Case IPR2016-01095
`Patent No. 6,667,061
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`
`
`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. IPR2016-01095
`__________________________________________________________________
`
`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
`
`

`

`Case IPR2016- 01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ...................................................................................III
`EXHIBIT LIST ........................................................................................................ iv
`MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1)) ..................................... 1
`I.
`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)) ...... 2
`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)) ......................................... 3
`STATEMENT OF PRECISE RELIEF REQUESTED (37 C.F.R.
`§ 42.22(A)) ...................................................................................................... 3
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 104(B)) .............. 3
`III.
`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
`THE ’061 PATENT .......................................................................................12
`A. The Claims ..............................................................................................12
`B. The Family History Of The ’061 Patent .................................................13
`
`II.
`
`V.
`
`i
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`Case IPR2016- 01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`C. The Specification Of The ’061 Patent ....................................................14
`D. The Pertinent Prosecution History Of The ’061 Patent ..........................15
`VI. PERSON OF SKILL IN THE ART (“POSA”) .............................................17
`VII. CLAIM CONSTRUCTION ..........................................................................18
`A. “Suitable For Injection” ..........................................................................18
`B. “Microparticles” ......................................................................................18
`C. “Injection Vehicle” .................................................................................19
`D. “Suspension” ...........................................................................................19
`E. “Fluid Phase Of Said Suspension” .........................................................20
`F. “Viscosity Greater Than About 20cp And Less Than About 600 cp” ..20
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT AT LEAST ONE
`CLAIM OF THE ’061 PATENT IS UNPATENTABLE .............................21
`A. Ground 1: Claims 1-3, 6-9, 12-13, 17-19, And 22-23 Are Anticipated By
`Goldenheim (Ex.1004) ............................................................................21
`1. Goldenheim Teaches Every Element Of Claims 1-3, 6-9, 12-13,
`17-19, And 22-23 .............................................................................22
`a.
`Claim 1 ...................................................................................22
`b.
`Claims 2-3 ..............................................................................24
`c.
`Claim 6 ...................................................................................25
`d.
`Claim 7 ...................................................................................25
`e.
`Claims 8-9 And 12-13 ...........................................................26
`f.
`Claims 17-19 ..........................................................................26
`g.
`Claims 22-23 ..........................................................................27
`
`ii
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`

`

`Case IPR2016- 01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`2. Claims 1-3, 6-9, 12-13, 17-19, And 22-23 Are Anticipated ............28
`B. Ground 2: Claims 1-3, 6-9, 12-13, And 17-23 Are Obvious Over
`Goldenheim (Ex.1004) In View Of Ramstack (Ex.1005), And The Two
`Pharmacopoeia (Exs.1006 And 1007) ....................................................33
`1. Goldenheim In View Of Ramstack And The Two Pharmacopoeia
`Teaches Every Element Of Claims 1-3, 6-9, 12-13, And 17-23 ....36
`a.
`Claims 1-3, 6-9, 12-13, 17-19, And 22-23 ............................36
`b.
`Claims 20 And 21 ..................................................................37
`2. Claims 1-3, 6-9, 12-13, And 17-23 Are Obvious ............................38
`C. Ground 3: Claims 1-13 And 17-23 Are Obvious Over Goldenheim
`(Ex.1004) In View Of Kino (Ex.1010) And The Two Pharmacopoeia
`(Exs.1006 And 1007) ..............................................................................43
`1. Goldenheim, In View Of Kino And The Two Pharmacopoeia,
`Teaches Every Element Of Claims 1-13 And 17-23 ......................44
`a.
`Claims 1-3, 6-9, 12-13, 17-19, And 22-23 ............................44
`b.
`Claims 4, 5, 10, And 11 .........................................................45
`c.
`Claims 20-21 ..........................................................................47
`2. Claims 1-13 And 17-23 Are Obvious ..............................................48
`IX. SECONDARY CONSIDERATIONS ...........................................................52
`X.
`CONCLUSION ..............................................................................................54
`
`
`
`iii
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`4558102_1.docx
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`

