UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner
`
`v.
`
`HALE BIOPHARMA VENTURES, LLC
`Patent Owner
`
`
`U.S. Patent No. 9,763,876
`
`Case IPR2019-00451
`
`
`EXPERT DECLARATION OF PROFESSOR SVEINBJÖRN GIZURARSON
`IN SUPPORT OF PATENT OWNER’S RESPONSE TO PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 9,763,876
`
`
`
`Neurelis - EX. 2012
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`TABLE OF CONTENTS
`
`I.
`
`Page
`Qualifications And Background ...................................................................... 2
`A.
`Education and Experience ..................................................................... 2
`B.
`Bases for Opinions and Materials Considered ...................................... 7
`C.
`Previous Litigation Experience ............................................................. 8
`D.
`Scope of Work ....................................................................................... 8
`Legal Standards ............................................................................................... 8
`II.
`Person of Ordinary Skill in the Art ................................................................ 12
`III.
`IV. Summary of Opinions .................................................................................... 16
`V.
`The ’876 Patent [Ex. 1001] ............................................................................ 18
`VI. Claim Construction ........................................................................................ 20
`A.
`“Consisting Of” ................................................................................... 20
`B.
`“In a Combined Amount” ................................................................... 21
`VII. Background .................................................................................................... 22
`A.
`Epilepsy and Acute Seizure Treatment ............................................... 22
`B.
`Benzodiazepine Solubility ................................................................... 24
`C.
`Treatment of Epileptic Patients with Benzodiazepine ........................ 26
`D.
`Challenges of Developing Intranasal Formulations ............................ 28
`1.
`Delivery Volume Limited to About 200 µl (100 µl Per
`Nostril) ......................................................................................28
`Residence Time of Therapeutic Agents is Decreased
`Significantly Because of Defense Mechanisms to Clear
`Foreign Agents ..........................................................................29
`Cellular Structures Within the Nasal Cell Wall Prevent
`Influx of Therapeutic Agents ....................................................31
`Difficulty in Developing Intranasal Benzodiazepine
`Formulations .............................................................................32
`VIII. All Challenged Claims Of The ’876 Patent Are Valid .................................. 40
`A.
`The Provisional Application Incorporates By Reference Alkyl
`Glycosides as Claimed ........................................................................ 40
`The Cited References Do Not Provide the Requisite Motivation
`or Reasonable Expectation of Success Needed to Support an
`Obviousness Case ................................................................................ 46
`1.
`Claim 1 is Not Obvious Over Gwozdz and Meezan .................49
`
`B.
`
`2.
`
`3.
`
`4.
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`TABLE OF CONTENTS
`(continued)
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`Page
`
`
`
`2.
`
`3.
`
`4.
`
`Claims 2, 7, 11 and 12 are Not Obvious Over Gwozdz and
`Meezan ......................................................................................64
`Claims 3-6 and 9-10 are Not Obvious Over Gwozdz and
`Meezan ......................................................................................64
`Claims 8 and 13-15 are Not Obvious Over Gwozdz and
`Meezan ......................................................................................65
`Claims 16 and 24-33 are Not Obvious Over Gwozdz and
`Meezan ......................................................................................65
`Claims 17-23 of the ’876 Patent are Not Obvious Over Meezan
`and Gwozdz, and Further In View of Cartt’784 ................................. 66
`IX. Secondary Considerations ............................................................................. 69
`X.
`Conclusion ..................................................................................................... 71
`
`5.
`
`C.
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`1. My name is Sveinbjörn Gizurarson. I am a Professor in the Faculty of
`
`Pharmaceutical Sciences, School of Health Science, University of Iceland, where I
`
`have worked on and developed pharmaceutical formulations for intranasal
`
`administration, including benzodiazepine formulations. Counsel for Patent Owner
`
`Neurelis, Inc. (“Neurelis”) retained me as a technical expert to provide my opinion
`
`regarding U.S. Patent No. 9,763,876 (the ’876 Patent) [Ex. 1001], specifically
`
`Aquestive Pharmaceuticals’ (“Aquestive”) challenge of claims 1-36 of the ’876 Patent
`
`based on the combination of Gwozdz [EX1014] and Meezan [EX1011] as it applies to
`
`claims 1-16 and 24-36, and the combination of Gwozdz, Meezan and Cartt’784
`
`[EX1015], as it applies to claims 17-23.1 My opinions in this expert declaration
`
`support Neurelis’ Response that all challenged claims of the ’876 Patent are valid.
