Ranbaxy Ex. 1037
`IPR Petition - USP 9,050,302
`
`
`IPR Petition - USP 9,050,302
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`1.
`
`I, David P. Rotella, Ph.D., have been retained by Knobbe, Martens,
`
`Olson & Bear, LLP, counsel for Ranbaxy Laboratories Limited ("Ranbaxy").
`
`I understand that Ranbaxy is petitioning for inter partes review of U.S. Patent
`
`No. 8,772,306 ("the '306 patent") (Ex. 1001), and is requesting that the United
`
`States Patent and Trademark Office cancel Claims 1-34 of the '306 patent as
`
`unpatentable. This declaration addresses the patentability of Claims 1-34 of the
`
`'306 patent.
`
`I.
`
`BACKGROUND, QUALIFICATIONS, AND COMPENSATION
`
`A.
`
`Background and Qualifications
`
`2.
`
`I am currently the Margaret and Herman Sokol Professor of
`
`Chemistry in the Department of Chemistry and Biochemistry and in the Sokol
`
`Institute of Pharmaceutical Life Sciences at Montclair State University. I have
`
`been a member of the faculty of this university since 2011.
`
`3.
`
`I am currently an adjunct professor
`
`in
`
`the Department of
`
`Pharmaceutical Sciences at the University of Pittsburgh, in the Center for Drug
`
`Discovery at Northeastern University, and in the Department of Medicinal
`
`Chemistry at the University of Mississippi. I have been a member of the faculty of
`
`these departments since 2010, 2010, and 2009, respectively.
`
`4.
`
`I am currently a registered pharmacist in the Commonwealth of
`
`Pennsylvania.
`
`- 1 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`5.
`
`I was formerly a research scientist at multiple pharmaceutical
`
`companies during the years 1991-2010, including at Bristol-Myers Squibb PRI,
`
`Lexicon Pharmaceuticals, and Wyeth Research/Pfizer. My industry experience
`
`focused on drug discovery and development.
`
`6.
`
`I received my B.S. Phann. from the University of Pittsburgh in 1981
`
`and Ph.D. in Medicinal Chemistry from The Ohio State University in 1985. I was a
`
`Postdoctoral Scholar in the Department of Chemistry at The Pennsylvania State
`
`University from 1985 to 1987.
`
`7. My current research focuses on protein kinase inhibitors for anti-
`
`infective and anti-inflammatory applications. Specifically, I work on the discovery
`
`of novel agents useful for treatment of parasitic and neurodegenerative diseases,
`
`including synthesis of new analogs of a lead structure as potential protein kinase
`
`inhibitors and investigation of structure-activity relationships in a compound with
`
`HSP90 inhibitor activity.
`
`8.
`
`I have authored or co-authored more than 20 abstracts for presentation
`
`at professional meetings, 40 peer-reviewed journal articles, and seven book
`
`chapters. I have also edited or co-edited five books in the field of Medicinal
`
`Chemistry. I have received numerous honors, fellowships and awards, and am an
`
`inventor or co-inventor on seven granted patents.
`
`- 2 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`9.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately (Ex. 1024 ).
`
`B.
`
`Compensation
`
`10.
`
`I am being compensated at my normal consulting rate of $500 per
`
`hour. I have no personal financial interest in any of the entities involved in this
`
`litigation, and my compensation does not depend in any way on my testimony, my
`
`conclusions or the outcome of my analysis.
`
`II. MATERIALS CONSIDERED
`
`11. Attached is a listing of the documents that I have considered and
`
`reviewed in connection with providing this declaration.
`
`III. THE '306 PATENT
`
`12.
`
`I have reviewed
`
`the
`
`'306 patent,
`
`including
`
`the claims and
`
`specification. I have also reviewed the substantive (as opposed to procedural)
`
`portions of the prosecution history of the '306 patent. The '306 patent pertains to
`
`the treatment of gamma hydroxybutyrate ("GHB") for the treatment of various
`
`sleep related disorders. See Ex. 1001 at 14 (Col. 1:24-29). According to the '306
`
`patent the "present invention is to improve the safety and efficacy of the
`
`administration of GHB of a salt thereof to a patient." See id. at Abstract. The '306
`
`patent also states that "[i]t has been discovered that the concomitant administration
`
`- 3 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`of ... valproate ... will affect GHB administration." Id. Also according to the
`
`'306 patent, it was "discovered that valproate increases the effect of GHB on the
`
`body, thereby potentially causing an unsafe condition." Id.
