`
`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
`__________________________________________________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`CLAIMS 1-13 AND 17-23 OF U.S. PATENT NO. 6,667,061
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`U.S. Patent And Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`4558100_1.docx
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ...................................................................................III
`
`EXHIBIT LIST ........................................................................................................ iv
`
`I.
`
`MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1)) ..................................... 1
`
`A. Notice Of Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .............. 1
`
`B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ................................. 1
`
`C. Designation Of Lead And Backup Counsel (37 C.F.R. § 42.8(b)(3)) ...... 1
`
`D. Notice Of Service Information (37 C.F.R. § 42.8(b)(4)) .......................... 2
`
`E. Grounds For Standing (37 C.F.R. §42.104(a)) ......................................... 2
`
`II.
`
`STATEMENT OF PRECISE RELIEF REQUESTED (37 C.F.R.
`§ 42.22(A)) ...................................................................................................... 3
`
`III.
`
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 104(B)) .............. 3
`
`IV. BACKGROUND ............................................................................................. 5
`
`A. Introduction ............................................................................................... 5
`
`B. Improving Injectability ............................................................................. 7
`
`C. Risperidone ............................................................................................... 8
`
`D. The Role of Viscosity In Injectable Formulations .................................... 8
`
`E. The Prior Art Taught Microparticle Suspensions With The Claimed
`Concentration And Viscosity .................................................................... 9
`
`V.
`
`THE ’061 PATENT .......................................................................................13
`
`A. The Claims ..............................................................................................13
`
`B. The Family History Of The ’061 Patent .................................................14
`
`
`
`i
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`C. The Specification Of The ’061 Patent ....................................................15
`
`D. The Pertinent Prosecution History Of The ’061 Patent ..........................16
`
`VI. PERSON OF SKILL IN THE ART (“POSA”) .............................................18
`
`VII. CLAIM CONSTRUCTION ..........................................................................19
`
`A. “Suitable For Injection” ..........................................................................20
`
`B. “Microparticles” ......................................................................................20
`
`C. “Injection Vehicle” .................................................................................20
`
`D. “Suspension” ...........................................................................................21
`
`E. “Fluid Phase Of Said Suspension” .........................................................21
`
`F. “Viscosity Greater Than About 20 cp And Less Than About 600 cp” ..22
`
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST ONE
`CLAIM OF THE ’061 PATENT IS UNPATENTABLE .............................22
`
`A. Ground 1: Claims 1-13 And 17-23 Are Obvious Over Johnson
`(Ex.1009) In View Of Kino (Ex.1010) ...................................................23
`
`1. Johnson in View Of Kino Teaches Every Element Of Claims 1-13
`And 17-23.........................................................................................24
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`Claims 1-3 ..............................................................................24
`
`Claims 4, 5, 10, And 11 ........................................................26
`
`Claims 6-9 And 12-13 ..........................................................27
`
`Claims 17-21 .........................................................................28
`
`Claims 22-23 .........................................................................30
`
`2. Claims 1-13 And 17-23 Are Obvious ............................................32
`
`
`
`ii
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`B. Ground 2: Claims 1-13 And 17-23 Are Obvious Over
`Gustafsson (Ex.1011) In View Of Ramstack (Ex.1005), and the
`Handbook (Ex.1008) ...............................................................................38
`
`1. Gustafsson In View Of Ramstack, And The Handbook Teaches
`Every Element Of Claims 1-13 And 17-23 .....................................38
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`h.
`
`Claim 1 ...................................................................................38
`
`Claims 2-3 ..............................................................................40
`
`Claims 4, 5, 10, And 11 .........................................................41
`
`Claims 6 and7 ........................................................................43
`
`Claims 8 and 9 .......................................................................43
`
`Claims 12 and 13 ...................................................................44
`
`Claims 17-21 ..........................................................................45
`
`Claims 22-23 ..........................................................................47
`
`2. Claims 1-13 And 17-23 Are Obvious ............................................48
`
`IX. SECONDARY CONSIDERATIONS ...........................................................56
`
`X.