`
`
`1 I understand from Neurelis’ counsel that while Dr. Nicholas Peppas’ declaration
`
`[EX1041] sets forth an additional ground for invalidity (Ground 1: Sonne [EX1013]
`
`and Meezan), that ground was rejected by the Patent Trials Appeal Board in a separate
`
`inter partes review petition filed by Aquestive. As such, my opinions relate to Dr.
`
`Nicholas Peppas’ positions only with regards to Ground 2 (Gwozdz and Meezan) as
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`well as Ground 3 (Gwozdz, Meezan and Cartt’784).
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`I.
`
`Qualifications And Background
`A. Education and Experience
`2.
`I received my Masters degree and Ph.D in Pharmacy from the University
`
`
`
`of Copenhagen in 1986 and 1990, respectively, in the laboratory of Dr. Erik
`
`Bechgaard. The title of my Ph.D thesis was “Intranasal application of insulin.
`
`Pharmaceutical and physiological factors affecting successful absorption of insulin.” I
`
`completed my graduate work while employed as a Project Manager at Novo Nordisk,
`
`one of the world’s leading pharmaceutical companies. Novo Nordisk at the time was
`
`very interested in insulin delivery via intranasal administration, but my work as a
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`Project Manager spanned a wide range of subject matter, and focused on intranasal
`
`delivery of benzodiazepines for the treatment of epileptic seizures, as well as the
`
`effects of various excipients on nasal membrane physiology.
`
`3.
`
`After graduate school, I became a post-doctoral fellow from 1990-1991
`
`at the National Institute of Health in Tokyo, Japan. When working at Novo Nordisk, I
`
`became interested in some of the immunological side-effects that occurred following
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`nasal administration, which introduced me to the field of mucosal vaccines and
`
`mucosal immunizations. It was there that I learned to know the newly developed
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`intranasal product, Rhinocort® (budesonide nasal spray) for relief of hay fever or other
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`
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`upper respiratory allergies, by the Japanese company Teijin.2 I became familiar with
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`
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`both the formulation and delivery aspects of intranasal administration while training in
`
`Tokyo. I have in my personal collection at the University the first bulb-type
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`applicator and multi-dose device that was used to deliver the Rhinocort® budesonide
`
`powder intranasally during my post-doctoral program.
`
`4.
`
`After my post-doctoral work in Japan, I was offered a position as an
`
`Assistant Professor, Faculty of Pharmaceutical Sciences at the University of Iceland in
`
`1991. I was promoted to Associate Professor in 1993, and appointed as a Tenured
`
`Full Professor in 1996. I currently teach, supervise university and graduate students
`
`and perform research in the pharmaceutical delivery field, including intranasal
`
`formulations of benzodiazepines. I have served as an opponent3 in six Ph.D
`
`dissertation defense proceedings in Iceland, Denmark and Sweden.
`
`
`2 Petitioner’s expert Dr. Nicholas Peppas in his brief review of the “General State
`
`of the Prior Art” states that Rhinocort® was used in the “treatment of the flu (i.e.,
`
`influenza) . . ..” See Peppas Declaration, EX1041), ¶100. That is incorrect. To my
`
`knowledge, Rhinocort® was never approved for the treatment of the flu.
`
`3 An outside expert participant in some university graduate school programs.
