Case IPR2016-01096
`Patent No. 6,667,061
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`LUYE PHARMA GROUP LTD., LUYE PHARMA(USA) LTD., SHANDONG
`LUYE PHARMACEUTICAL CO., LTD., and NANJING LUYE
`PHARMACEUTICAL CO., LTD.
`Petitioners
`
`v.
`
`ALKERMES PHARMA IRELAND LTD
`Patent Owner
`
`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. IPR2016-01096
`__________________________________________________________________
`
`(Exhibit 1002)
`
`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
`
`
`
`
`4558101_1.docx
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`INTRODUCTION ........................................................................................... 1
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 1
`III. A PERSON OF ORDINARY SKILL IN THE ART ...................................... 3
`IV. BACKGROUND ............................................................................................. 6
`A. Introduction ............................................................................................... 6
`
`B. Improving Injectability ............................................................................. 7
`
`C. Risperidone ............................................................................................... 9
`
`D. The Role Of Viscosity In Injectable Formulations ................................... 9
`
`E. The Prior Art Taught Microparticle Suspensions With The Claimed
`Concentration and Viscosity ...................................................................11
`
`V.
`
`THE ’061 PATENT .......................................................................................15
`A. The Claims ..............................................................................................15
`
`B. The Family History Of The ’061 Patent .................................................16
`
`C. The Specification ....................................................................................17
`
`D. The May 14, 2003 Response And The Tracy Declaration .....................18
`
`VI. CLAIM CONSTRUCTION ..........................................................................20
`A. “Suitable For Injection” ..........................................................................21
`
`B. “Microparticles” ......................................................................................21
`
`C. “Injection Vehicle” .................................................................................21
`
`D. “Suspension” ...........................................................................................21
`
`E. “Fluid Phase Of Said Suspension” .........................................................22
`
`F. “Viscosity Greater Than About 20 cp And Less Than About 600 cp” .22
`
`VII. THE PRIOR ART ..........................................................................................23
`
`i
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`A. Johnson ...................................................................................................23
`
`B. Kino .........................................................................................................24
`
`C. Gustafsson ...............................................................................................24
`
`D. Ramstack .................................................................................................24
`
`VIII. GROUND 1: CLAIMS 1-13 AND 17-23 ARE OBVIOUS OVER
`JOHNSON (EX.1009) IN VIEW OF KINO (EX.1010) ...............................25
`A. Claims 1-3 ...............................................................................................25
`
`B. Claims 4, 5, 10, And 11 ..........................................................................27
`
`C. Claims 6-9 And 12-13 .............................................................................28
`
`D. Claims 17-21 ...........................................................................................28
`
`E. Claims 22-23 ...........................................................................................29
`
`IX. GROUND 2: CLAIMS 1-13 AND 17-23 ARE OBVIOUS OVER
`GUSTAFSSON (EX.1011) IN VIEW OF RAMSTACK (EX.1008 AND
`THE HANDBOOK (EX.1008)......................................................................31
`A. Claim 1 ....................................................................................................31
`
`B. Claims 2-3 ...............................................................................................32
`
`C. Claims 4, 5, 10, And 11 ..........................................................................32
`
`D. Claims 6 And 7 .......................................................................................33
`
`E. Claims 8 And 9 .......................................................................................34
`
`F. Claims 12 And 13 ...................................................................................34
`
`G. Claims 17-21 ...........................................................................................34
`
`H. Claims 22-23 ...........................................................................................36
`
`X.
`
`CONCLUSION ..............................................................................................37
`
`ii
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`I.
`
`I, PATRICK P. DeLUCA, hereby declare and state as follows:
`
`INTRODUCTION
`I am a U.S. citizen and a resident of the State of Kentucky.
`1.
`
`2.
`
`I am a Professor Emeritus in the Department of Pharmaceutical
`
`Sciences, College of Pharmacy, at the University of Kentucky. I received a B.S.