`
`CONCLUSION ..............................................................................................57
`
`
`
`
`
`
`
`iii
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`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`TABLE OF AUTHORITIES
`
`
`CASES
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 23
`
`Page(s)
`
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 57
`
`In re DBC,
`545 F.3d 1373 (Fed. Cir. 2008) .......................................................................... 56
`
`Graham v. John Deere Co.,
`383 U.S. 1, 17-18 (1966) .................................................................................... 23
`
`J.T. Eaton & Co. v. Atl. Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .......................................................................... 57
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 23
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1373 (Fed. Cir. 2012) .......................................................................... 18
`
`Par Pharm. Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 23, 57
`
`Warner Chilcott Co. v. Lupin Ltd,
`Civ. Action Nos. 11-5048, 12-2928, 2014 U.S. Dist. LEXIS 6228 (D.N.J.
`Jan. 17, 2014) ...................................................................................................... 18
`
`STATUTES
`
`35 U.S.C. § 103(a) ................................................................................................... 23
`
`
`
`iv
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`EXHIBIT LIST
`
`
`
`1009
`1010
`1011
`1012
`1013
`1014
`
`1015
`1016
`1017
`1018
`1019
`1020
`
`Exhibit # Reference
`U.S. Patent No. 6,667,061 (“the ’061 Patent”)
`1001
`1002
`Declaration of Dr. Patrick P. DeLuca
`Curriculum Vitae of Dr. Patrick P. DeLuca
`1003
`Intentionally Left Blank
`1004
`1005
`International Publication No. WO 95/13799 (“Ramstack”)
`1006
`U.S. Pharmacopeia Entry re: CMC, viscosity pp.274-75, 1840 (1994)
`1007
`EP Pharmacopoeia Entry re: CMC, pp.547-48(3d ed. 1997)
`1008
`Handbook of Pharmaceutical Excipients pp.78-81, 135-38, 294-95,
`329-330, 375-78, 420-21, 439-42, 477-80, 481-82 (2nd ed. 1994)
`U.S. Patent No. 5,654,010 (“Johnson”)
`U.S. Patent No. 5,656,299 (“Kino”)
`International Publication No. WO199714408 (“Gustafsson”)
`Intentionally Left Blank
`Intentionally Left Blank
`Herbert A. Lieberman et al. (eds.), Pharmaceutical Dosage Forms:
`Disperse Systems, Vol.2, pp.26-35, 40, 43-46, 261, 285-318 (2nd ed.
`rev. expanded 1996)
`U.S. Patent No. 6,495,164 (“the ’164 Patent”)
`Serial No. 10/259,949, Office Action, Apr. 9, 2003
`Serial No. 10/259,949, Applicants’ Resp., May 14, 2003
`Serial No. 09/577,875, Declaration of Mark A. Tracy, May 17, 2002
`Serial No. 10/259,949, Notice of Allowability, July 24, 2003
`Kenneth E. Avis et al. (eds.), 1 (Chs.2, 4, 5) Pharmaceutical Dosage
`Forms:Parenteral Medications 17-25, 115-16, 140-43, 150-51,
`173-75, 190-212 (2nd ed. rev. expanded Marcel Dekker, Inc. 1992)
`Leon Lachman, PhD et al., The Theory and Practice of Industrial
`Pharmacy 642-44, 783-84 (Lea & Febiger 3rd ed. 1986)
`Herbert A. Lieberman et al., Pharmaceutical Dosage Forms:
`Disperse Systems, Vol.1, pp.287-313 (2nd ed. rev. expanded 1996)
`Orange Book entries for RISPERDAL®
`
`1021
`
`1022
`
`1023
`
`
`
`v
`
`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Luye Pharma Group
`
`Ltd., Luye Pharma (USA) Ltd., Shandong Luye Pharmaceutical Co., Ltd., and
`
`Nanjing Luye Pharmaceutical Co., Ltd. (collectively “Luye” or “Petitioners”)
`
`petition for Inter Partes Review (“IPR”) seeking cancellation of claims 1-13
`
`and 17-23 of U.S. Patent No. 6,667,061 (“the ’061 Patent”) (Ex.1001).