`
`13. As explained in this declaration, the assertion that the inventors of the
`
`'306 patent "discovered that valproate increases the effect of GHB on the body
`
`thereby potentially causing an unsafe condition" (id.) is incorrect.
`
`14. The '306 patent defines various terms. I address certain terms relevant
`
`to my analysis. The '306 patent states: "'Concomitant' and 'concomitantly' as used
`
`herein refer to the administration of at least two drugs to a patient either
`
`subsequently, simultaneously, or consequently within a time period during which
`
`the effects of the first administered drug are still operative in the patient." Id. at 17
`
`(Col. 8:37-41).
`
`15. One skilled in the art would thus understand that the definition of
`
`"concomitantly," as recited in the '306 patent, would vary depending on the
`
`identity of "the first administered drug," because the "time period during which the
`
`effects of the first administered drug are still operative in the patient" would
`
`depend on the dose and pharmacokinetics (e.g., metabolism and plasma level) of
`
`the first administered drug. See id.
`
`16. The '306 patent also states: "The terms 'therapeutically effective
`
`amount,' as used herein, refer to an amount of a compound sufficient to treat,
`
`- 4 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`ameliorate, or prevent the identified disease or condition, or to exhibit a detectable
`
`therapeutic, prophylactic, or inhibitory effect." Id. at 18 (Col. 9:8-12). I will use
`
`this definition.
`
`17. The '306 patent notes that GHB is sold commercially as Xyrem®.
`
`More specifically, the '306 patent states: "GHB (also called oxysorbate or oxybate)
`
`is approved in the United States (US) for the treatment of excessive daytime
`
`sleepiness (EDS) and for the treatment of cataplexy, both in patients with
`
`narcolepsy." Id. at 19 (Col. 11:22-25).
`
`18. The '306 patent further states that "[v]alproic acid (VPA, also called
`
`valproate or divalproex), an acidic chemical compound, has found clinical use as
`
`an anticonvulsant and mood-stabilizing drug ... . "Id. at 21 (Col. 15:20-22). The
`
`'306 patent goes on to state that "[t]he acid, salt, or a mixture of the two (valproate
`
`semisodium, divalproate) are marketed under the various brand names .... " Id. at
`
`21(Col.15:31-33).
`
`19. The '306 patent concludes with 34 claims directed towards methods
`
`of administering GHB when a patient is
`
`taking, or may take, valproate
`
`concomitantly with GHB. See id. at claims.
`
`IV. SUMMARY OF OPINIONS
`
`20.
`
`It is my opinion that, based on the teaching in the pnor art of
`
`valproate as an agent that increases physiological levels of GHB in patients, that
`
`- 5 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`one of ordinary skill in the art would have decreased the amount of GHB
`
`administered to a patients also taking valproate. Thus, as set forth in further detail
`
`herein, it is my opinion that each and every claim of the '306 patent would have
`
`been obvious to one having ordinary skill in the art.
`
`21.
`
`It is my opinion that one of ordinary skill in the art would have been
`
`aware of Maitre M, The y-Hydroxybutyrate Signalling System
`
`in Brain
`
`Organization and Functional Implications, Progress in Neurobiology, Vol. 51, pp.
`
`337-361 (1997) ("Maitre") (Ex. 1003) and would have been aware of the
`
`Physician's Desk Reference Edition 61, pp. 1688-1692, (2007) (Xyrem® Package
`
`Insert entry) ("the Xyrem® PI") (Ex. 1005). These references were germane to the
`
`relevant field; accordingly, a skilled artisan would have been motivated to combine
`
`the teachings of Maitre and the Xyrem® PI, and would have considered claims 1-
`
`5, 7-16, 18-26, and 28-34 of the '306 patent obvious in light of the combination of
`
`Maitre and the Xyrem® PL
`
`22.
`
`It is my opinion that one of ordinary skill in the art would have been
`
`aware of Okun, M., GHB: An Important Pharmacologic and Clinical Update, J.
