 (Exhibit 1011) for claims 1-16 and 24-36
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`and the combination of Gwodz, Meezan’962 and Cartt‘784 (Exhibit 1015) for
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`claims 17-23. A POSA would be motivated to combine these references based (at
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`least) on the POSA’s general knowledge of routine pharmaceutical and
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`formulation chemistry (including the well-known requirements related to nasal
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`delivery).
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`3.
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`I am being compensated at my ordinary and customary consulting rate for
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`my work. My compensation is in no way contingent on the nature of my findings,
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`the presentation of my findings in testimony, or the outcome of this or any other
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`proceeding. I have no other interest in this proceeding.
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`I. BASIS FOR OPINION
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`U.S. Patent No. 9,763,876
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`4.
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`In forming my opinion herein, I have relied on my own education, work
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`experiences and knowledge, and on other bases such as textbooks, articles and
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`other references as described herein. This declaration states my current opinions,
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`which could change if additional information or analyses becomes available.
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`5.
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`I have reviewed the Peppas Dec. (Exhibit 1041), and I agree with the
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`ultimate conclusions reached by Dr. Peppas that (1) the combination of Gwozdz
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`and Meezan’962 renders claims 1-16 and 24-36 obvious, and (2) the combination
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`of Gwozdz, Meezan’962, and Cartt’784 renders claims 17-23, obvious.
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`6.
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`I have reviewed the Declaration of Professor Sveinbjörn Gizurarson,
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`Exhibit 2012 (“Gizurarson Dec.”) and Patent Owner Response (“POR”), and I
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`disagree with their conclusions overall and as described in detail below.
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`7.
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`In forming my opinion herein, I have also relied on review of the following
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`documents:
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`EXHIBIT NO.
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`EXHIBIT DESCRIPTION
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`Exhibit 1001
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`U.S. Patent No. 9,763,876, Administration Of Benzodiazepine
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`Compositions, filed October 29, 2014 (‘876 Patent)
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`Exhibit 1002
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`File History for ‘876 Patent, Ser. No. 14/527,613 (‘876 FH)
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`Exhibit 1008
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`Provisional Patent Application No. 61/040,558, filed March
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`28, 2008 (‘558 Provisional)
`
`Exhibit 1011
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`Meezan et al., U.S. Patent Application Publication No. US
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`2006/0046962, Absorption Enhancers for Drug
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`Administration, Serial No. 11/127,786, published March 2,
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`2006 (Meezan‘962)
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`Exhibit 1014
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`Gwozdz et al., WO 2009/120933, Pharmaceutical Solutions
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`And Method For Solubilizing Therapeutic Agents, published
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`October 1, 2009, International Filing Date March 27, 2009
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`(PCT/US2009/038518) (Gwozdz)
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`Exhibit 1015
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`Cartt et al., U.S. Patent Application Publication No. US
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`2008/0279784, Nasal Administration Of Benzodiazepines,
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`Serial No. 12/116,842, published November 13, 2008
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`(Cartt‘784)
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`Exhibit 1025
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`Lindhardt et al., Electroencephalographic effects and serum
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`concentrations after intranasal and intravenous administration
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`of diazepam to healthy volunteers, Blackwell Science Ltd Br J
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`Clin Pharmacol, 52, 521-527, 2001 (Lindhardt)
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`Exhibit 1028
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`Ivaturi et al., Pharmacokinetics and tolerability of intranasal
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`diazepam and midazolam in healthy adult volunteers, Acta
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`Neurol Scand. 2009 Nov;120(5):353-7. doi: 10.1111/j.1600-
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`0404.2009.01170.x. Epub 2009 May 14 (Ivaturi)
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`Exhibit 1031
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`Rowe et al., editors, Handbook of Pharmaceutical Excipients,
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`Fourth Edition (2003), Monographs for “Alcohol” (i.e.,
`
`ethanol), “Alpha Tocopherol”, “Benzyl Alcohol”, “Glycerin”,
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`“Olive Oil”, “Polyethylene Glycol”, “Propylene Glycol”,
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`“Sesame Oil”, and “Triacetin”, American Pharmaceutical
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`Association, Washington DC (Rowe)
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`Exhibit 1041
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`Declaration of Dr. Nicholas A. Peppas
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`Exhibit 1042
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`PDR 54th Edition 2000, DIASTAT® (diazepam rectal gel);
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`MIACALCIN® (Calcitonin Nasal Spray); VALIUM®
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`(diazepam injection), Physicians’ Desk Reference.