`
`
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`5. My work at the University of Iceland has led to the submission and
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`
`
`acceptance in August 2018 by U.S. Food & Drug Administration of a New Drug
`
`Application (NDA) for intranasal midazolam (NAYZILAM®), a benzodiazepine nasal
`
`formulation indicated as a rescue drug for cluster seizures and acute repetitive seizures
`
`(intermittent, stereotypic episodes of frequent seizure activity) in patients 12 years of
`
`age and older. The drug is marketed by UCB in the United States. See
`
`https://www.biospace.com/article/releases/ucb-announces-nayzilam-midazolam-nasal-
`
`spray-now-approved-by-fda-to-treat-intermittent-stereotypic-episodes-of-frequent-
`
`seizure-activity-in-people-living-with-epilepsy-in-the-u-s-/ (accessed October 31,
`
`2019) [EX2018].
`
`6.
`
`I also started multiple pharmaceutical companies while an academic at
`
`the University of Iceland. I founded and was the Chief Executive Officer of
`
`Lyfjaþróun Biopharmaceuticals in Iceland from 1991-2005. My company was
`
`acquired by Actavis in 2007. I also founded LipoMedica ehf in 1998, which merged
`
`with Icelandic company Bio-Gels Pharmaceuticals in 2005, which specialized in
`
`mucosal drug delivery systems. In 2001, I founded Hananja ehf, an Icelandic entity
`
`accredited by the European Union and a specialty biopharmaceutical company
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`focused on discovery and development of innovative treatments for life-threatening
`
`diseases, specifically nasal spray drug products.
`
`
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`7.
`
`In 2004, I was a founder of Mentis Cura ehf, an Icelandic company
`
`
`
`focused on digital diagnostics based on machine learning for the diagnosis of
`
`disorders of the central nervous system, such as dementia and ADHD. Mentis Cura
`
`has two CE marked4 products on the European market: Sigla and Katla. I was also a
`
`founder of Nepsone ehf in 2005, a preclinical-stage pharmaceutical company
`
`developing peptides to treat dermatological conditions that arise due to an
`
`autoimmune disease (e.g., psoriasis and eczema). In 2015, I founded Capretto ehf, an
`
`Icelandic based medical device company utilizing antimicrobial lipids. We are
`
`working towards introducing a medical device incorporating monolipid antimicrobials
`
`(natural product) for infection therapy to the market shortly. I also founded Calor ehf
`
`in 2016, an Icelandic pharmaceutical company focused on excipients that enhance
`
`stability of therapeutic agents in solution. My latest venture is Eclampsin ehf, an
`
`Icelandic company I founded this year in 2019, which focuses on the development of
`
`a naturally occurring protein (placental protein 13), only found in the placenta, to
`
`prophylactically treat preeclampsia. I am also working on establishing a not-for-profit
`
`pharmaceutical manufacturing organization in Malawi, Africa, focusing on the
`
`manufacturing of life-saving medicine for infants and small children under 5 years of
`
`
`4 European health, safety and environmental certification.
`
`
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`age (a neglected population) in a form they need it, to treat neglected diseases in third
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`
`
`world countries, including severe and cerebral malaria and schistosomiasis, two of the
`
`major disease burdens in the world.
`
`8.
`
`I have published over 260 peer-reviewed articles, books, book chapters
`
`and review articles in the pharmaceutical field, many related to intranasal
`
`administration of therapeutic agents, including benzodiazepines. Articles especially
`
`relevant to the ’876 Patent include a 1993 review article on the relevance of nasal
`
`physiology to drug absorption studies (published as an invited contribution to the
`
`journal Advanced Drug Delivery Reviews), amongst others. I also hold numerous
`
`patents covering the same subject matter of intranasal administration and
`
`pharmaceutical preparations.
`
`9.
`
`I was on the Editorial Board for the Scandinavian Journal of Laboratory
`
`Animal Sciences, and am a reviewer for several peer-reviewed journals, including the
`
`International Journal of Pharmaceutical Sciences, European Journal of Pharmaceutics
`
`and Biopharmaceutics, Molecular Pharmaceutics, Expert Opinion on Drug Delivery,
`
`among others. I am or was a member of the American Association of Pharmaceutical
`
`Scientists, American College of Clinical Pharmacology, International Licensing
`
`Executive Society, Christian Pharmacists Fellowship International and the Icelandic
`
`Pharmaceutical Society.
