Case IPR2016-01095
`Patent No. 6,667,061
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
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`LUYE PHARMA GROUP LTD., LUYE PHARMA(USA) LTD., SHANDONG
`LUYE PHARMACEUTICAL CO., LTD., and NANJING LUYE
`PHARMACEUTICAL CO., LTD.
`Petitioners
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`v.
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`ALKERMES PHARMA IRELAND LTD
`Patent Owner
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`Patent No. 6,667,061 to Ramstack et al.
`Issue Date: December 23, 2003
`Title: PREPARATION OF INJECTABLE SUSPENSIONS HAVING
`IMPROVED INJECTABILITY
`____________________________
`Inter Partes Review No. IPR2016- 01095
`__________________________________________________________________
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`(Exhibit 1002)
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`DECLARATION OF PATRICK P. DeLUCA, Ph.D. IN
`SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF CLAIMS 1-13 AND 17-23 OF U.S. PATENT NO. 6,667,061
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`4558099_1.docx
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`I.
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 1
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`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 1
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`III. A PERSON OF ORDINARY SKILL IN THE ART ...................................... 3
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`IV. BACKGROUND ............................................................................................. 6
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`A. Introduction ............................................................................................... 6
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`B. Improving Injectability ............................................................................. 7
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`C. Risperidone ............................................................................................... 9
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`D. The Role of Viscosity In Injectable Formulations .................................... 9
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`E. The Prior Art Taught Microparticle Suspensions With The Claimed
`Concentration and Viscosity ...................................................................11
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`V.
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`THE ’061 PATENT .......................................................................................15
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`A. The Claims ..............................................................................................15
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`B. The Family History Of The ’061 Patent .................................................16
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`C. The Specification ....................................................................................17
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`D. The May 14, 2002 Response And The Tracy Declaration .....................17
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`VI. CLAIM CONSTRUCTION ..........................................................................19
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`A. “Suitable For Injection” ..........................................................................20
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`B. “Microparticles” ......................................................................................20
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`C. “Injection Vehicle” .................................................................................21
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`D. “Suspension” ...........................................................................................21
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`E. “Fluid Phase Of Said Suspension” .........................................................21
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`F. “Viscosity Greater Than About 20cp And Less Than About 600cp” ...22
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`VII. THE PRIOR ART ..........................................................................................22
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`A. Goldenheim .............................................................................................22
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`B. Ramstack .................................................................................................23
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`C. U.S. And European Pharmacopoeia .......................................................23
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`D. Kino .........................................................................................................24
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`VIII. GROUND 1: CLAIMS 1-3, 6-9, 12-13, 17-19, AND 22-23 OF THE
`’061 PATENT IS ANTICIPATED BY GOLDENHEIM (EX.1004) ...........24
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`A. Claim 1 ....................................................................................................24
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`B. Claims 2-3 ...............................................................................................25
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`C. Claim 6 ....................................................................................................25
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`D. Claim 7 ....................................................................................................26
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`E. Claims 8-9 And 12-13 .............................................................................26
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`F. Claims 17-19 ...........................................................................................26
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`G. Claims 22-23 ...........................................................................................27
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`IX. GROUND 2: CLAIMS 1-3, 6-9, 12-13, 17-19, AND 22-23 WOULD
`HAVE BEEN OBVIOUS OVER GOLDENHEIM (EX.1004) IN VIEW OF
`THE RAMSTACK (EX.1005), U.S. PHARMACOPEIA (EX.1006) AND
`THE EUROPEAN PHARMACOPOEIA (EX.1007) ...................................27
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`A. Claims 1-3, 6-9, 12-13, 17-19, And 22-23 .............................................27
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`B. Claims 20-21 ...........................................................................................30
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`X. GROUND 3: CLAIMS 1-13 AND 17-23 ARE OBVIOUS OVER
`GOLDENHEIM (EX.1004) IN VIEW OF KINO (EX.1010), U.S.
`PHARMACOPEIA (EX.1006) AND THE EUROPEAN
`PHARMACOPOEIA (EX.1007) ...................................................................31
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`A. Claims 1-3, 6-9, 12-13, 17-19, And 22-23 .............................................32
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`B. Claims 4, 5, 10, And 11 ..........................................................................34
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`C. Claims 20-21 ...........................................................................................35
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`XI. CONCLUSION ..............................................................................................36
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`I.