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`Exhibit 1043
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`Knoester PD, Jonker DM, Van Der Hoeven RT, et al.
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`Pharmacokinetics and pharmacodynamics of midazolam
`
`administered as a concentrated intranasal spray. A study in
`
`healthy volunteers. Br J Clin Pharmacol. 2002; 53: 501-507.
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`Exhibit 1069
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`Florida Regional Common EMS Protocols Field Guide, Jones
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`and Barlett Publishers, MA (2005).
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`Exhibit 1070
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`Gizurarson, Patent Application Publication No. US
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`2008/0275030, Nov. 6, 2008.
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`Exhibit 1072
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`Nayzilam Product Label and Instructions for Use
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`Exhibit 1074
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`Hardman, et al, Editors, Goodman & Gilman’s, The
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`Pharmacological Basis of Therapeutics, 10th Edition (2001).
`
`Exhibit 1076
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`Budavari, et al, Editors, The Merck Index, 12th Edition (1996).
`
`Exhibit 1077
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`Ritchel, W.A., et al., Handbook of Basic Pharmocokinetics ….
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`Including Clinical Applications, 6th Edition, 2004.
`
`Exhibit 1078
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`USP/NF 2003, The Official Compendia of Standards, Ethanol,
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`Copyright 2002.
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`Exhibit 1080
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`Valium® Tablet Label, Roche, January 2008.
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`Exhibit 1081
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`Drug Prices from Internet
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`Exhibit 1082
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`Chien, Y.W., et al., “Nasal Systemic Drug Delivery”, Chapter
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`1, Anatomy and Physiology of the Nose, Drugs and the
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`Pharmaceutical Sciences, Vol. 39, Marcel Decker, 1989.
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`Exhibit 1101
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`Lowenstein DH, Alldredge BK. Status epilepticus. N Eng J
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`Med 1998; 338: 970-976.
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`Exhibit 1102
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`Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise
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`the definition of status epilepticus. Epilepsia 1999; 40: 120-
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`122.
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`Exhibit 1103.
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`Wang HC, Chang WN, Chang HW, et al. Factors predictive of
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`outcome in posttraumatic seizures. J Trauma 2008; 64: 883-
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`888.
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`Exhibit 1104
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`Stavem K, BJornaes H, Langmoen IA. Long-term seizures and
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`quality of life after epilepsy surgery compared with matched
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`controls. Neurosurgery 2008; 62: 326-334.
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`Exhibit 1105
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`Logroscino G, Hessdorffer DC, Cascino G, et al. Time trends
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`in incidence, mortality, and case-fatality after first episode of
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`status epilepticus. Epilepsia 2001; 42: 1031-1035.
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`Exhibit 1106
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`Feen ES, Bershad EM, Suarez JI. Status Epilepticus. South
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`Med J 2008; 101: 400-406.
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`Exhibit 1107
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`Pang T, Hirsch L. Treatment of convulsive and nonconvulsive
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`status epilepticus. Cur Treat Options Neurol 2005; 7: 247-259.
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`Exhibit 1108
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`Smith B. Treatment of status epilepticus. Neurol Clin 2001;
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`19: 347-369.
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`Exhibit 1109
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`Ericksson K, Kalviainen R. Pharmacologic management of
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`convulsive status epilepticus in childhood. Expert Rev
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`Neurotherapeutics 2005; 5: 777-783.
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`Exhibit 1110
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`Wolfe T, Macfarlane T. Intranasal midazolam therapy for
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`pediatric status epilepticus. Am J Emerg Med 2006; 24: 343-
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`346.
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`Exhibit 1111
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`Meierkord H, Engelsen B, Gocke K, et al. EFNS guideline on
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`the management of status epilepticus. Eur J Neurol 2006; 13:
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`445-450.
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`Exhibit 1112
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`Prasad K, Krishman P, Al-Roomi K, et al., Anticonvulsant
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`therapy for status epilepticus. Br J Clin Pharmacol 2007; 63:
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`640-647.
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`Exhibit 1113
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`Illum L. Nasal Clearance in Health and Disease. J Aerosol
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`Med 2006; 19: 92-99.