`
`
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`10.
`
`I have received numerous awards for my work, including an Innovation
`
`
`
`Award in 2007 from the University of Iceland, and from the Trade Council of Iceland
`
`in 2004, as well as a Young Investigator Research Achievement Award in 1996 from
`
`the National Research Council. I have served on the Accreditation Board at the
`
`University of Iceland in 2010, 2015 and 2019 in order to prepare the Faculty of
`
`Pharmaceutical Sciences for accreditation audits during these time periods. On behalf
`
`of the Danish Ministry of Education, I have also accredited the Faculty of
`
`Pharmaceutical Sciences, Syd-Dansk University in Denmark in 2010. I was
`
`designated an expert in biopharmaceutics by the Ministry of Health, Iceland, in 1994,
`
`and as a Qualified Person in 2000 by the Icelandic Medicine Agency, amongst other
`
`special authorizations that I have received from various governmental agencies.
`
`11.
`
`In all, I have over thirty years of hands-on research experience
`
`specializing in the formulation of intranasal therapeutics, including benzodiazepines.
`
`12. Attached as Appendix C is a copy of my curriculum vitae in support of
`
`my opinions.
`
`B.
`13.
`
`Bases for Opinions and Materials Considered
` Materials I have relied on in preparing this declaration are referenced
`
`throughout, as well as listed in the attached Appendix B. My opinions are based on
`
`my education, on my experience, and on other bases such as articles and other
`
`
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`references, as well as other relevant knowledge. This declaration states my current
`
`opinions, which could change if additional information or analyses become available
`
`
`
`to me.
`
`C.
`14.
`
`Previous Litigation Experience
`I have served as an expert witness in a patent proceeding:
`
` Lannett Holdings, Inc. v. AstraZeneca AB (IPR2015-001629) (expert for
`
`Petitioner Lannett Holdings, Inc.)
`
`D.
`15.
`
`Scope of Work
`I have been retained by Neurelis as a technical expert in this matter to
`
`provide various opinions regarding the ’876 Patent. I receive $500 per hour for my
`
`services or $750 per hour for depositions. No part of my compensation is dependent
`
`upon my opinions given or the outcome of this case.
`
`II. Legal Standards
`16. For my opinions in this declaration, I understand from patent owner
`
`Neurelis’ counsel that this requires applying various legal principles. As I am not an
`
`attorney, I have been informed about various legal principles that involve my analysis.
`
`I have used my understanding of those principles in forming my opinions. I
`
`summarize these principles as I understand them below.
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`17. For example, I have been told by Neurelis’ counsel that the Petitioner, in
`
`
`
`this case Aquestive, bears the burden of proving unpatentability in this proceeding by
`
`a preponderance of the evidence. I am informed that this preponderance of the
`
`evidence standard means that Petitioner must show that unpatentability is more
`
`probable than not.
`
`18.
`
`I have also been told by counsel that when I review and consider the
`
`claims, the claims should be construed in light of the specification from the
`
`perspective of a person of ordinary skill in the art (“POSA”). I discuss who qualifies
`
`as the person of ordinary skill in the art in more detail below. See Section III.
`
`19.
`
`I have been asked by counsel to consider the question of
`
`obviousness/non-obviousness. I am told by counsel that this analysis must be from
`
`the perspective of the person of ordinary skill in the art, and whether the skilled artisan
`
`would consider any differences between the prior art and what is claimed to have been
`
`obvious. To make this assessment, I have been informed by Neurelis’ counsel that the
`
`concept of patent obviousness involves four factual inquiries: (1) the scope and
`
`content of the prior art; (2) the differences between the claimed invention and the prior
`
`art; (3) the level of ordinary skill in the art; and (4) secondary considerations of non-
`
`obviousness. I further note that I have been instructed by counsel that one cannot use
`
`an existing patent as a guide to select from prior art elements, or otherwise engage in
`
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`hindsight. Rather, the better approach is to consider what the POSA knew, and what
`
`the art taught, suggested, or motivated the person of ordinary skill in the art to further
`
`
`
`pursue, and to differentiate between steps that were routinely done (such as in
`
`response to known problems, steps or obstacles), and those which, for example, may
`
`have represented a different way of solving existing or known problems.