`
`I. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`A. Notice Of Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`The real parties-in-interest for this Petition are Luye Pharma Group Ltd.,
`
`Luye Pharma (USA) Ltd., Shandong Luye Pharmaceutical Co., Ltd., and Nanjing
`
`Luye Pharmaceutical Co., Ltd.. The ’061 Patent is assigned on its face to Alkermes
`
`Controlled Therapeutics, Inc., but by later assignment is owned by Alkermes
`
`Pharma Ireland Limited. (collectively “Patent Owner” or “Alkermes”).
`
`B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Petitioners have concurrently filed a second petition for Inter Partes Review
`
`IPR2016- 01095 seeking cancelation of claims 1-13 and 1-23 on other grounds.
`
`There are no related litigation matters between the parties involving this patent.
`
`C. Designation Of Lead And Backup Counsel (37 C.F.R. § 42.8(b)(3))
`Lead Counsel:
`Backup Counsel:
`William L. Mentlik
`Paul H. Kochanski
`(Reg. No. 27,108)
`(Reg. No. 29,660)
`
`
`
`
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`wmentlik.ipr@lernerdavid.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Tel: 908.654.5000
`Fax: 908.654.7866
`
`pkochanski@lernerdavid.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Tel: 908.654.5000
`Fax: 908.654.7866
`
`Tedd W. Van Buskirk
`(Reg. No. 46,282)
`tvanbuskirk@lernerdavid.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Tel: 908.654.5000
`Fax: 908.654.7866
`
`Nichole M. Valeyko
`(Reg. No. 55,832)
`nvaleyko@lernerdavid.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Tel: 908.654.5000
`Fax: 908.654.7866
`D. Notice Of Service Information (37 C.F.R. § 42.8(b)(4))
`Please address all correspondence to the lead and backup counsel at the
`
`address shown above. Petitioners also consent to electronic service by e-mail at the
`
`above-listed e-mail addresses.
`
`E. Grounds For Standing (37 C.F.R. §42.104(a))
`Petitioners certify that (1) the ’061 Patent is available for IPR; and
`
`(2) Petitioners are not barred or estopped from requesting IPR of the ’061 Patent
`
`2
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`on the grounds identified herein. The fee for this petition has been paid. The Office
`
`is hereby authorized to charge any fee deficiencies to, or credit any overpayments
`
`to, Deposit Acct No. 12-1095 in connection with this petition.
`
`II.
`
`STATEMENT OF PRECISE
`RELIEF REQUESTED (37 C.F.R. § 42.22(a))
`For the reasons set forth herein, the information presented shows that there is
`
`a reasonable likelihood that Luye will prevail with respect to at least one of the
`
`claims challenged in this petition. Petitioners request institution of an IPR and
`
`cancellation of claims 1-13 and 17-23 of the ’061 Patent. The text of the
`
`challenged claims can be found in the claim charts included herein.
`
`III.
`
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 104(b))
`IPR of claims 1-13 and 17-23 of the ’061 Patent is requested on the two
`
`separate grounds of unpatentability listed below. Per 37 C.F.R. § 42.6(d), a copy of
`
`each of the references is filed herewith. In support of the proposed grounds for
`
`unpatentability, this petition includes the declaration of technical expert Patrick
`
`DeLuca Ph.D. (Ex.1002), explaining what the art would have conveyed to a person
`
`of ordinary skill in the art (“POSA”). Dr. DeLuca’s Curriculum Vitae is included
`
`as well. (Ex.1003.) Dr. DeLuca is an expert in the field of formulations involving
`
`risperidone microparticles, pharmaceutics, parenteral dosage form design,
`
`3
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`microparticles, sustained release delivery systems, and pharmaceutical patents,
`
`among others. (Ex.1002 ¶¶ 4-7.)