`
`and M.S. in Pharmacy from Temple University in 1957 and 1960, respectively. I
`
`received my Ph.D. in Pharmaceutical Sciences from Temple University in 1963.
`
`3.
`
`I have been retained by Lerner, David, Littenberg, Krumholz &
`
`Mentlik, LLP (“counsel”) to provide my opinions in the fields of pharmaceutical
`
`formulation for purposes of this IPR. I have read and understood U.S. Patent
`
`No. 6,667,061 (“the ’061 Patent”) (Exh. 1001) as well as all other references
`
`discussed in this declaration. I am being compensated for my time in an amount
`
`consistent with my customary consulting fee and my compensation is not
`
`contingent on my opinion or the outcome of this proceeding.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`During my career of over 50 years, my research and teaching interests
`4.
`
`in pharmaceutical science and technology have been in various areas, including
`
`parenteral and intravenous pharmaceutical formulations and drug product stability.
`
`I have published over 225 research articles and authored or co-authored chapters in
`
`
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`several textbooks pertaining to physical pharmacy and pharmaceutical research
`
`focusing on the above principles.
`
`5.
`
`I have received numerous awards and honors for my research and
`
`teaching achievements. I am a founding member and Fellow of the American
`
`Association of Pharmaceutical Scientists (“AAPS”) and served as its President
`
`between 2008 and 2009. I was the first Editor-in-Chief of the international journal
`
`Pharmaceutical Development and Technology between 1995 and 1999, the first
`
`Editor-in-Chief of the AAPS online journal PharmSciTech between 2000 and
`
`2007, and also served on the editorial boards of several other scientific journals in
`
`the broad field of pharmaceutical sciences with special focus on pharmaceutical
`
`technology and drug product development.
`
`6.
`
`In addition to my research and teaching, I have consulted over the
`
`years for both brand and generic pharmaceutical companies on matters related to
`
`pharmaceutical formulation and development. Additional details of my education,
`
`experience, and credentials are set forth in my curriculum vitae. (Ex.1003.)
`
`7.
`
`Noteworthy is my expertise and pioneering efforts in the research,
`
`development, processing and in vitro and in vivo evaluation of injectable
`
`microparticulate dosage forms
`
`including risperidone microspheres. I have
`
`published extensively on the processing effects on the morphology and degradation
`
`of the polylactide-co-glycolide polymers and have correlated in-vivo blood levels
`
`2
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`with in-vitro release. My pioneering efforts have extended to the area of Freeze
`
`Drying of Pharmaceuticals.
`
`III. A PERSON OF ORDINARY SKILL IN THE ART
`I understand from counsel that patents such as the ’061 Patent are
`8.
`
`neither addressed to experts nor to layman, but to persons of ordinary skill in the
`
`relevant art at the time the invention was made. I’m told by counsel to assume the
`
`earliest effective filing date is May 25, 2000. I understand from counsel that factors
`
`relevant to the level of ordinary skill in the art include, without limitation: the
`
`education of the inventor, the types of problems encountered in the relevant area,
`
`prior art solutions to those problems, the rapidity with which innovations are made,
`
`the sophistication of the technology, and the education level of active workers in
`
`the field. In my opinion, considering these factors, a person of ordinary skill in the
`
`art would be a pharmaceutical formulator, who has experience in parenteral
`
`formulations. When I give my opinions herein, unless stated otherwise, it is my
`
`opinion of what such a person of ordinary skill in the art would know or do at the
`
`time.
`
`9.
`
`I note that the claims in question, claims 1-13 and 17-23, are directed
`
`to an injectable suspension having a concentration of greater than 30 mg/ml of
`
`microparticles, wherein the suspension has a viscosity greater than about 20cp to
`
`less than 600cp at 20°C and provides injectability of the composition through an
`
`3
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`18-22 gauge needle. I would not consider this technology to be sophisticated,
`
`particularly relative to other injectable suspensions that include microparticles.