`
`20.
`
`I am also informed by counsel that there must be some motivation or
`
`rationale for a POSA to combine references, and that the combination of the
`
`references to arrive at the claimed elements must have a reasonable expectation of
`
`success to a POSA at the time of filing.
`
`21.
`
`I understand from counsel that before reaching any final conclusion on
`
`obviousness, the obviousness analysis requires consideration of objective indicia of
`
`non-obviousness. These must be considered to ensure that, for example, there were
`
`not some unanticipated problems, obstacles or hurdles that may seem easy to
`
`overcome in hindsight, but which were not readily overcome prior to the relevant
`
`invention date of the patents/claims at issue here. I understand from counsel that these
`
`objective indicia are also known as “secondary considerations of non-obviousness,”
`
`and may include long-felt but unmet need and unexpected results, among others. I
`
`also understand, however, that any offered evidence of secondary considerations of
`
`non-obviousness must be comparable with the scope of the challenged claims. This
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`means, from my understanding, that for any offered evidence of secondary
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`
`
`considerations of non-obviousness to be given substantial weight, I understand from
`
`counsel that the proponent of that evidence must establish a “nexus” or a sufficient
`
`connection or tie between that evidence and the merits of the claimed invention, which
`
`I understand specifically incorporates any novel element(s) of the claimed
`
`invention. I also understand from counsel it is the patentee that has the burden of
`
`proving that a nexus exists.
`
`22. With respect to long-felt need, I understand from Neurelis’ counsel that
`
`the evidence must show that a particular problem existed for a long period of
`
`time. More specifically, I understand that for a “need” to be long-felt and unmet: 1)
`
`the need must be persistent and recognized by those of ordinary skill in the art, 2) the
`
`need must not be satisfied by another before the alleged invention, and 3) the claimed
`
`invention itself must satisfy the alleged need. I also understand from counsel that
`
`long-felt need is analyzed as of the date that the problem is identified. Furthermore, I
`
`understand from Neurelis’ counsel that long-felt need should be based upon
`
`inadequacies in the technical knowledge of those skilled in the art, not due to
`
`business-driven market forces.
`
`23. With respect to failure of others, I understand from counsel that the focus
`
`of the analysis is on the prior failure of others in the relevant industry, not the
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`inventors. I further understand from Neurelis’ counsel that, absent a showing of a
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`long-felt, unmet need or the failure of others, the mere passage of time without the
`
`
`
`claimed invention is not evidence of non-obviousness.
`
`24. With respect to unexpected results, I understand from counsel that any
`
`results upon which a patentee wishes to rely as an indicator of non-obviousness must
`
`be based on a comparison of the purported inventions with the closest prior art.
`
`III. Person of Ordinary Skill in the Art
`25. As above, I have been informed by Neurelis’ counsel that the analysis is
`
`to be conducted from the perspective of a POSA at the time of the invention.
`
`26.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the educational
`
`level of the inventor; (2) the type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; and (5)
`
`sophistication of the technology and educational level of active workers in the field.
`
`27.
`
`I understand that Petitioner’s expert, Dr. Nicholas Peppas, submitted the
`
`following definition of a POSA:
`
`It is my opinion that as of the earliest priority date that the ’876 Patent as
`a whole is entitled to (i.e., no earlier than March 27, 2009), as discussed
`in ¶¶68-70, above) a POSITA would have been a medicinal chemist,
`pharmaceutical chemist, chemist, or biologist involved in the research
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`and development of pharmaceutical formulations for the treatment of
`epilepsy and related diseases/disorders. Such an individual would have at
`least a B.S. degree in chemical, biological, or pharmaceutical sciences or
`a medical degree and several years of experience in the field of
`transmucosal (including intranasal, rectal, vaginal, ocular, lacrimal,
`nasolacrimal, buccal, sublingual, urethral, inhalation, and auricular)
`pharmaceutical formulation development, the amount of post-graduate
`experience depending upon the level of formal education. The individual
`would also have some experience in design and testing of formulations
`for mucosal delivery (and particularly in intranasal formulations) of
`systemic-acting drugs.