`
`Ground
`
`References
`
`Basis
`
`Claims
`
`1
`
`2
`
`Johnson (Ex.1009)
`in view of Kino (Ex.1010)
`Gustafsson (Ex.1011) in view of
` Ramstack (Ex.1005), and the
`Handbook (Ex.1008)
`
`§ 103
`
`§ 103
`
`1-13 and
`17-23
`
`1-13 and
`17-23
`
`In Ground 1, Petitioners show that claims 1-13 and 17-23 are unpatentable
`
`over U.S. Patent No. 5,654,010 to Johnson et al. (“Johnson”) (Ex.1009) in view of
`
`Kino (Ex.1010). Johnson alone renders obvious every element of claims 1-3, 6-9,
`
`12-13, 17-19, and 22-23. Johnson, in combination with Kino, would render
`
`claims 4-5, 10-11, and 20-21 obvious to a POSA as of the priority date.
`
`In Ground 2, Petitioners show that claims 1-13 and 17-23 are unpatentable
`
`over WO 1997/144408 to Gustafsson et al. (“Gustafsson”) (Ex.1011) in view of
`
`WO 1995/13799 to Ramstack et al. (“Ramstack”) (Ex.1005), and the Handbook of
`
`Pharmaceutical Excipients, 2nd Edition (“the Handbook”) (Ex.1005). Gustafsson,
`
`in combination with Ramstack, and the Handbook render claims 1-13 and 17-23
`
`obvious to a POSA as of the priority date.
`
`4
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`Although Petitioner provides multiple grounds of unpatentability, they are
`
`meaningfully distinct. Ground 1 and Ground 2 rely upon different primary and
`
`secondary references. All of the Grounds in this Petition also represent
`
`meaningfully different arguments than those made in the corresponding IPR
`
`Petition filed on
`
`the same date as
`
`this Petition bearing case number
`
`IPR2016-01095.
`
`IV. BACKGROUND
`Introduction
`A.
`The allowed claims of the ’061 Patent are directed to a composition suitable
`
`for injection through a needle into a host. (Exs.1001 cl.1; 1002 ¶ 14.) The claims
`
`require microparticles (which are particles that include an active agent dispersed or
`
`dissolved in a polymeric binder) and an injection vehicle. (Exs.1001 cl.1; 1002
`
`¶ 14.) The microparticles are suspended in the injection vehicle at a concentration
`
`of 30mg/ml to form a suspension. (Exs.1001 cl.1; 1002 ¶ 14.) The fluid phase of
`
`the suspension has a viscosity of greater than about 20cp and less than about 600cp
`
`at 20°C. (Exs.1001 cl.1; 1002 ¶ 14.) This viscosity allows the composition to be
`
`injected
`
`through an 18-22 gauge needle, according
`
`to
`
`the ’061 Patent.
`
`(Exs.1001 cl.1; 1002 ¶ 14.)
`
`5
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`Patent Owner’s alleged invention was using known viscosity enhancing
`
`agents to increase the viscosity of an injectable composition that includes
`
`microparticles to improve injectability of the composition. (Exs.1001 Abstract;
`
`1002 ¶ 15.) Patent Owner alleged that increasing viscosity of the fluid phase was
`
`an unexpected improvement in injectability and reduced in vivo injection failures.
`
`(Exs.1001, at 4:57-60; 1002 ¶ 15.)
`
`But Patent Owner did not invent a new microparticle. (Exs.1005, at 35-36,
`
`Examples 2, 3; 1002 ¶ 16.) Nor did Patent Owner invent viscosity enhancing agent
`
`or new injection vehicles. (Exs.1009, at 12:42-45; 1002 ¶ 16.) Indeed, Patent
`
`Owner did not invent combining a viscous injection vehicle with microparticles.