`
`Adjusting excipients, all of which are known in the art and used for their well-
`
`known functions, to provide a suitable suspendability and distribution of
`
`microparticles for injectability purposes is well within the general knowledge of a
`
`skilled artisan. Further, the skilled artisan would know that the type and amount of
`
`excipients, e.g. suspending or viscosity enhancing agents, required to maintain
`
`uniform distribution of such microparticles in the injection vehicle will, by nature,
`
`add viscosity to the injection vehicle.
`
`10.
`
`In reaching my conclusion, I have also considered the type of
`
`problems addressed by the ’061 Patent, and prior art solutions to these types of
`
`problems. In my opinion they all involve merely adjusting excipients to ensure the
`
`proper amount of pharmaceutically active agent is administered to the patient in a
`
`parenteral formulation. This is a problem that is faced by every pharmaceutical
`
`formulator, every time they are instructed to prepare an injectable suspension. And
`
`the solutions, that of deciding to the appropriate viscosity for syringeability and
`
`injectability, determining the size and concentration of the suspended particulates,
`
`and the density of the injection vehicle, are well established in this field. (Ex.1014,
`
`at 33.)
`
`4
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`11.
`
`It is my understanding from publicly available information that the
`
`inventors of the ’061 Patent possess Ph.D. degrees in various fields, such as
`
`chemical engineering, biomedical engineering, and chemistry, plus at least five
`
`years of experience in product development in the pharmaceutical industry.
`
`Considering the lack of sophistication in the subject matter of the claims, this is a
`
`higher level of experience than what would be considered a person of ordinary skill
`
`in the art.
`
`12. Taking into consideration each of these factors, a person of ordinary
`
`skill in the art (a “POSA”) as to the patent at issue in this case would have at least a
`
`bachelor’s degree and a number of years of industry training or experience in one
`
`or more
`
`the
`
`following
`
`fields: pharmaceutical
`
`formulation,
`
`chemistry,
`
`pharmaceutical science, polymer chemistry, pharmaceutics, pharmaceutical
`
`technology, pharmacokinetics, and/or pharmacology. A POSA would draw on the
`
`pharmaceutical science literature, general textbooks, research articles and abstracts,
`
`and other sources of information in the field of pharmaceutical formulation and
`
`polymer microparticle science. I consider myself to be a person of greater than
`
`ordinary skill and one who has mentored nearly 100 scientists at the graduate
`
`degree and post doctorate level.
`
`13. Because of my work experience, my supervision of graduate students,
`
`and my review of the relevant literature from the relevant time period (prior to
`
`5
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`May 25, 2000), I believe that I am well situated to understand what a person of
`
`ordinary skill in the art would have known and understood at the relevant time.
`
`IV. BACKGROUND
`A. Introduction
`14. The allowed claims of the ’061 Patent are directed to a composition
`
`suitable for injection through a needle into a host. (Ex.1001 cl.1.) The claims
`
`require microparticles (which are particles that include an active agent dispersed or
`
`dissolved in a polymeric binder) and an injection vehicle. (Id.) The microparticles
`
`are suspended in the injection vehicle at a concentration of 30mg/ml to form a
`
`suspension. (Id.) The fluid phase of the suspension has a viscosity of greater than
`
`about 20cp and less than about 600cp at 20°C. (Id.) This viscosity allows the
`
`composition to be injected through an 18-22 gauge needle, according to the
`
`’061 Patent. (Id.)
`
`15. Patent Owner’s alleged invention was using viscosity enhancing
`
`agents to increase the viscosity of an injectable composition that includes
`
`microparticles to improve injectability of the composition. (Id Abstract.) Patent
`
`Owner alleged that increasing viscosity of the fluid phase was an unexpected
`
`improvement in injectability and reduced in vivo injection failures. (Id. 4:57-60.)