`
`Pharm. Pharmaceut. Sci., Vol. 4(2), pp. 167-175 (2001) ("Okun") (Ex. 1004) and
`
`would have been aware of the Xyrem® Titration Schedule ("the Xyrem® Titration
`
`Schedule") (Ex. 1006). These references were germane to the relevant field;
`
`accordingly, a skilled artisan would have been motivated to combine the teachings
`
`- 6 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`of Okun and the Xyrem® Titration Schedule, and would have considered claims 1-
`
`5, 7-16, 18, 30, and 31 of the '306 patent obvious in light of Okun and the Xyrem®
`
`Titration Schedule.
`
`23.
`
`It is my opinion that a person of ordinary skill in the art would have
`
`been aware of U.S. Patent No. 6,780,889 to Cook et al., ("Cook") (Ex. 1007), and
`
`would have combined the teachings of Okun and the Xyrem® Titration Schedule
`
`with Cook. It is also my opinion that a skilled artisan would have considered
`
`claims 19-26, 28, 29, 32, and 34 of the '306 patent obvious in light of the
`
`combination of Okun, the Xyrem® Titration Schedule, and Cook.
`
`24.
`
`It is my opinion that one of ordinary skill in the art would have been
`
`aware of Sandson et al., An Interaction Between Aspirin and Valproate: The
`
`Relevance of Plasma Protein Displacement Drug-Drug Interactions, Am. J
`
`Psychiatry, Vol. 163, pp. 1891-1896 (2006) ("Sandson") (Ex. 1023) and would
`
`have combined the teachings of Maitre and the Xyrem® PI with Sandson. It is my
`
`opinion a skilled artisan would have considered claims 6, 17, and 27 of the '306
`
`patent obvious in light ofMaitre, the Xyrem® PI, and Sandson.
`
`V.
`
`LEGALSTANDARDS
`
`25.
`
`I understand from counsel that the first step in evaluating the validity
`
`of an issued claim is interpreting the words of the claim to determine the scope of
`
`the invention defined therein and the meaning of the words used in the claim. I
`
`- 7 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`understand claim construction is done through the eyes of a person of ordinary skill
`
`in the art. I have been informed that, in interpreting a claim, a court first considers
`
`the intrinsic evidence, i.e., the claims, the written description, and the prosecution
`
`history of the patent.
`
`26.
`
`I understand from counsel that U.S. patent law precludes the issuance
`
`of a patent when the differences between the subject matter sought to be patented
`
`and the prior art are such that the subject matter as a whole would have been
`
`obvious, at the time the invention was made, to a person having ordinary skill in
`
`the art to which the subject matter pertains. I also understand that obviousness is an
`
`inquiry taking into account the following factors:
`
`(A)
`
`determining the scope and content of the prior art;
`
`(B)
`
`determining the differences between the prior art and the
`
`claimed invention;
`
`(C)
`
`resolving the level of ordinary skill in the art; and
`
`(D)
`
`considering any secondary considerations of non-obviousness.
`
`27.
`
`I understand from counsel that the issue of obviousness is determined
`
`with reference to a hypothetical person having ordinary skill in the art. The person
`
`of ordinary skill is not the inventor, but an imaginary person possessing only
`
`"ordinary skill," whose subjective analysis of the prior art and the claimed
`
`invention is applied to an obviousness determination. I understand that the person
`
`- 8 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`of ordinary skill in the art is not necessarily an individual, but may be a team of
`
`individuals.
`
`28.
`
`I additionally understand from counsel that a person or ordinary skill
`
`is not an automaton, but a person of ordinary creativity in his/her field. He or she
`
`generally thinks along the line of conventional wisdom in the art during the time
`
`period an invention took place. He or she is assumed to be aware of all relevant
`
`prior art at that time an invention took place. The person or ordinary skill would
`
`have also understood and considered design incentives and market forces that
`
`would prompt a person to seek variations of a product known to have a particular
`
`utility in his/her area of expertise.
`
`29.