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`I, PATRICK P. DeLUCA, hereby declare and state as follows:
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`INTRODUCTION
`I am a U.S. citizen and a resident of the State of Kentucky.
`1.
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`2.
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`I am a Professor Emeritus in the Department of Pharmaceutical
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`Sciences, College of Pharmacy, at the University of Kentucky. I received a B.S.
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`and M.S. in Pharmacy from Temple University in 1957 and 1960, respectively. I
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`received my Ph.D. in Pharmaceutical Sciences from Temple University in 1963.
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`3.
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`I have been retained by Lerner, David, Littenberg, Krumholz &
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`Mentlik, LLP (“counsel”) to provide my opinions in the fields of pharmaceutical
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`formulation for purposes of this IPR. I have read and understood U.S. Patent
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`No. 6,667,061 (“the ’061 Patent”) (Exh. 1001) as well as all other references
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`discussed in this declaration. I am being compensated for my time in an amount
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`consistent with my customary consulting fee and my compensation is not
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`contingent on my opinion or the outcome of this proceeding.
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`II. MY BACKGROUND AND QUALIFICATIONS
`During my career of over 50 years, my research and teaching interests
`4.
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`in pharmaceutical science and technology have been in various areas, including
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`parenteral and intravenous pharmaceutical formulations and drug product stability.
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`I have published over 225 research articles and authored or co-authored chapters in
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`several textbooks pertaining to physical pharmacy and pharmaceutical research
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`focusing on the above principles.
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`5.
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`I have received numerous awards and honors for my research and
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`teaching achievements. I am a founding member and Fellow of the American
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`Association of Pharmaceutical Scientists (“AAPS”) and served as its President
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`between 2008 and 2009. I was the first Editor-in-Chief of the international journal
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`Pharmaceutical Development and Technology between 1995 and 1999, the first
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`Editor-in-Chief of the AAPS online journal PharmSciTech between 2000 and
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`2007, and also served on the editorial boards of several other scientific journals in
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`the broad field of pharmaceutical sciences with special focus on pharmaceutical
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`technology and drug product development.
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`6.
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`In addition to my research and teaching, I have consulted over the
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`years for both brand and generic pharmaceutical companies on matters related to
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`pharmaceutical formulation and development. Additional details of my education,
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`experience, and credentials are set forth in my curriculum vitae. (Ex.1003.)
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`7.
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`Noteworthy is my expertise and pioneering efforts in the research,
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`development, processing, and in vitro and in vivo evaluation of injectable
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`microparticulate dosage forms
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`including risperidone microspheres. I have
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`published extensively on the processing effects on the morphology and degradation
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`of the polylactide-co-glycolide polymers and have correlated in vivo blood levels
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`with in vitro release. My pioneering efforts have extended to the area of Freeze
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`Drying of Pharmaceuticals.
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`III. A PERSON OF ORDINARY SKILL IN THE ART
`I understand from counsel that patents such as the ’061 Patent are
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`neither addressed to experts nor to layman, but to persons of ordinary skill in the
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`relevant art at the time the invention was made. I’m told by counsel to assume the
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`earliest effective filing date is May 25, 2000. I understand from counsel that factors
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`relevant to the level of ordinary skill in the art include, without limitation: the
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`education of the inventor, the types of problems encountered in the relevant area,
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`prior art solutions to those problems, the rapidity with which innovations are made,
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`the sophistication of the technology, and the education level of active workers in
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`the field. In my opinion, considering these factors, a person of ordinary skill in the
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`art would be a pharmaceutical formulator, who has experience in parenteral
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`formulations. When I give my opinions herein, unless stated otherwise, it is my
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`opinion of what such a person of ordinary skill in the art would know or do at the
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`time.
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`9.
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`I note that the claims in question, claims 1-13 and 17-23, are directed
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`to an injectable suspension having a concentration of greater than 30mg/ml of
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`microparticles, wherein the suspension has a viscosity greater than about 20cp to
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`less than 600cp at 20°C and provides injectability of the composition through an
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`18-22 gauge needle. I would not consider this technology to be sophisticated,
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`particularly relative to other injectable suspensions that include microparticles.
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`Adjusting excipients, all of which are known in the art and used for their well-
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`known functions, to provide a suitable suspendability and distribution of
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`microparticles for injectability purposes is well within the general knowledge of a
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`skilled artisan. Further, the skilled artisan would know that the type and amount of
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`excipients, e.g. suspending or viscosity enhancing agents, required to maintain
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`uniform distribution of such microparticles in the injection vehicle will, by nature,
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`add viscosity to the injection vehicle.