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`Exhibit 1114
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`Merkus P, Ebbens FA, Muller B, Fokkens WJ. Influence of
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`anatomy and head position on intranasal drug deposition. Eur
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`Arch Otorhinolaryngol 2006; 263: 827-832.
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`Exhibit 1115
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`Illum L. Transport of drugs from the nasal cavity to the
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`central nervous system. Eur J Pharm Sci 2000; 11: 1-18.
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`Exhibit 1116
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`Illum L. Is nose to brain transport of drugs a reality?. JPP
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`2004; 56: 3-17.
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`Exhibit 1117
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`Merkus F, van den Berg MP. Can nasal drug delivery bypass
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`the blood-brain barrier? Questioning the direct transport
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`theory. Drugs 2007; 8: 133-144.
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`Exhibit 1118
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`Constantino HR, Illum L, Brandt G, et al. Intl J Pharmaceutics
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`2007; 337: 1-24.
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`Exhibit 1119
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`Davis GA, Rudy AC, Archer SA, Wermeling DP, McNamara
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`PJ. Effect of fluticasone propionate nasal spray on
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`bioavailability of hydromorphone hydrochloride in patients
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`with allergic rhinitis. Pharmacotherapy 2004; 24: 26-32.
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`Exhibit 1120
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`Davis GA, Rudy AC, Archer SM, Wermeling DP, McNamara
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`PJ. Bioavailability and pharmacokinetics of intranasal
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`hydromorphone in patients experiencing vasomotor rhinitis.
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`Clin Drug Invest 2004; 24: 1-7.
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`Exhibit 1121
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`Holsti M, Sill B, Firth S, et al., Prehospital intranasal
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`midazolam for the treatment of pediatric seizures. Ped Emerg
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`Care 2007; 23: 148-153.
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`Exhibit 1122
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`Rudy AC, Coda BA, Archer SM, Wermeling DP. A multiple
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`dose phase 1 study of intranasal hydromorphone
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`hydrochloride in healthy volunteers. Anesth Analg 2004; 99:
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`1379-1386.
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`Exhibit 1125
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`Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, et al.
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`Cyclodextrin solubilization of benzodiazepines: formulation of
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`midazolam nasal spray. Int J Pharm 2001; 212: 29-40.
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`Exhibit 1127
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`Gudmundsdottir H, Sigurjonsdottir JF, Masson M, et al.
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`Intranasal administration of midazolam in a cyclodextrin
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`based formulation: bioavailability and clinical evaluation in
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`humans. Pharmazie 2001; 56: 963-966.
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`Exhibit 1128
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`Dale O., Nilsen T., Loftsson T. Intranasal midazolam: a
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`comparison of two delivery devices in human volunteers. J
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`Pharmacy Pharmacol 2006; 58: 1311-1318.
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`Exhibit 1129
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`Burstein AH, Modica R, Hatton M, et al. Pharmacokinetics
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`and pharmacodynamics of midazolam after intranasal
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`administration. J Clin Pharmacol 1997; 37: 711-718.
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`Exhibit 1130
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`Wermeling, D, Record K, Kelly T, et al., Pharmacokinetics
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`and pharamcodynamics of a new intranasal midazolam
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`formulation in healthy volunteers. Anesth Analg 2006; 103:
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`344-349.
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`Exhibit 1131
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`Schols-Hendriks MWG, Lohman JJHM, Janknegt R, et al.
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`Absorption of clonazepam after intranasal and buccal
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`administration. Br J Clin Pharmacol, 1995; 39: 449-451.
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`Exhibit 1133
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`Lau SWJ, Slattery JT. Intl J Pharmaceutics. Absorption of
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`diazepam and lorazepam following intranasal administration.
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`Int J Pharmaceutics 1989; 54: 171-174.
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`Exhibit 1134
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`Wermeling DP, Miller JL, Archer SM, et al. Bioavailability
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`and pharmacokinetics of lorazepam after intranasal,
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`intravenous, and intramuscular administration. J Clin
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`Pharmacol, 2001; 41: 1225-1231.
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`Exhibit 1135
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`Greenblatt D, Gan L, Harmatz, et al. Pharmacokinetics and
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`pharmacodynamics of single-dose triazolam: EEG compared
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`with digital symbol substitution test. Br J Clin Pharmacol
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`2005; 60: 244-248.