`
`I also understand from counsel that rationales that may support a
`
`conclusion of obviousness include:
`
`(A)
`
`combining prior art elements according to known methods to
`
`yield predictable results;
`
`(B)
`
`simple substitution of one known element for another to obtain
`
`predictable results;
`
`(C)
`
`use of known technique to improve similar devices (methods,
`
`or products) in the same way;
`
`(D)
`
`applying a known technique to a known device (method, or
`
`product) ready for improvement to yield predictable results;
`
`- 9 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`(E)
`
`"obvious to try," i.e., choosing from a finite number of
`
`identified, predictable solutions, with a reasonable expectation
`
`of success;
`
`(F)
`
`known work in one field of endeavor may prompt variations of
`
`it for use in either the same field or a different one based on
`
`design incentives or other market forces if the variations are
`
`predictable to one of ordinary skill in the art;
`
`(G)
`
`some teaching, suggestion, or motivation in the prior art that
`
`would have led one of ordinary skill to modify the prior art
`
`reference or to combine prior art reference teachings to arrive at
`
`the claimed invention.
`
`VI. A PERSON OF ORDINARY SKILL IN THE ART
`
`30.
`
`I have been asked to opine on the experience and qualifications of a
`
`person of ordinary skill in the art at the time of the alleged invention. It is my
`
`opinion that a person of ordinary skill in the art would be a collaborative team,
`
`spanning several disciplines in the pharmaceutical sciences. It is my opinion that
`
`the person of ordinary skill in the art at the time of the alleged invention would
`
`have had an advanced degree, or access to those with advanced degrees, in
`
`medicine or pharmacy, including a medical doctors, and/or pharmacists. It is my
`
`opinion that the person of ordinary skill would also have had advanced knowledge
`
`- 10 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`of medicinal chemistry, and would have collaborated with a person having
`
`advanced knowledge of pharmacology, and familiarity with, typical methods for
`
`reducing drug-drug interactions. It is my opinion that the person of ordinary skill in
`
`the art would have had an understanding of the drug pharmacokinetics and
`
`pharmacodynamics, and the risks of concomitant administration of certain drug
`
`combinations, for example, through evaluation of relevant literature, including
`
`drug package inserts.
`
`VII. TECHNICAL BACKGROUND AND STATE OF THE PRIOR ART
`
`31. Both medical doctors and pharmacists are trained to monitor and
`
`assess the risk of drug-drug interactions. There are a substantial number of
`
`resources available in evaluating drug-drug interactions, including drug package
`
`inserts, publications such as
`
`the Physician's Desk Reference, as well as
`
`commercial databases. Accordingly, it is routine practice for a pharmacist to
`
`determine whether particular medications being prescribed have the potential for
`
`adverse reactions. In particular, physicians and pharmacists will often refer to a
`
`drug package insert for information regarding dosing and drug-drug interactions.
`
`Moreover, the practice of assessing drug-drug interactions is so commonplace that
`
`it has become automated: the same system that tracks prescriptions, also flags
`
`potential drug-drug interactions when a new prescription is entered in a patient
`
`profile.
`
`- 11 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`32. Likewise, it is well-understood that, while two medications may have
`
`undesired side-effects when administered concomitantly, such side-effects may be
`
`ameliorated or eliminated entirely through titration of the dosage of one or more of
`
`the drugs at issue. Patients are commonly administered combinations of two or
`
`more drugs to treat a disease and in some cases patients may have more than one
`
`disease that requires drug therapy, thus physicians and pharmacists commonly
`
`monitor the administered doses of the drugs used in these cases, to ensure that the
`
`drugs achieve the necessary efficacy while minimizing any side-effects from
`
`concomitant administration of multiple drugs that may have adverse interactions.
`
`33. Accordingly, armed with the appropriate package inserts, or other
`
`references, physicians and pharmacists would have recognized that concomitant
`
`administration of valproate and GHB could result in deleterious side-effects due to
`
`high GHB levels in the body, and similarly, concomitant administration of
`
`valproate and aspirin with GHB could exacerbate these side-effects.
`
`VIII. PROSECUTION HISTORY OF THE '306 PATENT
`
`34.
`
`It is my opinion that the challenged claims of the '306 patent are
`
`generally directed to various methods of treating patients suffering from various sleep
`
`disorders, including narcolepsy, by administering a reduced dose of gamma-
`
`hydroxybutyrate (GHB) in patients who are concomitantly receiving valproate.
`
`- 12 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`3 5.