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`10.
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`In reaching my conclusion, I have also considered the type of
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`problems addressed by the ’061 Patent, and prior art solutions to these types of
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`problems. In my opinion they all involve merely adjusting excipients to ensure the
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`proper amount of pharmaceutically active agent is administered to the patient in a
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`parenteral formulation. This is a problem that is faced by every pharmaceutical
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`formulator, every time they are instructed to prepare an injectable suspension. And
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`the solutions, that of deciding to the appropriate viscosity for syringeability and
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`injectability, determining the size and concentration of the suspended particulates,
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`and the density of the injection vehicle, are well established in this field. (Ex.1014,
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`at 33.)
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`11.
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`It is my understanding from publicly available information that the
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`inventors of the ’061 Patent possess PhD degrees in various fields, such as
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`chemical engineering, biomedical engineering, and chemistry, plus at least five
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`years of experience in product development in the pharmaceutical industry.
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`Considering the lack of sophistication in the subject matter of the claims, this is a
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`higher level of experience than what would be considered a person of ordinary skill
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`in the art.
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`12. Taking into consideration each of these factors, a person of ordinary
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`skill in the art (a “POSA”) as to the patent at issue in this case would have at least a
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`bachelor’s degree and a number of years of industry training or experience in one
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`or more
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`the
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`following
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`fields: pharmaceutical
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`formulation,
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`chemistry,
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`pharmaceutical science, polymer chemistry, pharmaceutics, pharmaceutical
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`technology, pharmacokinetics, and/or pharmacology. A POSA would draw on the
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`pharmaceutical science literature, general textbooks, research articles and abstracts,
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`and other sources of information in the field of pharmaceutical formulation and
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`polymer microparticle science. I consider myself to be a person of greater than
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`ordinary skill and one who has mentored nearly 100 scientists at the graduate
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`degree and postdoctorate level.
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`13. Because of my work experience, my supervision of graduate students,
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`and my review of the relevant literature from the relevant time period (prior to
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`May 25, 2000), I believe that I am well situated to understand what a person of
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`ordinary skill in the art would have known and understood at the relevant time.
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`IV. BACKGROUND
`Introduction
`A.
`14. The allowed claims of the ’061 Patent are directed to a composition
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`suitable for injection through a needle into a host. (Ex.1001 cl.1.) The claim
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`requires microparticles (which are particles that include an active agent dispersed
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`or dissolved in a polymeric binder) and an injection vehicle. (Id.) The
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`microparticles are suspended in the injection vehicle at a concentration of 30mg/ml
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`to form a suspension. (Id.) The fluid phase of the suspension has a viscosity of
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`greater than about 20cp and less than about 600cp at 20°C. (Id.) This viscosity
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`allows the composition to be injected through an 18-22 gauge needle, according to
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`the ’061 Patent. (Id.)
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`15. Patent Owner’s alleged invention was using viscosity enhancing
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`agents to increase the viscosity of an injectable composition that includes
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`microparticles to improve injectability of the composition. (Id. Abstract.) Patent
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`Owner alleged that increasing viscosity of the fluid phase was an unexpected
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`improvement in injectability and reduced in vivo injection failures. (Id. 4:57-60.)
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`16. Patent Owner did not invent microparticles, nor did it invent a new
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`risperidone microparticle. (Ex.1005, at 35:1-36:26, Examples 2, 3.) Patent Owner
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`did not invent viscosity enhancing agents or an injection vehicle that includes
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`viscosity enhancing agents. (Ex.1004, at 52:25-30.) Patent Owner did not invent
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`combining a viscous injection vehicle with microparticles; Patent Owner did
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`nothing more than combine well-known elements to arrive at a known
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`concentration and viscosity for an injectable composition. (Id. 35:8-12.) Injecting a
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`microparticle suspension through an 18-22 gauge needle was also known in the
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`prior art, together with knowledge of injectable viscosities greater than about 20cp.
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`(Id. 35:10-12; 41:18-19.)
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`Improving Injectability
`B.