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`Exhibit 1136
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`O’Regan M, Brown J, Clarke M. Nasal rather than rectal
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`benzodiazepines in the management of acute childhood
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`seizures. Develop Med and Child Neurol 1996; 38: 1037-
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`1045.
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`Exhibit 1137
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`Mittal P, Manohar R, Rawat A. Comparative study of
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`intranasal midazolam and intravenous diazepam sedation for
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`procedures and seizures. Ind J Pediatrics 2006;73: 975-978.
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`Exhibit 1138
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`Mahmoudian T, Zadeh M. Comparison of intranasal
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`midazolam with intravenous diazepam for treating acute
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`seizures in children. Epilepsy and Behavior 2004; 5: 253-255.
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`Exhibit 1139
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`Lahat E, Goldman M, Barr J, et al. Comparison of intranasal
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`midazolam with intravenous diazepam in treating febrile
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`seizures in children: prospective randomized study. BMJ
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`2000; 321: 83-87.
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`Exhibit 1140
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`Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs
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`rectal diazepam in acute childhood seizures. Pediatric
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`Neurology 2006; 34: 355-359.
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`Exhibit 1141
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`Wilson, M.T., S. Macleod, and M.E. O'Regan, Nasal/buccal
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`midazolam use in the community. Arch Dis Child, 2004. 89(1):
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`p. 50-1.
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`Exhibit 1142
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`Harbord, M.G., et al., Use of intranasal midazolam to treat
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`acute seizures in paediatric community settings. J Paediatr
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`Child Health, 2004. 40(9-10): p. 556-8.
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`Exhibit 1143
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`Jeannet, P.Y., et al., Home and hospital treatment of acute
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`seizures in children with nasal midazolam. Eur J Paediatr
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`Neurol, 1999. 3(2): p. 73-7.
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`AQUESTIVE EXHIBIT 1150
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`IPR2019-00451
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`U.S. Patent No. 9,763,876
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`Exhibit 1144
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`Ahmad S, Ellis J, Kamwendo H, et al. Efficacy and safety of
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`intranasal lorazepam versus intramuscular paraldehyde for
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`protracted convulsions in children: an open label trial. Lancet
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`2006; 367: 1591-1597.
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`Exhibit 1145
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`Wolfe T, Bernstone T, Intranasal Drug Delivery: An
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`Alternative to Intravenous Administration in Selected
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`Emergency Cases, J Emerg Nurs. 2004 Apr;30(2):141-7.
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`Exhibit 1146
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`FDA GUI FINAL, Determining Whether to Submit an ANDA
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`or a 505(b)(2) Application, Published May 2019,
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`https://www.fda.gov/media/123567/download
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`Exhibit 1147
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`CDER 2019-09-19-Abbreviated Approval Products:
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`
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`505(b)(2) or ANDA? https://www.fda.gov/drugs/cder-small-
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`business-industry-assistance-sbia/abbreviated-approval-
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`pathways-drug-product-505b2-or-anda-september-19-2019-
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`issue
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`Exhibit 1148
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`FDA GUIDANCE FOR INDUSTRY (1999), Applications
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`Covered by Section 505(b)(2),
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`https://www.fda.gov/media/72419/download
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`Exhibit 1149
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`Transcript of the January 14, 2020 deposition of Dr.
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`Gizararson,
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`U.S. Patent No. 9,763,876
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`Exhibit 1151
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`Wermeling, D.P., Intranasal delivery of antiepileptic
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`medications for treatment of seizures, Neurotherapeutics,
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`April 2009, Volume 6, Issue 2, pp 352–358
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`Exhibit 2006
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`SIGMA Chemical Company Catalog (1988)
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`Exhibit 2012
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`Declaration of Dr. Sveinbjorn Gizurarson, Ph.D.
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`Exhibit 2014
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`D. Wermeling, U.S. Patent No. 6,610,271, issued August 26,
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`2003.
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`
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`PAPER NO.
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`PAPER DESCRIPTION
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`3
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`Petition
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`PTAB Decision to Institute the IPR
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`II. RELEVANT CONSIDERATIONS
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`8.
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`9.
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`I provide my opinions in this declaration as informed below.