`
`16. Patent Owner did not invent microparticles, nor did it invent a new
`
`risperidone microparticle. (Ex.1005, at 35:1-36:26, Examples 2, 3.) Patent Owner
`
`6
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`did not invent a viscosity enhancing agents or an injection vehicle that includes
`
`viscosity enhancing agents. (Ex.1009, at 12:42-45.) Patent Owner did not invent
`
`combining a viscous injection vehicle with microparticles; Patent Owner did
`
`nothing more than combine well-known elements to arrive at a known
`
`concentration and viscosity for an injectable composition. (Exs.1009, at 12:39-42;
`
`1008, at 78, 135, 137, 329, 420, 481.) Injecting a microparticle suspension through
`
`an 18-22 gauge needle was also known in the prior art, together with knowledge of
`
`injectables having viscosities greater than about 20cp. (Ex.1008, at 78, 135, 137,
`
`329, 420, 481.)
`
`Improving Injectability
`B.
`17. By May 25, 2000, the general principles for developing injectable
`
`formulations were well known and well understood. Such formulation procedures
`
`were documented in general texts on the subject including: Lieberman et al.,
`
`Pharmaceutical Dosage Forms: Disperse Systems, Vol. 2, 2nd ed. (1996)
`
`(“Lieberman 2” (Ex.1014, at 26-35, 40, 43-46, 261, 285-318)); Kenneth E.
`
`Avis et al., 1 (Chs.2, 4, 5) Pharmaceutical Dosage Forms: Parenteral Medications
`
`(Marcel Dekker Inc. 2nd ed. 1992) (“Avis” (Exh.1020, at 17-25, 115-16, 140-43,
`
`150-51, 173-75, 190-212)); L. Lachman et al., The Theory and Practice of
`
`Industrial Pharmacy (Lea & Febiger 3rd ed. 1986) (“Lachman” (Exh.1021,
`
`at 642-44, 783-84)); and Lieberman et al., Pharmaceutical Dosage Forms: Disperse
`
`7
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`Systems, Vol. 1, 2nd ed. (1996) (“Lieberman 1” (Ex.1022, at 287-313)). My
`
`review of the ’061 Patent indicates that the Patent Owner simply followed these
`
`well-known steps and developed the formulation in a way that was routine in the
`
`art.
`
`18.
`
`Injectable suspensions are heterogeneous systems that include a solid
`
`phase and a liquid phase. (Exs.1014, at 285; 1001, at 1:17-25.) Aqueous and
`
`nonaqueous liquid phases were known to be used in injectable suspensions.
`
`(Exs.1014, at 285; 1001, at 1:17-25.) The solid phase of the suspension may
`
`include microparticles, which have an active pharmaceutical
`
`ingredient
`
`encapsulated in a polymeric binder provide extended release in injectable
`
`suspensions. (Exs.1014, at 285; 1001, at 1:17-25.)
`
`19.
`
`Injectable suspensions must be syringeable and injectable. (Exs.1014,
`
`at 285; 1001, at 1:17-25.) A composition is “syringeable” if it is capable of flowing
`
`through a needle from a vial. (Exs.1014, at 298; 1001, at 1:53-60.) Some common
`
`issues associated with syringeability are clogging of the needle, withdrawal of the
`
`composition from the vial, and accuracy of the dose to be administered. (Exs.1014,
`
`at 298-99; 1001, at 1:53-60.) “Injectable” refers to how the suspension performs
`
`during the actual injection of the composition. (Exs.1014, at 299; 1001,
`
`at 1:61-64.) Common issues associated with injectability are force required to
`
`8
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`administer the injection, evenness of the flow, aspiration, and clogging. (Exs.1014,
`
`at 299; 1001, at 1:61-64.)
`
`C. Risperidone
`20. Risperidone is a well-known hydrophobic antipsychotic drug, which
`
`first gained market approval in 1993. (Exs.1023, 1010, at 2:38-41.) Risperidone
`
`was initially available as a tablet or oral solution, and later approved as a depot
`
`injection. (Ex.1023.)