`
`(Ex.1002 ¶16.) 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, 239, 420; 1002 ¶ 16.) 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 at 20°C. (Exs.1008, at 78, 135, 137, 239, 420; 1002 ¶ 16, 32.)
`
`Accordingly, Petitioners request institution of an IPR of claims 1-13 and 17-23 of
`
`the ’061 Patent.
`
`6
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`Improving Injectability
`B.
`Injectable suspensions are heterogeneous systems that include a solid phase
`
`and a liquid phase. (Exs.1014, at 285; 1001, at 1:17-25; 1002 ¶ 18.) Aqueous and
`
`nonaqueous liquid phases were known to be used in injectable suspensions.
`
`(Exs.1014, at 285; 1001, at 1:17-25; 1002 ¶ 18.) The solid phase of the suspension
`
`are known to include microparticles, which have an active pharmaceutical
`
`ingredient encapsulated in a polymeric binder and provides extended release in
`
`injectable suspensions. (Exs.1014, at 285; 1001, at 1:17-25; 1002 ¶ 18.)
`
`Injectable suspensions must be syringeable and injectable. (Exs.1014,
`
`at 285; 1001, at 1:17-25; 1002 ¶ 19.) 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; 1002
`
`¶ 19.) 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 1:61-64; 1002 ¶ 19.) “Injectable”
`
`refers to how the suspension performs during the actual injection of the
`
`composition. (Exs.1014, at 299; 1001, at 1:53-60; 1002 ¶ 19.) Common issues
`
`associated with injectability are force required to administer the injection, evenness
`
`of the flow, aspiration, and clogging. (Exs.1014, at 299; 1001, at 1:53-60; 1002
`
`¶ 19.)
`
`7
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`C. Risperidone
`Risperidone is a well-known hydrophobic antipsychotic drug, which first
`
`gained market approval in 1993. (Exs.1023; 1002 ¶ 20.)
`
`D. The Role of Viscosity In Injectable Formulations
`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. (Exs.1014, at 33-34; 1002
`
`¶ 21.) 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.)
`
`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. (Exs.1014, at 33-34; 1002 ¶ 22.)An
`
`injectable formulation must have the proper viscosity to ensure it is capable of
`
`being forced through a syringe (i.e., syringeable) and capable of being injected
`
`through a needle into a host (i.e., injectable). (Id.)
`
`Aqueous injection vehicles primarily include water and require additives if
`
`the active particles do not readily dissolve in water. (Exs.1014, at 291; 1002 ¶ 24.)
`
`8
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`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. (Exs.1014, at 288; 1002 ¶ 24.)
`
`Viscosity is a measurement that is also dependent on temperature.
`
`(Exs.1022, at 305; 1006, at 1840; 1002 ¶ 25.) As the temperature increases, the
`
`viscosity decreases. (Exs.1002, at 305; 1006 at 1840; 1002 ¶ 25.) 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.
`
`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; 1002 ¶26.)
`
`Johnson is not in the same patent family as the ’061 Patent, but is owned by
`
`Patent Owner and shares a common inventor, OluFunmi L(ily) Johnson.
`
`(Exs.1001, 1009.) Johnson teaches a formulation suitable for injection, which may
`
`include microparticles. (Exs.1009, at 4:54-60, 12:39-45; 1002 ¶ 27.) Johnson also
`
`9
`
`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
`
`teaches a microparticle concentration greater than 30mg/ml and an injection
`
`vehicle that includes 3% w/w carboxymethylcellulose (sodium salt). (Exs.1009,
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`at 12:42-45; 1002 ¶ 27.) Johnson further teaches incorporating a wetting agent,
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`such as polysorbate, and a tonicity agent, such as sodium chloride. (Exs.1009,
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`at 12:42-45; 1002 ¶ 27.) Johnson states that such formulation may be injected
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`through a 20 gauge needle. (Exs.1009, at 12:40-42; 1002 ¶ 27.)