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`I have been informed that to be entitled to an earlier priority date each claim
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`limitation must be expressly, implicitly, or inherently supported in the originally
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`filed disclosure, in this case Provisional Application Serial No. 61/040,558, Exhibit
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`1008 (“the ‘558 Provisional application”).
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`10.
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`I have been informed that a claim is interpreted by giving its terms the
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`meaning that the term would have to a person of ordinary skill in the art in
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`question at the time of the invention.
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`11.
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`I have been informed that to benefit from a claim of priority to an originally
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`filed disclosure, the originally filed disclosure must contain a written description of
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`the invention as claimed in the later applications, and of the manner and process of
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`making and using it, in such full, clear, concise, and exact terms as to enable any
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`person of ordinary skill in the art to make and use the invention as claimed. I have
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`been informed that to meet this requirement, the originally filed disclosure must
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`reasonably convey to one of skill in the art that the inventor possessed the later-
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`claimed subject matter at the time the parent application was filed. I have been
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`further informed, a disclosure in a parent application (the originally filed
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`disclosure) that merely renders the later-claimed invention obvious is not sufficient
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`to meet the written description requirement; the disclosure itself must describe the
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`claimed invention with all its limitations.
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`12.
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`I have been informed that for a disclosure to be enabling it must teach those
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`in the art enough that they can make and use the invention without “undue
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`experimentation” and that in determining whether a disclosure is enabling I should
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`consider: (1) the quantity of experimentation necessary; (2) the amount of direction
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`or guidance disclosed in the disclosure; (3) the presence or absence of working
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`examples in the disclosure; (4) the nature of the invention; (5) the state of the prior
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`art; (6) the relative skill of those in the art; (7) the predictability of the art; and (8)
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`the breadth of the claims. I was informed that these are called the Wands’ factors
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`and that only those factors relevant to the claim scope need be considered.
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`13.
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`I have been further informed that in order to determine if the later
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`application (i.e., the ‘876 Patent, Ex. 1001) is to receive the benefit of an earlier
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`filed application or patent (i.e., the ‘558 Provisional, Ex. 1008), the question is
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`whether a person of ordinary skill in the art would recognize that the applicant
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`possessed what is claimed in the later filed application (i.e., the ‘876 Patent, Ex.
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`1001) as of the filing date of the earlier filed application or patent (i.e., the ‘558
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`Provisional, Ex. 1008). The disclosure as originally filed in the earlier applications
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`or patent (i.e., ‘558 Provisional, Ex. 1008) must convey with reasonable clarity to
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`those skilled in the art that the inventor was in possession of the invention. That is,
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`one skilled in the art, reading the original disclosure, must immediately discern the
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`limitation at issue in the claims.
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`14.
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`I have been informed that these requirements for written support, possession
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`of the invention and enablement, are referred to as § 112(a) requirements. I have
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`further been informed that if a patent’s claims do not have § 112(a) support, it is
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`unpatentable and invalid.
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`15.
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`I have been informed that a claimed invention is unpatentable if the
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`differences between the invention and the prior art are such that the subject matter
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`as a whole would have been obvious at the time the alleged invention was made to
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`a person having ordinary skill in the art to which the subject matter pertains. I
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`have also been informed that an obviousness analysis takes into account factual
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`inquiries including the level of a person of ordinary skill in the art, the scope and
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`content of the prior art, and the differences between the prior art and the claimed
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`subject matter, as well as secondary considerations such as commercial success,
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`long felt but unsolved needs, failure of others and unexpected results.
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`16.
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`I have also been informed that objective evidence or “secondary
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`considerations,” such as unexpected results, commercial success, long felt need,
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`failure of others, copying by others, licensing, and skepticism of experts can be
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`relevant to the issue of obviousness. However, where the differences between the
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`claimed invention and the prior art are “minor,” objective evidence of non-
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`obviousness may not be sufficiently compelling to support the patentability of a
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`claim. I have also been informed that to be considered the secondary
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`considerations must have a nexus to claims.
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`17.
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`I have also been informed that in order for the results to be unexpected the
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`claimed invention must exhibit some superior property or advantage that a person
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`of ordinary skill in the relevant art would have found surprising or unexpected and
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`that to establish unexpected results over a claimed range, the patent owner must
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`compare a sufficient number of tests both inside and outside the claimed range to
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`show the criticality of the claimed range.