`
`D. The Role Of Viscosity In Injectable Formulations
`21. Syringeability is defined as the ability of a parenteral solution or
`
`suspension to pass easily through a hypodermic needle and considered one of the
`
`most important properties of a suitable parenteral suspension. (Ex.1014, at 33-34.)
`
`Increases in various characteristics may make the syringeability more difficult. For
`
`example, the following should be considered when determining an appropriate
`
`syringeability: viscosity of the vehicle, density of the vehicle, size of the suspended
`
`particulate, and concentration of the drug. (Id.)
`
`22. Viscosity is a necessary component of injectable formulations. As
`
`described by Lieberman, the viscosity measurement is one of the most important
`
`factors and the easiest for a formulator to control. (Id.) An injectable formulation
`
`must have the proper viscosity to ensure it is capable of being forced through a
`
`9
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`syringe (i.e., syringeable) and capable of being injected through a needle into a
`
`host (i.e., injectable). (Id.)
`
`23. There are two types of injection vehicles: aqueous and nonaqueous.
`
`(Id. at 285.) Nonaqueous, or oleaginous, injection vehicles are those that include an
`
`oil. (Id. at 290.) Corn oil, cottonseed oil, peanut oil, sesame oil, and soybean oil are
`
`examples of a nonaqueous vehicle used for intramuscular injections. (Exs.1008,
`
`at 135, 137, 329, 420, 481; 1014, at 290-91.) The viscosity of these commonly
`
`used nonaqueous vehicles, all of which may be used for injections, can be found in
`
`Table 1 below:
`
`Non-Aqueous Vehicle
`
`Viscosity
`
`TABLE I
`
`Corn Oil
`
`Cottonseed Oil
`
`Peanut Oil
`
`Sesame Oil
`
`Soybean Oil
`
`38.83 mPa s (or 38.83cps)
`
`37.36 mPa s (or 37.36cps)
`
`70 mPa s (or 70cps) at 20°C
`
`35 mPa s (or 35cps) at 37°C
`
`43.37 mPa s (or 43.37cps)
`
`99.7 mPa s (99.7cps) at 10°C
`
`50 mPa s (50cps) at 25°C
`
`28.86 mPa s (28.86cps) at 40°C
`
`(Ex.1008, at 135, 137, 329, 420, 481.)
`
`10
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`24. Aqueous injection vehicles primarily include water and require
`
`additives if the active particles do not readily dissolve in water. (Ex.1014, at 291.)
`
`Accordingly, the formulator must include various substances such as suspending
`
`agents, tonicity agents, wetting agents, etc. to arrive at a suitable aqueous injection
`
`vehicle capable of satisfying the syringeability and injectability properties required
`
`to make a formulation suitable for injection. (Id. at 288.)
`
`25. Viscosity is a measurement that is also dependent on temperature.
`
`(Exs.1006, at 1840; 1024, at 305.) As the temperature increases, the viscosity
`
`decreases. (Exs.1006, at 1840; 1024, at 305.) A POSA would know to create an
`
`injectable formulation that was viscous enough to hold the microparticles in
`
`solution, but not too viscous that it presents syringeability or injectability
`
`problems.
`
`E.
`
`26.
`
`The Prior Art Taught Microparticle Suspensions
`With The Claimed Concentration and Viscosity
`Injectable formulations that include microspheres would include a
`
`viscosity enhancing or suspending agent. Sodium carboxymethylcellulose (CMC)
`
`is one of the most commonly used suspending and viscosity enhancing agents.
`
`(Exs.1008, at 78-81; 1022, at 305.)
`
`27.
`
`Johnson teaches a formulation suitable for injection. (Ex.1009
`
`Abstract, 12:39-45.) Johnson
`
`teaches
`
`that such formulation may
`
`include
`
`microparticles.
`
`(Id. 4:54-57, 10:64-11:1, 12:39-45.) Johnson
`
`teaches a
`
`11
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`microparticle concentration greater than 30mg/ml and teaches an injection vehicle
`
`that includes 3% w/w carboxymethylcellulose (sodium salt). (Id. 12:39-45.)