`

`Case IPR2016- 01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`TABLE OF AUTHORITIES
`
`
`CASES
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362, 1369 (Fed. Cir. 2012) ................................................................ 34
`
`Page(s)
`
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 53
`
`In re DBC,
`545 F.3d 1373 (Fed. Cir. 2008) .......................................................................... 53
`
`Graham v. John Deere Co.,
`383 U.S. 1, 17-18 (1966) .................................................................................... 33
`
`J.T. Eaton & Co. v. Atl. Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .......................................................................... 53
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 33, 34
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1373 (Fed. Cir. 2012) .......................................................................... 17
`
`Par Pharm. Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 34, 54
`
`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) .......................................... 17
`
`STATUTES, RULES & OTHER AUTHORITIES
`
`35 U.S.C. § 103(a) ................................................................................................... 33
`
`iv
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`4558102_1.docx
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`

`Case IPR2016- 01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`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
`International Publication No. WO 99/01114 (“Goldenheim”)
`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, 294-98,
`329-330, 375-78, 420-21, 439-42, 477-80, 481-82 (2nd ed. 1994)
`Intentionally left blank
`U.S. Patent No. 5,656,299 (“Kino”)
`Intentionally left blank
`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
`
`4558102_1.docx
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`

`

`Case IPR2016-01095
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-001
`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 as reflected in the USPTO’s
`
`assignment records is owned by Alkermes Pharma Ireland Limited ( “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
`
`IPR2016-01096 seeking cancellation of claims 1-13 and 1-23 on other grounds.
`
`There are no related litigation matters between the parties involving this patent.
`
`
`
`
`
`
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`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`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)
`wmentlik.ipr@lernerdavid.com
`pkochanski@lernerdavid.com
`Postal and Hand-Delivery Address
`Postal and Hand-Delivery Address
`600 South Avenue West
`600 South Avenue West
`Westfield, NJ 07090
`Westfield, NJ 07090
`Tel: 908.654.5000
`Tel: 908.654.5000
`Fax: 908.654.7866
`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.
`
`2
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`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`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
`
`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 requests 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))
`Inter Partes Review (“IPR”) of claims 1-13 and 17-23 of the ’061 Patent is
`
`requested on the three 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
`
`3
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`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`field of formulations
`involving risperidone microparticles, pharmaceutics,
`
`parenteral dosage form design, microparticles, sustained release delivery systems,
`
`and pharmaceutical patents, among others. (Ex.1002 ¶¶ 4-7.)
`
`Ground
`
`References
`
`Basis
`
`Claims
`
`Goldenheim (Ex.1004)
`
`§ 102
`
`1
`
`2
`
`3
`
`Goldenheim (Ex.1004) in view of
`Ramstack (Ex.1005), the U.S.
`Pharmacopeia (Ex.1006), and the
`European Pharmacopoeia (Ex.1007)
`Goldenheim (Ex.1004) in view of
`Kino (Ex.1010), U.S. Pharmacopeia
`(Ex.1006), and the European
`Pharmacopoeia (Ex.1007)
`
`1-3,
`6-9,12-13,
`17-19, and
`22-23
`
`1-3,
`6-9,12-13,
`and 17-23
`
`§ 103
`
`§ 103
`
`1-13 and
`17-23
`
`In Ground 1, Petitioners show that claims 1-3, 6-9, 12-13, 17-19, and 22-23
`
`are anticipated by International Publication No. WO 99/01114 to Goldenheim et al.
`
`(“Goldenheim”) (Ex.1004).
`
`If not anticipated by Goldenheim, claims 1-3, 6-9, 12-13, 17-19, and 22-23
`
`are obvious. In Ground 2, Petitioners show that claims 1-3, 6-9, 12-13, and 17-23
`
`are unpatentable over Goldenheim (Ex.1004) in view of International Publication
`
`4
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`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`to Ramstack et al.
`No. WO 95/13799
`
`(“Ramstack”)
`
`(Ex.1005),
`
`the U.S.
`
`Pharmacopeia (Ex.1006) and the European Phamacopoeia (Ex.1007), which
`
`together disclosed the claimed subject matter more than one year before Patent
`
`Owner filed its patent application.
`
`In Ground 3, Petitioners show that claims 1-13 and 17-23 are unpatentable
`
`over Goldenheim (Ex.1004) in view of U.S. Patent No. 5,656,299 to Kino et al.
`
`(“Kino”) (Ex.1010), the U.S. Pharmacopeia (Ex.1006) and the European
`
`Phamacopoeia (Ex.1007), which together disclosed the claimed subject matter
`
`more than one year before Patent Owner filed its patent application..
`
`Although Petitioner provides multiple grounds of unpatentability, they are
`
`meaningfully distinct. Ground 1 is meaningfully distinct from Grounds 2 and 3
`
`because Ground 1 is an anticipation argument. Further, Ground 2 and Ground 3 do
`
`not apply to all of the same claims and rely upon different 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 IPR2016-01096.
`
`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
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`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`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.)
`
`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 microparticles. (Exs.1005, at 35:1-36:26,
`
`Examples 2, 3; 1002 ¶ 16.) Nor did Patent Owner invent viscosity enhancing
`
`agents or new injection vehicles. (Exs.1004, at 52:25-30; 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
`
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`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`well-known elements to arrive at a known concentration and viscosity for an
`
`injectable composition.
`
`(Exs.1004, at 35:10-12; 1002 ¶ 16.)
`
`Injecting a
`
`microparticle suspension through an 18-22 gauge needle was also known in the
`
`prior art, together with knowledge of injectable viscosities greater than about 20cp
`
`at 20°C. (Exs.1004, at 35:10-12, 41:18-19; 1002 ¶ 16.) Accordingly, Petitioners
`
`request institution of an IPR of claims 1-13 and 17-23 of the ’061 Patent.
`
`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.) It was also known that suitable
`
`injectable suspensions should be sterile, stable, suspendable, injectcable, and
`
`isotonic. (Exs.1014, at 285; 1001, at 1:17-25; 1002 ¶ 18.) The solid phase of the
`
`suspension may 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.)
`
`Suspensions suitable for injection 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
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`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`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; 1002 ¶ 19.)
`
`“Injectable” refers to how the suspension performs during the actual injection of
`
`the composition. (Exs.1014, at 299; 1001, at 1:61-64; 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 1:61-64; 1002
`
`¶¶ 19.)
`
`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
`
`8
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`