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`As mentioned above, the ’061 Patent appeared to disclaim the exact Johnson
`
`vehicle in the Summary of the Invention, “the injection vehicle not being the
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`aqueous injection vehicle that consists of 3% by volume carboxymethyl cellulose,
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`1% by volume polysorbate 20, 0.9% by volume sodium chloride,” but the claims
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`include no such limitation. (Exs.1001, at 3:4-7.) Thus the Johnson injection vehicle
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`directly reads upon the claims. Even if the Johnson injection vehicle were
`
`interpreted to be disclaimed by the ’061 Patent, Patent Owner never provided any
`
`arguments or supporting documentation to prove that their injection vehicle was
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`anything other than an obvious variation of that the exact injection vehicle taught
`
`by Johnson.
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`Gustafsson teaches a sustained release formulation that includes polymer
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`microparticles in a suspension suitable for injection. (Exs.1011 Abstract; 1002
`
`¶ 28.) Gustafsson teaches that such formulations can be used for any known active
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`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
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`pharmaceutical ingredient. (Exs.1011, at 6:33-35; 1002 ¶ 28.) Gustafsson teaches
`
`that such formulations can include 3% sodium carboxymethylcellulose and
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`microparticles in a concentration of greater than 30mg/ml, and in a suspension that
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`is suitable for injection through a 21 gauge needle. (Exs.1011, at 18:19-24,
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`19:19-24; 1002 ¶ 28.) Gustafsson further teaches incorporating a physiological
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`sodium chloride solution, which is a well-known tonicity agent. (Exs.1011,
`
`at 18:19-24, 19:21-22; 1002 ¶ 28.)
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`Ramstack teaches the preparation of biodegradable microparticles that
`
`include a biologically active agent and specifically identifies risperidone.
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`(Exs.1005 Abstract, 35:1-36:26; 1002 ¶ 29.) Ramstack teaches that a polymer, such
`
`as 75:25 dl (polylactide-co-glycolide), may be used for encapsulating risperidone.
`
`(Exs.1005,
`
`at 5:19-22, 35:1-36:26, Examples 2, 3; 1002
`
`¶ 29.) The
`
`poly(lactide-co-glycolide) may have a molar ratio of lactide to glycolide in a range
`
`of 85:15 to 50:50. (Exs.1005, at 16:28-31; 1002 ¶ 29.) Additional polymer
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`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),
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`poly(acetals), poly(lactic acidcaprolactone), polyorthoesters, poly(glycolic acid-
`
`caprolactone), polyanhydrides, polyphosphazines, and natural polymers including
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`albumin, casein, and waxes. (Exs.1005, at 16:7-13; 1002 ¶ 29.) Ramstack teaches
`
`an aqueous injection vehicle that includes CMC, mannitol, and polysorbate.
`
`(Exs.1005, at 37:6-7; 1002 ¶ 29.)
`
`Kino teaches sustained release microspheres of antipsychotic drugs,
`
`including risperidone. (Exs.1010, at 1:65-2:3, 2:41; 1002 ¶ 30.) Kino teaches that
`
`such microspheres can be used in aqueous injection solutions that include
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`carboxymethylcellulose. (Exs.1010, at 4:39-41; 1002 ¶ 30.) Kino teaches the
`
`inclusion of wetting agents, such as polysorbate, and tonicity agents, such as
`
`sodium chloride. (Exs.1010, at 38-51; 1002 ¶ 30.) Kino teaches the addition of
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`sorbitol to an injection vehicle. (Exs.1010, at 4:52:55; 1002 ¶ 30.)