`17. By May 25, 2000, the general principles for developing injectable
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`formulations were well known and well understood. Such formulation procedures
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`were documented in general texts on the subject including: Lieberman et al.,
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`Pharmaceutical Dosage Forms: Disperse Systems, Vol. 2 (2nd ed. 1996)
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`(“Lieberman 2” (Ex.1014, at 26-35, 40, 43-46, 261, 285-318)); Kenneth E.
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`Avis et al., 1 (Chs.2, 4, 5) Pharmaceutical Dosage Forms: Parenteral Medications
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`(Marcel Dekker Inc. 2nd ed. 1992) (“Avis” (Ex.1020. at 17-25, 115-116, 140-143,
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`150-151, 173-175, 190-212)); L. Lachman et al., The Theory and Practice of
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`Industrial Pharmacy at 642-44, 783-84 (Lea & Febiger 3rd ed. 1986) (“Lachman”
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`(Ex.1021)); and Lieberman et al., Pharmaceutical Dosage Forms: Disperse
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`Systems, Vol. 1 (2nd ed. 1996) (“Lieberman 1” (Ex.1022, at 287-313)). My review
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`of the ’061 Patent indicates that the Patent Owner simply followed these
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`well-known steps and developed the formulation in a way that was routine in the
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`art.
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`18.
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`Injectable suspensions are heterogeneous systems that include a solid
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`phase and a liquid phase. (Exs.1014, at 285; 1001, at 1:17-25.) Aqueous and
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`nonaqueous liquid phases were known to be used in injectable suspensions.
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`(Exs.1014, at 285; 1001, at 1:17-25.) Suitable injectable suspensions should be
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`sterile, stable, suspendable, injectable, and isotonic. (Exs.1014, at 285; 1001,
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`at 1:17-25.) The solid phase of the suspension may include microparticles, which
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`have an active pharmaceutical ingredient encapsulated in a polymeric binder and
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`provides extended release in injectable suspensions. (Exs.1014, at 285; 1001,
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`at 1:17-25.)
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`19. Suspensions suitable for injection must be syringeable and injectable.
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`(Exs.1014, at 285; 1001, at 1:17-25.) A composition is “syringeable” if it is
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`capable of flowing through a needle from a vial. (Exs.1014, at 298; 1001,
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`at 1:53-60.) Some common issues associated with syringeability are clogging of
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`the needle, withdrawal of the composition from the vial, and accuracy of the dose
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`to be administered. (Exs.1014, at 298-99; 1001, at 1:53-60.) “Injectable” refers to
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`how the suspension performs during the actual injection of the composition.
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`(Exs.1014, at 299; 1001, at 1:61-64.) Common issues associated with injectability
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`are force required to administer the injection, evenness of the flow, aspiration, and
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`clogging. (Exs.1014, at 299; 1001, at 1:61-64.)
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`C. Risperidone
`20. Risperidone is a well-known hydrophobic antipsychotic drug, which
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`first gained market approval in 1993. (Exs.1023; 1010, at 2:38-41.) Risperidone
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`was initially available as a tablet then oral solution, and later approved as a depot
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`injection. (Id.)
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`D. The Role of Viscosity In Injectable Formulations
`21. Syringeability is defined as the ability of a parenteral solution or
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`suspension to pass easily through a hypodermic needle and considered one of the
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`most important properties of a suitable parenteral suspension. (Ex.1014, at 33-34.)
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`Increases in various characteristics may make the syringeability more difficult. For
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`example, the following should be considered when determining an appropriate
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`syringeability: viscosity of the vehicle, density of the vehicle, size of the suspended
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`particulate, and concentration of the drug. (Id.)
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`22. Viscosity is a necessary component of injectable formulations. As
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`described by Lieberman, the viscosity measurement is one of the most important
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`factors and the easiest for a formulator to control. (Id.) An injectable formulation
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`must have the proper viscosity to ensure it is capable of being forced through a
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`syringe (i.e., syringeable) and capable of being injected through a needle into a
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`host (i.e., injectable). (Id.)
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`23. There are two types of injection vehicles: aqueous and nonaqueous.