`
`It is my understanding that the alleged advance recited in each and every
`
`claim of the '306 patent is administering a reduced dose of GHB in treating sleep
`
`disorders when valproate is also administered. More specifically, the '306 patent asserts
`
`that the inventors unexpectedly discovered that valproate increases GHB in the body.
`
`(Ex. 1001 at, e.g., Abstract; at 18 (Col. 10:47-51); at 20 (Col. 13:9-12; 48-50);
`
`Applicants repeated this assertion during prosecution. (See, e.g., '306 Patent File
`
`History Amendment and Response filed October 31, 2013 (Ex. 1026) and
`
`Supplemental Amendment and Response filed November 13, 2013 (Ex. 1027 at 10)
`
`(stating that the cited art "would not teach or suggest that there would be a change in
`
`the GHB in vivo effect caused by valproate. Furthermore, it would not have been
`
`known prior to the present application what that effect would be, such as an increase or
`
`decrease in the in vivo effect ofGHB.") (emphasis in original).)
`
`36.
`
`I disagree with the Patentee's repeated assertions regarding what was
`
`unknown in the prior art. Indeed, contrary to this repeated assertion, as set forth
`
`herein, the prior art recognized that concomitant administration of GHB with
`
`valproate would increase the physiological GHB concentration.
`
`IX. SCOPE AND CONTENT OF THE PRIOR ART
`
`37. GHB was marketed as sodium oxybate under the trade name Xyrem®
`
`at least as early as 2002 (see Ex. 1005 at 1688; see also Ex. 1006), and GHB was
`
`known to be useful for treating narcolepsy in patients (e.g., to improve sleep
`
`- 13 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`patterns). (See, e.g., Ex. 1003 at 352; see also, e.g., Ex. 1004 at 167, 169; see also,
`
`e.g., Ex. 1005 at 1688.) It was also known in the art that GHB could be
`
`administered orally, as an aqueous solution. (See, e.g., Ex. 1005 at 1688; see also,
`
`e.g., U.S. Patent No. 6,780,889 to Cook et al. ("Cook")(Ex. 1007 at Abstract).)
`
`38.
`
`I have reviewed each of Maitre, Okun, and the Xyrem® PI, and each
`
`teach the use of GHB for sleep-related disorders such as narcolepsy. Moreover, I
`
`have also reviewed numerous other prior art references that disclose the use of
`
`GHB to treat narcolepsy. See, e.g., Broughton R., The Treatment of Narcolepsy-
`
`Cataplexy with Nocturnal Gamma-Hydroxybutyrate, Can J. Neural Sci, Vol. 6,
`
`No.l
`
`(1979)
`
`(Ex. 1008); Broughton R, Effects of Nocturnal Gamma-
`
`Hydroxybutyrate on Sleep/Waking Patterns in Narcolepsy-Cataplexy; Can. J.
`
`Neural. Sci. Vol. 7, No.l (1980) (Ex. 1009); Cash CD, Gammahydroxybutyrate:
`
`An Overview of the Pros and Cons for it Being a Neurotransmitter And/Or a
`
`Useful Therapeutic Agent, Neurosci. Biobehavioral Rev., Vol. 18(2), 291-304
`
`(1994)
`
`(Ex. 1010); Mamelak et al., Treatment of Narcolepsy with
`
`Hydroxy butyrate. A Review of Clinical and Sleep Laboratory Findings, Sleep, Vol.
`
`9(1), pp. 285-289 (1986) (Ex. 1011); Scharf M. et al., The Effects and
`
`Effectiveness of y-Hydroxybutyrate
`
`in Patients with Narcolepsy; J. Clin.
`
`Psychiatry, 46:222-225 (1985) (Ex. 1012); and Scharf et al., Pharmacokinetics of
`
`- 14 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`Gammahydroxybutyrate (GHB) in Narcoleptic Patients, Sleep, Vol. 21(5), pp. 507-
`
`514 (1998) (Ex. 1013).