`
`Johnson further teaches incorporating a wetting agent, such as polysorbate, and a
`
`tonicity agent, such as sodium chloride. (Id.) Johnson teaches that such formulation
`
`may be injected through a 20 gauge needle. (Id. 12:40-42.)
`
`28. Gustafsson teaches a sustained release formulation that includes
`
`polymer microparticles. (Ex.1011 Abstract.) Gustafsson
`
`teaches
`
`that such
`
`formulations can be used for any known active pharmaceutical ingredient.
`
`(Id. 6:33-35.) Gustafsson teaches a vehicle that includes a sodium chloride solution
`
`containing 3% sodium carboxymethylcellulose and microparticles
`
`in a
`
`concentration of greater than 30mg/ml, and wherein the resulting suspension is
`
`suitable for injection through a 21 gauge needle. (Id. 18:19-24, 19:19-24.)
`
`Gustafsson further teaches incorporating a physiological sodium chloride solution.
`
`(Id. 18:19-24, 19:21-22.)
`
`29. Ramstack teaches the preparation of biodegradable microparticles that
`
`include a biologically active agent and specifically identifies risperidone.
`
`(Ex.1005 Abstract, 35:1-36:26, Examples 2, 3.) Ramstack teaches that a polymer,
`
`such as 75:25 dl (polylactide-co-glycolide), may be used for encapsulating
`
`risperidone.
`
`(Ex.1005,
`
`at 5:19-22,
`
`35:1-36:26, Examples 2,
`
`3.) The
`
`poly(lactide-co-glycolide) may have a molar ratio of lactide to glycolide in a range
`
`12
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`of 85:15 to 50:50. (Ex.1005, at 16:28-31.) Additional polymer materials useful for
`
`encapsulation may include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic
`
`acid,
`
`copolymers of
`
`the
`
`foregoing, poly(aliphatic
`
`carboxylic
`
`acids),
`
`copolyoxalates, polycaprolactone, polydioxonene, poly(ortho
`
`carbonates),
`
`poly(acetals), poly(lactic acidcaprolactone), polyorthoesters, poly(glycolic acid-
`
`caprolactone), polyanhydrides, polyphosphazines, and natural polymers including
`
`albumin, casein, and waxes. (Id. at 16:7-13.) Ramstack also teaches microparticles
`
`suspended in an injection vehicle that includes a viscosity enhancing agent, a
`
`wetting agent, and a density enhancing agent. (Id. at 37:6-7.)
`
`30. Kino teaches sustained release microspheres of antipsychotic drug,
`
`including risperidone. (Ex.1010, at 1:65-2:4, 2:38-41.) Kino teaches that such
`
`microspheres can be used in aqueous injection solutions. (Id. 4:38-40.) Kino
`
`teaches the inclusion of carboxymethyl cellulose, a viscosity enhancing agent,
`
`polycorbat 20, a wetting agent, sodium chloride, a tonicity agent. (Id. 4:38-51.)
`
`Kino teaches the addition of sorbitol to an injection vehicle. (Id. 4:52:55.)
`
`31. The U.S. Pharmacopeia teaches that viscosity is typically measured at
`
`about 25°C. (Ex.1006. at 275, 1840.) The European Pharmacopoeia teaches that
`
`viscosity is typically measured at about 20°C. (Ex.1007, at 547.)
`
`32. The Handbook of Pharmaceutical Excipients, 2nd Edition, was
`
`published in 1994. The Handbook teaches that carboxymethylcelluose sodium is
`
`13
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`also known as CMC sodium, sodium carboxymethylcellulose, and sodium CMC
`
`(“CMC”) and that CMC is a “viscosity-increasing agent” and a “suspending
`
`agent.” (Ex.1008, at 78.) The Handbook teaches that various different types of oils
`
`are suitable for intramuscular injections. The Handbook teaches that corn oil has a
`
`viscosity of 38.83 or 37.36 mPa s. (Id. at 135.) The Handbook teaches that
`
`cottonseed oil can be used in intramuscular injections and has a viscosity of about
`
`70 mPa s at 20°C. (Id. at 137.) The Handbook teaches that peanut oil may be used
`
`in intramuscular injections and has a viscosity of about 40 at 37°C. (Id. at 329.)