`
`Peppas Decl. (EX1041), ¶74.
`
`28.
`
`I disagree with Dr. Peppas’ definition on several points. As I explain in
`
`detail below, the formulation of a benzodiazepine for intranasal administration, as the
`
`claims recite, is difficult and complex science. The physiological constraints of active
`
`ingredient uptake due to the nasal anatomy, as well as the very low solubility of
`
`benzodiazepines requires a higher skill set and knowledge than a POSA with a
`
`bachelor’s degree “with several years of experience.”
`
`29.
`
`Instead, in my opinion and experience, a person of ordinary skill in the
`
`art related to the ’876 Patent should at least have held a Masters degree with many
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`years of experience, or a Ph.D. or Pharm.D degree5 with several years of experience,
`
`
`
`or its equivalent research experience.6 The reason is because there is a difference
`
`between how a person with a graduate degree and training processes scientific
`
`information, as compared to a person with only a bachelor’s degree. A person of
`
`ordinary skill in the art with the requisite educational background above and the direct
`
`experience in intranasal formulations and benzodiazepines, could appreciate the
`
`difficult task of first formulating benzodiazepines to obtain a clinically-relevant dose
`
`5 Dr. Peppas cites to a “medical degree” as within the educational background of a
`
`POSA. It is unclear if he is referring to an “MD”, or generally a degree in the medical
`
`field, which could be other types of healthcare professionals (for example, a dentist
`
`(DMD)). In my experience a health-care focused degree would likely not have
`
`provided the training necessary for a POSA in the context of the ’876 patent.
`
`6 I include “or its equivalent research experience” because in Iceland, there is the
`
`possibility that a professorship could be obtained by working in the relevant field for
`
`an extended period of time. That time period would be equivalent to the length of
`
`time it takes to obtain the information and knowledge needed to receive a graduate
`
`degree and obtain the relevant experience for the academic position. This is seldom
`
`awarded, and can be difficult to obtain.
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`in the formulation, while ensuring that sufficient uptake occurs in the nasal cavity. In
`
`
`
`my experience, a person with a bachelor’s degree would be hard-pressed to succeed at
`
`this difficult task.
`
`30.
`
`I also disagree with Dr. Peppas’ list of the scientific background of one of
`
`ordinary skill in the art. Dr. Peppas contends that a POSA “would have been a
`
`medicinal chemist, pharmaceutical chemist, chemist, or biologist involved in the
`
`research and development of pharmaceutical formulations for the treatment of
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`epilepsy and related diseases/disorders.” Peppas Declaration (EX1041), ¶74. It is
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`difficult to ascertain what role a medicinal chemist would play in the research and
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`development of benzodiazepine pharmaceutical formulations for intranasal
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`administration. Chemists (medicinal chemists in particular) are primarily concerned
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`with chemical structures and synthesizing new chemical compounds. The chemical
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`structures are known here.
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`31.
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`Instead, in my opinion the POSA would have had knowledge of
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`benzodiazepine structure and function, including solubility issues with
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`benzodiazepines in general. The POSA would also have knowledge and practical
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`experience working with intranasal formulations, including knowledge of the
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`physiology and anatomy of the nasal cavity, with relevant experience in developing
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`intranasal formulations.
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`32.
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`I also disagree with Dr. Peppas’ statement that the POSA could have had
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`
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`experience in what he deems as related fields, including “rectal, vaginal, ocular,
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`lacrimal, nasolacrimal, buccal, sublingual, urethral, inhalation, and auricular.” While
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`those fields can be informative, the pathway to successfully formulating an intranasal
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`product can be distinguishable from the mucosal systems above. For example, as I
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`explain below, the use of rectal formulations of diazepam (a commercially available
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`product) for intranasal administration would not work.