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`(Id. at 285.) Nonaqueous, or oleaginous, injection vehicles are those that include an
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`oil. (Id. at 290.) Corn oil, cottonseed oil, peanut oil, sesame oil, and soybean oil are
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`examples of a nonaqueous vehicle used for intramuscular injections. (Exs.1008,
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`at 135, 137, 329, 420, 481; 1014, at 290-291.) The viscosity of these commonly
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`used nonaqueous vehicles, all of which may be used for injections, can be found in
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`Table 1 below:
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`Non-Aqueous Vehicle
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`Viscosity
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`TABLE I
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`Corn Oil
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`Cottonseed Oil
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`Peanut Oil
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`Sesame Oil
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`Soybean Oil
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`38.83 mPa s (or 38.83cps)
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`37.36 mPa s (or 37.36cps)
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`70 mPa s (or 70cps) at 20°C
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`35 mPa s (or 35cps) at 37°C
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`43.37 mPa s (or 43.37cps)
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`99.7 mPa s (99.7cps) at 10°C
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`50 mPa s (50cps) at 25°C
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`28.86 mPa s (28.86cps) at 40°C
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`(Ex.1008, at 135, 137, 329, 420, 481.)
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`24. Aqueous injection vehicles primarily include water and require
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`additives if the active particles do not readily dissolve in water. (Ex.1014, at 291.)
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`Accordingly, the formulator must include various substances such as suspending
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`agents, tonicity agents, wetting agents, etc. to arrive at a suitable aqueous injection
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`vehicle capable of satisfying the syringeability and injectability properties required
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`to make a formulation suitable for injection. (Id. at 288.)
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`25. Viscosity is a measurement that is also dependent on temperature.
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`(Exs.1022, at 305; 1006, at 1840.) As the temperature increases, the viscosity
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`decreases. (Exs.1002, at 305; 1006 at 1840.) (Id.) A POSA would know to create
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`an injectable formulation that was viscous enough to hold the microparticles in
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`solution, but not too viscous that it presents syringeability or injectability
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`problems.
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`E.
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`26.
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`The Prior Art Taught Microparticle Suspensions
`With The Claimed Concentration and Viscosity
`Injectable formulations that include microspheres would include a
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`viscosity enhancing or suspending agent. Sodium carboxymethylcellulose (CMC)
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`is one of the most commonly used suspending and viscosity enhancing agents.
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`(Exs.1008, at 78-81; 1022, at 305.)
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`27. Goldenheim teaches a sustained release formulation that includes
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`polymer microparticles in a suspension suitable for injection. (Ex.1004 Abstract.)
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`Goldenheim teaches that such formulations can be used for any known active
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`pharmaceutical ingredient. (Id. 13:22-30.) Goldenheim teaches a concentration of
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`microparticles greater than 30mg/ml. (Id. 54:1-12, Table 4.) Goldenheim teaches
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`that the final reconstituted product viscosity (i.e., the microparticles in suspension)
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`of such formulations is approximately 35cps. (Id. 35:8-12.) Goldenheim also
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`discloses compositions suitable for injection through an 18 gauge needle.
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`(Id. 41:18-19.) Goldenheim further teaches incorporating a viscosity enhancing
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`agent, such as CMC, (id. 47:30-32) a tonicity agent , such as isotonic saline, (id.
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`8:16-17) and a wetting agent, such as Tween 80, (id. 47:30-32) into such
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`formulations.
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`28. Ramstack teaches the preparation of biodegradable microparticles that
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`include a biologically active agent and specifically identifies risperidone.
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`(Ex.1005 Abstract, 35:1-36:26, Examples 2, 3.) Ramstack teaches that a polymer,
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`such as dl (polylactide-co-glycolide), may be used for encapsulating risperidone.
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`(Ex.1005, at 5:19-22, Examples 2, 3.) The poly(lactide-co-glycolide) may have a
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`molar ratio of lactide to glycolide in a range of 85:15 to 50:50. (Ex.1005,
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`at 5:19-22, 16:28-31, 35:1-36:26, Examples 2, 3.) Additional polymer materials
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`useful for encapsulation may include poly(glycolic acid), poly-D,L-lactic acid,
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`poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids),
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`copolyoxalates, polycaprolactone, polydioxonene, poly(ortho
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`carbonates),
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`poly(acetals), poly(lactic acidcaprolactone), polyorthoesters, poly(glycolic acid-
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`caprolactone), polyanhydrides, polyphosphazines, and natural polymers including
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`albumin, casein, and waxes. (Id. 16:7-13.) Ramstack teaches an aqueous injection
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`vehicle that includes CMC, mannitol, and polysorbate. (Id. at 37:5-7.)
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`29. The U.S. Pharmacopeia teaches that viscosity is typically measured at
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`about 25°C and that viscosity decreases as temperature increases. (Ex.1006, at 275,
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`1840.) The European Pharmacopoeia teaches that viscosity is typically measured at
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`about 20°C. (Ex.1007, at 547.)