`
`The Handbook teaches that sesame oil, which has a viscosity of 43.37 mPa s, can
`
`be used in combination with sustained-release intramuscular injections. (Id.
`
`at 420.) The Handbook teaches that soybean oil has a viscosity of about 50 mPa s
`
`at 25°C and can be used for intravenous injection of drugs. (Id. at 481.)The
`
`Handbook teaches that polyoxyethylene sorbitan fatty acid esters are also known as
`
`polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. (Id. at 375.)
`
`The Handbook teaches that polysorbate 20 is also known as Tween 20, polysorbate
`
`40 is also known as Tween 40, polysorbate 60 is also known as Tween 60, and
`
`polysorbate 80 is also known as Tween 80. (Id.) The Handbook teaches that
`
`polysorbates are wetting agents that can be used in parenteral suspensions. (Id.
`
`at 376.) The Handbook teaches that sodium chloride is a tonicity agent, that a
`
`0.9% w/v sodium chloride aqueous solution is iso-osmotic with serum and can be
`
`14
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`used in intravenous injections. (Id. at 439-440.) The Handbook teaches also that
`
`mannitol is a well-known tonicity agent and is an isomer of sorbitol. (Id. at 294.)
`
`And the Handbook teaches that sorbitol may be used in intramuscular injections
`
`and increases the density of aqueous solutions. (Id. at 477, 479.)
`
`33. All of the principles, studies, and strategies described above reflect the
`
`core role of a formulator working on the development of an injectable product. I
`
`would have expected a POSA working in the field of injectable formulation
`
`development in 1999 to have considered all of the aspects described.
`
`V. THE ’061 PATENT
`A. The Claims
`Independent claim 1 is directed to a composition that is suitable for
`34.
`
`injection through a needle into a host, which includes microparticles with a
`
`polymeric binder, and an injection vehicle. (Ex.1001 cl.1.) The microparticles are
`
`suspended in the injection vehicle to form a suspension, which includes a fluid
`
`phase having a viscosity of greater than about 20cp and less than about 600cp at
`
`20°C and provides injectability of the composition through a needle having a
`
`diameter from 18-22 gauge.
`
`35. Dependent claims 2 and 3 require the addition of a viscosity
`
`enhancing agent, such as sodium carboxymethyl cellulose. (Id. cls.2-3.) Dependent
`
`claims 4 and 5 require the addition of a density enhancing agent, such as sorbitol.
`
`15
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`(Id. cls.4-5.) Dependent claims 6 and 7 require the addition of a tonicity adjusting
`
`agent, such as sodium chloride. (Id. cls.6-7.) Dependent claims 8 and 9 require the
`
`addition of a wetting agent, such as polysorbate 20, polysorbate 40, or
`
`polysorbate 80. (Id. cls.8-9.) Dependent claims 10 and 11 require the addition of a
`
`combination of a density enhancing agent and a wetting agent, such as polysorbate
`
`20, polysorbate 40, or polysorbate 80. (Id. cls.10-11.) Dependent claims 12 and 13
`
`require the addition of a combination of a tonicity adjusting agent and a wetting
`
`agent, such as polysorbate 20, polysorbate 40, or polysorbate 80. (Id. cls.12-13.)