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`33.
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`I also note that the experience may come from the POSA’s own
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`experience, or may come through research or work collaborations with other
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`individual(s) with experience in the medical, pharmaceutical or biotech industry, e.g.,
`
`as members of a research team or group. For example, the person of ordinary skill in
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`the art may work as part of a team or collaboration to develop a benzodiazepine
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`formulation for intranasal administration, including consulting with others to select
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`the benzodiazepine for use in the intended treatment, in this case a quick-acting
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`formulation for use in patients experiencing an epileptic seizure, as well as subsequent
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`testing of the intranasal benzodiazepine formulation.
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`IV. Summary of Opinions
`34.
`I have been asked to provide my opinions regarding claims 1-36 of the
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`’876 Patent, from the perspective of a POSA at the time of the ’876 Patent’s earliest
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`filing date. While I understand that petitioner Aquestive asserts that this date should
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`
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`be March 27, 2009, I understand from Neurelis’ counsel that there are legal arguments
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`that establish that the ’876 Patent is entitled to the priority date of March 28, 2008, the
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`filing date of the ’558 Provisional Application. I do not provide any opinions on the
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`legal argument at issue here; however, it is my opinion that the ’558 Provisional
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`Application, which incorporated by reference the 1988 SIGMA catalogue excerpt
`
`[EX2006], disclosed alkyl glycosides, and thus a POSA would have known and
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`recognized from the incorporation by reference that the ’558 Provisional Application
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`highlighted alkyl glycosides as part of the claimed invention.
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`35. Moreover, it is also my opinion that claims 1-16 and 24-36 are not
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`obvious in view of Gwozdz [EX1014] and Meezan [EX1011] (Ground 2 of Dr.
`
`Peppas’ Declaration [EX1041]) and claims 17-23 are not obvious in view of Gwozdz,
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`Meezan and Cartt’784 [EX1015] (Ground 3 of Dr. Peppas’ Declaration [EX1041]).
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`Instead, Aquestive and Dr. Peppas failed to provide in my opinion a motivation to
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`combine or reasonable expectation of success to achieve an intranasal formulation of
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`benzodiazepines as claimed in claims 1-36.
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`36.
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`In addition, it is also my opinion that the unexpected and surprising
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`success of the ’876 Patent at formulating an intranasal non-aqueous diazepam
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`formulation as claimed in claims 1-36, especially in view of the failure of others to
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`successfully formulate an intranasal diazepam or benzodiazepine formulation, for
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`intranasal administration, further supports the non-obviousness of the ’876 Patent’s
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`claims. The eventual approval of Neurelis’ NDA for NRL-1 (Valtoco®), which will
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`fill a long-felt and unmet need for an alternative to rectal and intravenous diazepam
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`products, only serves to strengthen the non-obviousness of Neurelis’ challenged
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`
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`claims.
`
`V. The ’876 Patent [Ex. 1001]
`37. The ’876 Patent, titled “Administration of Benzodiazepine
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`Compositions”, was filed on October 29, 2014 as U.S. Patent Application No.
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`14/527,613. See EX1001, pg. 0001. The ’876 Patent issued on September 19, 2017.
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`The ’876 Patent is a continuation of U.S. Patent Application No. 13/495,942 (now
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`U.S. Patent No. 8,895,546), which was filed on June 13, 2012, which is a
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`continuation-in-part of U.S. Patent Application No. 12/413,439, which was filed on
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`March 27, 2009. Id. The ’876 Patent claims priority to U.S. Provisional Application
`
`No. 61/040,558, which was filed on March 28, 2008, U.S. Provisional Application
`
`No. 61/497,017, which was filed on June 14, 2011 and U.S. Provisional Application
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`No. 61/570,110, which was filed on December 13, 2011. Id. The abstract, which
`
`comports with the title of the patent, states that the patent “relates to pharmaceutical
`
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`compositions comprising one or more benzodiazepine drugs for nasal administration,
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`
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`methods for produ