`
`39. One having ordinary skill in the art would have known that GHB, as
`
`with all drugs, should be administered at a dose to maximize efficacy while
`
`minimizing side-effects. Indeed, with respect to GHB, it was known in the art that
`
`GHB should be titrated to effect. Indeed, the Xyrem® PI and the Xyrem® Titration
`
`Schedule each teach a particular GHB titration schedule. (See, e.g., Ex. 1005 at
`
`1692; see also, e.g., Ex. 1006.) According to the Xyrem® PI and the Xyrem®
`
`Titration Schedule, the starting dose of GHB should be 4.5 grams per night. (See,
`
`e.g., Ex. 1005 at 1692; see also, e.g., Ex. 1006.) The dose of GHB is thereafter
`
`increased in 1.5 g increments until achieving the desired effect. (See, e.g., Ex. 1005
`
`at 1692; see also, e.g., Ex. 1006 at 1.)
`
`40. A person of ordinary skill m the art would have known that
`
`administration of increasing doses of GHB leads to increased plasma levels of
`
`GHB, which may result in adverse effects, including coma or death. (See e.g., Ex.
`
`1004 at 167, 170; see also, e.g., Ex. 1005 at 1688-1689.) Moreover, these effects
`
`were known to be dose dependent (see, e.g., Ex. 1004 at 170; see also, e.g., Ex.
`
`1005 at 1692.) and were known to be exacerbated when GHB was administered
`
`along with alcohol or certain other drugs. (See, e.g., Ex. 1004 at 167; see also, e.g.,
`
`Ex. 1005 at 1688). It was also known, as shown in the Xyrem® PI for example,
`
`- 15 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`that a GHB doses should be decreased when treating a patient with compromised
`
`metabolic function (Ex. 1005 at 1692.)
`
`41.
`
`In particular, concomitant administration of valproate (a known anti-
`
`convulsant) with GHB was known to increase plasma levels of GHB. More
`
`specifically, it was understood that valproate inhibits GHB dehydrogenase - the
`
`enzyme responsible for metabolizing GHB. (Ex. 1003 at 340; Ex. 1004 at 170.).
`
`Thus, as a GHB dehydrogenase inhibitor, concomitant administration of valproate
`
`and GHB would increase GHB levels in the body compared to GHB administration
`
`alone. (See, e.g., Ex. 1003 at 339-340.) Moreover, concomitant administration of
`
`valproate and GHB was understood, specifically, to increase GHB levels in the
`
`brain. (See Ex. 1003 at 340.) Indeed, in reviewing the prior art references provided
`
`by Counsel (see, e.g., Ex. 1003 at 350, 353)), the increase in plasma and brain
`
`GHB levels by concomitant administration of valproate was well-known in the art,
`
`as described in numerous prior art references: Bernasconi et al., Experimental
`
`Absence Seizures: Potential Role of y-Hydroxybutyric Acid and GABAB
`
`Receptors, J. Neural Transm., 35, 155-177 (1992) (Ex. 1014); Cash CD,
`
`Gammahydroxybutyrate: An Overview of the Pros and Cons for it Being a
`
`Neurotransmitter And/Or a Useful Therapeutic Agent, Neurosci. Biobehavioral
`
`Rev., Vol. 18(2), 291-304 (1994) (Ex. 1010); Bechler et al., y-Hydroxybutyrate
`
`Conversion into GABA Induces Displacement of GABAB Binding that is Blocked
`
`- 16 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`by Valproate and Ethosuximide, JPET, Vol. 281(2), pp. 753-760 (1997) (Ex.