`
`Dependent claims 17, 18, and 19 require the microparticle to include an active
`
`agent encapsulated with a polymeric binder, such as poly(d,l-lactide-co-glycolide)
`
`having a molar ratio of lactide to glycolide in the range of from about 85:15 to
`
`about 50:50. (Id. cls.17-19.) Dependent claims 20 and 21 require the active agent
`
`of claim 17 and 19, respectively, to be risperidone, 9-hydroxyrisperidone, or a
`
`pharmaceutically acceptable salt. (Id. cls.20-21.) Finally dependent claims 22 and
`
`23 require the microparticles to have a mass median diameter of less than about
`
`250µm or from about 20µm to about 150µm. (Id. cls.22-23.)
`
`The Family History Of The ’061 Patent
`B.
`36. The ’061 Patent issued on December 23, 2003, from U.S. Application
`
`No. 10/259,949. The patent states on its face that it is a continuation of U.S. Patent
`
`Application No. 09/577,875, filed on May 25, 2000, which issued as U.S. Patent
`
`16
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`No. 6,495,164 (“the ’164 Patent”) on December 17, 2002. (Ex.1015.) I have
`
`reviewed these applications to confirm that their relevant disclosures are
`
`substantially the same, which they are.
`
`C. The Specification
`37. The ’061 Patent states that it is directed to injectable compositions
`
`having improved injectability. (Ex.1001 Abstract.) As the “Background of the
`
`Invention” states, adding viscosity enhancers to injection vehicles is known.
`
`(Id. 2:25-27.) The ’061 Patent teaches that this was done “in order to retard settling
`
`of the particles in the vial and syringe.” (Id.)
`
`38. The
`
`’061 Patent provides
`
`examples of known
`
`injectable
`
`pharmaceuticals. For example, the ’061 Patent admits that “[t]he fluid phase of a
`
`suspension of Decapeptyl . . . mean particle size of 40 µm . . . when prepared as
`
`directed, has a viscosity of approximately 19.7 cp.” (Id. 2:34-37.) The Background
`
`then states that there is a need in the art to improve the injectability of injectables
`
`that include microparticle suspensions. (Id. 2:55-61.)
`
`39. The Summary of the Invention and the Detailed Description provide
`
`different embodiments of the alleged invention. (Id. 2:63-5:40.) In one aspect, the
`
`injection vehicle is defined as “not being the aqueous injection vehicle that consists
`
`of 3% by volume carboxymethyl cellulose, 1% by volume polysorbate 20, 0.9% by
`
`volume sodium chloride.” (Exs.1001, at 3:4-7.) The patent then lists a preferred
`
`17
`
`LUYE1002
`IPR of Patent No. 6,667,061
`
`

`
`
`
`injection vehicle that “is an aqueous injection vehicle that comprises 3% sodium
`
`carboxymethyl cellulose, 0.9% saline, and 0.1% polysorbate 20.” (Ex.1001,
`
`at 16:64-67.) A POSA would appreciate that the only difference between the two
`
`sentences is polysorbate 20 in the amount of 0.9%. The Method and Examples
`
`section provides various studies, such as an in vitro test study, animal studies,
`
`ex vivo injectability tests, and methods of preparing the injectable compositions.
`
`D. The May 14, 2003 Response And The Tracy Declaration
`40. The Examiner issued a nonfinal office action on April 9, 2003
`
`(Ex.1016), which rejected claims 1-21 and 41-42 under 35 U.S.C. § 103 as being
`
`unpatentable over U.S. Patent No. 5,656,299 to Kino et al. and further in view of
`
`U.S. Patent No. 5,540,912 to Roorda et al..
`
`41.
`
`In regards to Kino, the Examiner stated that Kino disclosed sustained
`
`release microsphere preparations of antipsychotic drugs that are suitable for
`
`injection. (Ex.1016, at 3.) The Examiner stated that although “Kino does not
`
`disclose the viscosity to be greater than about 60 cp and less than about 600cp,” it
`
`would have been obvious “to determine the optimal viscosity for application.”
`
`(Ex.1016, at 4.) According to the Examiner:
`
`Both the prior art and the instant claims are drawn to a composition suitable
`
`for injection through a needle host comprising micropar