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`18.
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`I have been informed that there are several accepted rationales for
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`combining references or modifying a reference to show obviousness of the claimed
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`subject matter. Some of these rationales include the following: combining prior art
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`elements according to known methods to yield predictable results; simple
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`substitution of one known element for another to obtain predictable results; a
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`predictable use of prior art elements according to their established functions;
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`applying a known technique to a known device to yield predictable results;
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`choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success; and some teaching, suggestion, or motivation in
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`the prior art that would have led one of ordinary skill to modify the prior art
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`reference or to combine prior art reference teachings to arrive at the claimed
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`invention.
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`19.
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`I have been informed that “a person of ordinary skill in the art”, a POSA, is
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`not a specific, real individual, but rather a hypothetical individual or team of
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`individuals working closely together, who is presumed to have known the relevant
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`art at the time of the invention. In defining the POSA, I have been informed to
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`consider factors such as the educational level and years of experience not only of
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`the person or persons who have developed the invention that is the subject of the
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`case, but also others working in the pertinent art at the time of the invention; the
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`types of problems encountered in the art; the teachings of the prior art; patents and
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`publications of other persons or companies; and the sophistication of the
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`technology.
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`
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`A.
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`POSA
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`20. Patent Owner and Dr. Gizurarson take issue with Petitioner’s description of
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`a POSA. See POR, Paper 16, p. 15-17; and Gizurarson Dec. ¶¶ 25-33, Exhibit
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`2012.
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`21. Petitioner’s definition (which was objected to by Patent Owner), see
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`Petition, Paper 3, p. 4, reads as follows:
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`“As of the earliest priority date that the Challenged Claims of ‘876
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`Patent are entitled to, a person of ordinary skill in the art (“POSA”)
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`would have been a medicinal chemist, pharmaceutical chemist,
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`chemist, or biologist involved in the research and development of
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`pharmaceutical formulations and/or delivery. The POSA would have at
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`least a bachelor’s degree in chemical, biological, or pharmaceutical
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`sciences or a medical degree, and several years of experience in the
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`field of transmucosal (including intranasal, rectal, vaginal, ocular,
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`lacrimal, nasolacrimal, buccal, sublingual, urethral, inhalation, and
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`auricular) pharmaceutical formulation development and/or delivery,
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`the amount of post-graduate experience depending upon the level of
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`formal education. The individual would also have some experience in
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`design and testing of formulations for mucosal delivery (and
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`particularly in intranasal formulations) of systemic-acting drugs.”
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`22.
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`It is my opinion that at least the following of Dr. Gizurarson’s statements in
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`his declaration (Exhibit 2012) regarding the definition of a POSA must be
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`corrected:
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`(a) in response to Gizurarson Dec. ¶ 31, it is necessary to add “transmembrane”
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`to “intranasal” because all the other routes listed in (b) below are
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`transmembrane;
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`(b) in response to Gizurarson Dec. ¶ 32, I agree that experience formulating
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`“rectal, vaginal, ocular, lacrimal, nasolacrimal, buccal, sublingual, urethral,
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`inhalation, and auricular” formulations can be very “informative”. In fact,
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`such experience can be very useful to formulating intranasal products, and
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`further the use of rectal formulations of diazepam (a commercially available
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`product) for intranasal administration would give POSA clues and direction
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`as to what could and should work in intranasal formulations.
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`U.S. Patent No. 9,763,876
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`1. Ethanol Versus Dehydrated Ethanol
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`23.
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`I have been asked to consider what a POSA would understand the terms
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`“ethanol” and “dehydrated ethanol” to mean. A POSA would understand that the
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`ordinary meaning of the terms “ethanol” and “dehydrated ethanol” would be the
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`meanings given in the U.S. Pharmacopeia (“USP”). See Ex. 1078, pp. 0004-0005.
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`24. Thus, a POSA would understand that ethanol “contains not less than 92.3%
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`and not more than 93.8%, by weight, corresponding to not less than 94.9% and not
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`more than 96.0%, by volume, at 15.56o, of C2H5OH.” Id. A POSA would
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`understand the remaining 4-5% (by volume) to be mostly – if not all – water.
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`25. Thus, a POSA would understand that dehydrated ethanol “contains not less
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`than 99.2 percent, by weight, corre
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