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`30. Kino teaches sustained release microspheres of antipsychotic drugs,
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`including risperidone. (Ex.1010, at 1:65-2:4, 2:38-41.) Kino teaches that such
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`microspheres can be used in aqueous injections. (Id. 4:38-40.) Kino also teaches
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`the inclusion of CMC, a viscosity enhancing agent, polysorbate, a wetting agent,
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`and sodium chloride, a tonicity agent. (Id. 4:38-51.) Kino teaches the addition of
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`sorbitol to an injection vehicle. (Id. 4:52-55.)
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`31. The Handbook of Pharmaceutical Excipients, 2nd edition, was
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`published in 1994. The Handbook teaches that carboxymethylcellulose sodium is
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`also known as CMC sodium, sodium carboxymethylcellulose, and sodium CMC
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`(“CMC”) and that CMC is a “viscosity-increasing agent” and a “suspending
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`agent.” (Ex.1008, at 78.) The Handbook teaches that various different types of oils
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`are suitable for intramuscular injections. The Handbook teaches that corn oil has a
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`viscosity of 38.83 or 37.36 mPa s. (Id. at 135.) The Handbook teaches that
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`cottonseed oil can be used in intramuscular injections and has a viscosity of about
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`70 mPa s at 20°C. (Id. at 137.) The Handbook teaches that peanut oil may be used
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`in intramuscular injections and has a viscosity of about 40 at 37°C. (Id. at 329.)
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`The Handbook teaches that sesame oil, which has a viscosity of 43.37 mPa s, can
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`be used in combination with sustained-release intramuscular injections. (Id.
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`at 420.) The Handbook teaches that soybean oil has a viscosity of about 50 mPa s
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`at 25°C and can be used for intravenous injection of drugs. (Id. at 481.)The
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`Handbook teaches that polyoxyethylene sorbitan fatty acid esters are also known as
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`polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. (Id. at 375.)
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`The Handbook teaches that polysorbate 20 is also known as Tween 20, polysorbate
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`40 is also known as Tween 40, polysorbate 60 is also known as Tween 60, and
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`polysorbate 80 is also known as Tween 80. (Id.) The Handbook teaches that
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`polysorbates are wetting agents that can be used in parenteral suspensions. (Id.
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`at 376.) The Handbook teaches that sodium chloride is a tonicity agent, that
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`0.9% w/v sodium chloride aqueous solution is iso-osmotic with serum, and that
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`sodium chloride can be used in intravenous injections. (Id. at 439-40.) The
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`Handbook teaches also that mannitol is a well-known tonicity agent. (Id. at 294.)
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`And the Handbook teaches that sorbitol may be used in intramuscular injections
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`and increases the density of aqueous solutions. (Id. at 477, 479.)
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`32. All of the principles, studies, and strategies described above reflect the
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`core role of a formulator working on the development of an injectable product. I
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`would have expected a POSA working in the field of injectable formulation
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`development in 1999 to have considered all of the aspects described.
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`V. THE ’061 PATENT
`A. The Claims
`Independent claim 1 is directed to a composition that is suitable for
`33.
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`injection through a needle into a host, which includes microparticles with a
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`polymeric binder, and an injection vehicle. (Ex.1001 cl.1.) The microparticles are
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`suspended in the injection vehicle to form a suspension, which includes a fluid
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`phase having a viscosity of greater than about 20cp and less than about 600cp at
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`20°C and provides injectability of the composition through a needle having a
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`diameter from 18-22 gauge. (Id.)
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`34. Dependent claims 2 and 3 require the addition of a viscosity
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`enhancing agent, such as sodium carboxymethyl cellulose. (Id. cls.2-3.) Dependent
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`claims 4 and 5 require the addition of a density enhancing agent, such as sorbitol.
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`(Id. cls.4-5.) Dependent claims 6 and 7 require the addition of a tonicity adjusting
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`agent, such as sodium chloride. (Id. cls.6-7.) Dependent claims 8 and 9 require the
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`addition of a wetting agent, such as polysorbate 20, polysorbate 40, or polysorbate
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`80. (Id. cls.8-9.) Dependent claims 10 and 11 require the addition of a combination
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`of a density enhancing agent and a wetting agent, such as polysorbate 20,
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`polysorbate 40, or polysorbate 80. (Id. cls.10-11.) Dependent claims 12 and 13
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`require the addition of a combination of a tonicity adjusting agent and a wetting
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`agent, such as polysorbate 20, polysorbate 40, or polysorbate 80. (Id. cls.12-13.)