`
`1015); Kaufman (1987), E.E., Evidence for the Participation of a Cytosolic
`
`NADP+-Dependent Oxidoreductase m
`
`the Catabolism
`
`of Gamma-
`
`Hydroxybutyrate In Vivo, J Neurochem., 48(6) (1987) (Ex. 1016); Kaufman &
`
`Nelson, An Overview of y-Hydroxybutyrate Catabolism: The Role of the Cytosolic
`
`NADP+-Dependent Oxidoreductase EC
`
`1.1.1.19
`
`and
`
`a Mitochondrial
`
`Hydroxyacid-Oxoacid Transhydrogenase in the Initial, Rate-Limiting Step in This
`
`Pathway, Neurochem. Research, Vol. 16(9), pp. 965-974 (1991) (Ex. 1017); Knerr
`
`et al., Therapeutic Concepts in Succinate Semialdehyde Dehydrogenase (SSADH;
`
`ALDH5al) Deficiency (y-Hydroxybutyric Aciduria). Hypotheses Evolved From
`
`25 Years of Patient Evaluation, Studies in Aldh5ar1- Mice and Characterization of
`
`y-Hydroxybutyric Acid Pharmacology, J Inherit. Metab. Dis., Vol. 30, pp. 279-
`
`294
`
`(2007) (Ex. 1018); Loscher, W., Valproate: A Reappraisal of Its
`
`Pharmacodynamic Properties and Mechanisms of Action, Progress in Neurobiol.,
`
`Vol. 58, pp. 31-59 (1999) (Ex. 1019); Loscher, W., Basic Pharmacology of
`
`Valproate: A Review After 35 Years of Clinical Use for the Treatment of Epilepsy,
`
`CNS Drugs, Vol. 16(1), pp. 669-694 (2002) (Ex. 1020); Vayer et al., 3'-5' Cyclic-
`
`Guanosine Monophosphate Increase in Rat Brain Hippocampus after Gamma-
`
`Hydroxybutyrate Administration. Prevention by Valoprate and Naloxone, Life
`
`Sciences, Vol. 41, pp. 605-610 (1987) (Ex. 1021); and Vayer et al., Is the
`
`- 17 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`Anticonvulsant Mechanism of Valproate Linked to its Interaction with the Cerebral
`
`y-Hydroxybutyrate System? TIPS, Vol. 9, pp. 127-129 (1988) (Ex. 1022). I also
`
`disagree with Applicants' unsupported assertion, (See supra ~35), that valproate's
`
`possible function as an MCT inhibitor might offset its possible function as a GHB
`
`dehydrogenase inhibitor. Properly understood in view of the substantial body of
`
`prior art, concomitant administration of valproate and GHB would have been
`
`understood to directly increase GHB levels through valproate' s known function as a
`
`GHB dehydrogenase inhibitor regardless of any other effect on transport systems.
`
`Any potential for valproate to decrease GHB levels through its function as a MCT
`
`inhibitor would have been minimal. (See, e.g., Morris et al., Overview of the Proton-
`
`coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role
`
`in the Transport of the Drug of Abuse y-Hydroxybutyric Acid, AAPS J., 10(2), pp.311-
`
`321
`
`(2008)
`
`("Morris I")
`
`(2008)
`
`("Morris I")
`
`(Ex. 1028); Morris et al.,
`
`Monocarboxylate Transporter with Osmotic Diuresis Increases y-Hydroxybutyrate
`
`Renal Elimination in Humans: A Proof-of-Concept Study, J. Clin. Tox., 1(2), 1000105,
`
`pp. 1-4 (2011) ("Morris II") (Ex. 1029 ). ) Indeed, I note that the data presented in the
`
`'306 patent (Ex. 1001 at 19 (Col. 11:6-9) that was allegedly to be related to MCT
`
`inhibition - a 30% increase in renal clearance rate upon concomitant administration
`
`of valproate and GHB - would have been better accounted for by the increase in
`
`GHB plasma levels caused by valproate's known function as a GHB dehydrogenase
`
`- 18 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`inhibitor - the reported 26% increase in GHB plasma levels. Such an increase in
`
`GHB plasma levels provides an increase the amount of GHB available to be cleared
`
`through the kidneys. In other words, concomitant administration of valproate and
`
`GHB would have been understood to increase GHB plasma levels by directly
`
`inhibiting GHB metabolism, and an increase in renal clearance rates would have
`
`been expected based on those increased GHB plasma levels, rather than based on
`
`valproate's potential role as an MCT inhibitor.
`
`42.
`
`It was also known in the art that concomitant administration of
`
`valproate and aspirin may result in a significant drug-drug interaction, due to an
`
`increase in valproate concentration that results in increased likelihood of adverse
`
`events. (See, e.g., Sandson et al., An Interaction Between Aspirin and Valproate:
`
`The Relevance of Plasma Protein Displacement Drug-Drug Interactions, Am. J
`
`Psychiatry, Vol. 163, pp. 1891-1896 (2006) ("Sandson", (Ex. 1023 at 1893).)