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`The Handbook of Pharmaceutical Excipients, 2nd Edition, was published in
`
`1994. The Handbook teaches that polysorbates are wetting agents that can be used
`
`in parenteral suspensions. (Exs.1008, at 376; 1002 ¶ 32.) And the Handbook
`
`teaches that mannitol and sorbitol may be used in injections and can be used to
`
`increase the density of an aqueous solution. (Exs.1008, at 294, 477, 479; 1002
`
`¶ 32.)
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`Case IPR2016- 01096
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-004
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`V. THE ’061 PATENT
`A. The Claims
`Independent claim 1 is directed to a composition that is suitable for injection
`
`through a needle into a host, which includes microparticles with a polymeric
`
`binder, and an injection vehicle. (Exs.1001 cl.1; 1002 ¶34.) 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. (Id.)
`
`Dependent claims 2 and 3 require the addition of a viscosity enhancing
`
`agent, such as sodium carboxymethyl cellulose. (Exs.1001 cls.2-3; 1002 ¶35.)
`
`Dependent claims 4 and 5 require the addition of a density enhancing agent, such
`
`as sorbitol. (Exs.1001 cls.4-5; 1002 ¶35.) Dependent claims 6 and 7 require the
`
`addition of a tonicity adjusting agent, such as sodium chloride. (Exs.1001 cls.6-7;
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`1002 ¶35.) Dependent claims 8 and 9 require the addition of a wetting agent, such
`
`as polysorbate 20, polysorbate 40, or polysorbate 80. (Exs.1001 cls.8-9; 1002 ¶35.)
`
`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. (Exs.1001 cls.10-11; 1002 ¶35.) Dependent claims 12 and 13
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`Case IPR2016- 01096
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`require the addition of a combination of a tonicity adjusting agent and a wetting
`
`agent, such as polysorbate 20, polysorbate 40, or polysorbate 80. (Exs.1001
`
`cls.10-11; 1002 ¶35.) 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. (Exs.1001 cls.17-19; 1002 ¶35.)
`
`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. (Exs.1001 cls.20-21; 1002 ¶35.) 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. (Exs.1001 cls.22-23; 1002 ¶35.)
`
`The Family History Of The ’061 Patent
`B.
`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
`
`No. 6,495,164 (“the ’164 Patent”) on December 17, 2002. (Exs.1015; 1002 ¶ 36.)
`
`The specifications of the ’164 Patent and ’061 Patent are substantially the same.
`
`(Ex.1002 ¶ 36.)
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`
`C. The Specification Of The ’061 Patent
`The
`’061 Patent discloses
`injectable suspensions having
`
`improved
`
`injectability. (Exs.1001 Abstract; 1002 ¶ 37.)
`
`The Background of the Invention admits that adding viscosity enhancers to
`
`injection vehicles was known. (Exs.1001, at 2:25-27; 1002 ¶ 37.) The ’061 Patent
`
`also admits that this was done “in order to retard settling of the particles in the vial
`
`and syringe.” (Exs.1001, at 2:25-27; 1002 ¶ 37.) The ’061 Patent provides an
`
`example of a known formulation of microparticles in an aqueous injectable
`
`suspension. (Ex.1002 ¶ 38.)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.” (Exs.1001,
`
`at 2:34-37; 1002 ¶ 38.) The Background then states that there is a need in the art to
`
`improve the injectability of injectables that include microparticle suspensions.
`
`(Ex.1001, at 2:55-61; 1002 ¶ 38.)
`
`The Summary of the Invention and the Detailed Description describes
`
`different embodiments of the alleged invention. 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; 1002 ¶ 39.) The specification then provides
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`a preferred embodiment for an injection vehicle that includes “3% sodium
`
`carboxymethyl cellulose, 0.9% saline, and 0.1% polysorbate 20.” (Exs.1001,
`
`at 16:64-67; 1002 ¶ 39.) 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. (Exs.1001, at 5:41-17:60; 1002
`
`¶ 39.)
`
`D. The Pertinent Prosecution History Of The ’061 Patent
`The prosecution history of the ’061 Patent is rela