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`Dependent claims 17, 18, and 19 require the microparticle to include an active
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`agent encapsulated with a polymeric binder, such as poly(d,l-lactide-co-glycolide)
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`having a molar ratio of lactide to glycolide in the range of from about 85:15 to
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`about 50:50. (Id. cls.17-19.) Dependent claims 20 and 21 require the active agent
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`of claims 17 and 19, respectively, to be risperidone, 9-hydroxyrisperidone, or a
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`pharmaceutically acceptable salt. (Id. cls.20-21.) Finally dependent claims 22 and
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`23 require the microparticles to have a mass median diameter of less than about
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`250µm or from about 20µm to about 150µm. (Id. cls.22-23.)
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`The Family History Of The ’061 Patent
`B.
`35. The ’061 Patent issued on December 23, 2003, from U.S. Application
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`No. 10/259,949. The patent states on its face that it is a continuation of U.S. Patent
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`Application No. 09/577,875, filed on May 25, 2000, which issued as U.S. Patent
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`No. 6,495,164 (“the ’164 Patent”) on December 17, 2002. (Ex.1015.) I have
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`reviewed these applications to confirm that their relevant disclosures are
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`substantially the same, which they are.
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`C. The Specification
`36. The ’061 Patent discloses injectable suspensions having improved
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`injectablity. (Ex.1001 Abstract.) As the “Background of the Invention” states,
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`adding viscosity enhancers to injection vehicles is known. (Id. 2:25-27.) The
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`’061 Patent teaches that this was done “in order to retard settling of the particles in
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`the vial and syringe.” (Id.)
`
`37. The
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`’061 Patent provides
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`examples of known
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`injectable
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`pharmaceuticals. For example, the ’061 Patent admits that “[t]he fluid phase of a
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`suspension of Decapeptyl . . . mean particle size of 40 µm . . . when prepared as
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`directed, has a viscosity of approximately 19.7 cp.” (Id. 2:34-37.) The Background
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`then states that there is a need in the art to improve the injectability of injectables
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`that include microparticle suspensions. (Id. 2:55-61.)
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`38. The Summary of the Invention and the Detailed Description provide
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`different embodiments of the alleged invention. (Id. 2:63-5:40.)The Method and
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`Examples section provides various studies, such as an in vitro test study, animal
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`studies, ex vivo injectability tests, and methods of preparing the injectable
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`compositions. (Id. 5:41-17:60.)
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`D. The May 14, 2003 Response And The Tracy Declaration
`39. The Examiner issued a nonfinal office action on April 9, 2003
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`(Ex.1016), which rejected claims 1-21 and 41-42 under 35 U.S.C. § 103 as being
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`unpatentable over U.S. Patent No. 5,656,299 to Kino et al. and further in view of
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`U.S. Patent No. 5,540,912 to Roorda et al.
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`40.
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`In regards to Kino, the Examiner stated that Kino disclosed sustained
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`release microsphere preparations of antipsychotic drugs that are suitable for
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`injection. (Ex.1016, at 3.) The Examiner stated that although “Kino does not
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`disclose the viscosity to be greater than about 60 cp and less than about 600 cp,” it
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`would have been obvious “to determine the optimal viscosity for application.”
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`(Ex.1016, at 4.)
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`41. According to the Examiner:
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`Both the prior art and the instant claims are drawn to a composition
`suitable for injection through a needle host comprising microparticles
`comprising a polymeric binder in combination with a viscosity enhancing
`agent, a density enhancing agent, a tonicity enhancing agent, a wetting
`agent and an active agent. Therefore, absent unexpected results regarding
`the criticality of the viscosity, Kino discloses all the limitations of the
`instant claims. (Id.)
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`42. Patent Owner filed a response to the April 9, 2003 Office Action on
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`May 14, 2003 (Ex.1017, at 3), and included a declaration from Dr. Mark A. Tracy
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`(“Tracy Declaration”) (Ex.1018). The Tracy Declaration is dated May 17, 2002,
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`and was used in the application for the ’164 Patent to overcome a similar rejection
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`based on the Kino reference. (Ex.1017, at 2.)
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