`
`43. Thus, it is my opinion that prior to the '306 patent, it was known in
`
`the art that:
`
`(i) GHB is effective for treating narcolepsy;
`
`(ii) valproate inhibits the activity of GHB dehydrogenase, an enzyme responsible
`
`for metabolizing GHB;
`
`(iii) concomitant administration of GHB and valproate results in increased GHB
`
`levels in the brain;
`
`- 19 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`(iv) concomitant administration of aspirin and valproate results in increased
`
`valproate levels in the body; and
`
`(v) concomitant administration ofvalproate and GHB, or valproate, aspirin, and
`
`GHB, may lead to dangerously high GHB levels in the body.
`
`44.
`
`Thus, the prior art directed the skilled artisan to reduce the dose of GHB
`
`administered to a patient concomitantly taking valproate, or valproate and aspirin, in
`
`order to safely administer an efficacious dose ofGHB.
`
`X.
`
`CLAIMS 1-34 OF THE '306 PATENT WOULD HAVE BEEN
`OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART
`
`45.
`
`I have reviewed the '306 patent and each of Claims 1-34. I have
`
`interpreted Claims 1-34 according to the ordinary and customary meaning that a
`
`person of ordinary skill in the art would have given the claim terms.
`
`A.
`
`Claim 1
`
`46. Claim 1 recites:
`
`A method for treating a patient who is suffering from excessive daytime
`
`sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep
`
`time
`
`disturbances, hypnagogic hallucinations, sleep arousal,
`
`insomnia, or
`
`nocturnal myoclonus with gamma-hydroxybutyrate (GHB) or a salt thereof,
`
`said method comprising:
`
`- 20 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`orally administering to the patient in need of treatment at least 5% decrease
`
`in an effective dosage amount of the GHB or salt thereof when the patient is
`
`receiving a concomitant administration of valproate, an acid, salt, or mixture
`
`thereof.
`
`4 7. With respect to orally administering GHB to treat certain sleep
`
`disorders, Maitre and the Xyrem® PI each disclose oral administration of GHB
`
`(also known as y-hydroxybutyrate, gamma-hydroxybutyrate, or as the sodium salt,
`
`sodium oxybate) as a therapeutic agent for the treatment of narcolepsy. (See Ex.
`
`1003 at 351-352; see also Ex. 1005 at 1688.) Thus, because such a method was
`
`known in the art, it is my opinion that it would have been obvious to a person of
`
`skill in the art to orally administer GHB to treat narcolepsy. (Id.).
`
`48. With respect to decreasing the GHB dose, the Xyrem® PI also teaches
`
`that administration of excessive doses of GHB could have adverse effects, including
`
`coma or death. (See e.g., Ex. 1005 at 1688, 1692.) Moreover, Maitre teaches that
`
`concomitant administration of valproate will lead to increased levels of GHB in the
`
`brain. (Ex. 1003 at 340.) Specifically, valproate increases levels of GHB in the
`
`brain by inhibiting GHB dehydrogenase, an enzyme that metabolizes GHB. (Id. at
`
`340, 343, 351.) Accordingly, the skilled artisan would have recognized the
`
`potential for drug-drug interactions when co-administering GHB and valproate.
`
`- 21 -
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`49. Based on the understanding of (i) the danger associated with excess
`
`GHB levels and (ii) valproate's role in increasing GHB levels, a skilled artisan
`
`would have been keenly aware that concomitant administration of valproate and
`
`GHB would result in a potentially dangerous increase in GHB levels in the brain
`
`and in the peripheral circulation. Thus, one of ordinary skill would have been
`
`motivated to decrease the dosage of GHB in patients "receiving a concomitant
`
`administration of valproate, an acid, salt, or mixture thereof," precisely as recited
`
`in claim 1.
`
`50.
`
`It is also my opinion that selection of at least a 5% reduction in GHB
`
`dosage would have been obvious to one skilled in the art. The Xyrem® PI
`
`recommends a starting GHB dose of 4.5 g/night, to be titrated to effect, up to a
`
`maximum dose of 9 g/night. (Ex. 1005 at 1692). The Xyrem® PI teaches that the
`
`GHB dosage should be adjusted by 1.5 g/night increments (Id.). Thus, following
`
`this dosing schedule, the Xyrem® PI discloses doses of 4.5 g/night, 6.0 g/night, 7.5
`
`g/night, and 9.0 g/night. (Jd.). Because valproate causes a significant increase of
`
`GHB lev
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