`

`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`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.)
`
`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
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`enhancing or suspending agent. Sodium carboxymethylcellulose (CMC) is one of
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`Case IPR2016-
`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`the most commonly used suspending and viscosity enhancing agents. (Exs.1008,
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`at 78-81; 1022, at 305; 1002 ¶ 26.)
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`Goldenheim teaches a sustained release formulation that includes polymer
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`microparticles in a suspension suitable for injection. (Exs.1004 Abstract; 1002
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`¶ 27.) Goldenheim further teaches that such formulations can be used for any
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`known active pharmaceutical ingredient. (Exs.1004, at 13:22-30; 1002 ¶ 27.)
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`Goldenheim also teaches incorporating a viscosity enhancing agent (Exs.1004, at
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`52:27-28; 1002 ¶ 27), a tonicity agent (Exs.1004, at 8:16-17; 1002 ¶ 27) and a
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`wetting agent (Exs.1004, at 47:30-32; 1002 ¶ 27) into such formulations.
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`Goldenheim teaches a concentration of microparticles that can be greater than 30
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`mg/ml. (Exs.1004, at 54:1-12, Table 4; 1002 ¶ 27.) Goldenheim in addition 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. (Exs.1004, at 35:12; 1002 ¶ 27.)
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`Finally, Goldenheim also discloses compositions suitable for injection through a 22
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`gauge needle. (Exs.1004, at 41:17-19; 1002 ¶ 27.)
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`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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`(Exs.1005 Abstract, 35:1-36:26; 1002 ¶ 28.) Ramstack teaches that a polymer, such
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`as dl (polylactide-co-glycolide), may be used for encapsulating risperidone.
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`Attorney Docket No. 9LUYE 7.1R-001
`(Exs.1005,
`at 5:19-22, 35:1-36:26, Examples 2, 3; 1002
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`¶ 28.) The
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`poly(lactide-co-glycolide) may have a molar ratio of lactide to glycolide in a range
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`of 85:15 to 50:50. (Exs.1005, at 5:19-22, 16:28-31, 35:1-36:26 Examples 2 and 3;
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`1002 ¶ 28.) Additional polymer materials useful for encapsulation may include
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`poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the
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`foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,
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`polydioxonene,
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`poly(ortho
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`carbonates),
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`poly(acetals),
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`poly(lactic
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`acidcaprolactone),
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`polyorthoesters,
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`poly(glycolic
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`acid-caprolactone),
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`polyanhydrides, polyphosphazines, and natural polymers including albumin,
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`casein, and waxes. (Exs.1005, at 16:7-13; 1002 ¶ 28.) Ramstack teaches an
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`aqueous injection vehicle that includes CMC, mannitol, and polysorbate.
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`(Exs.1005, at 37:6-7; 1002 ¶ 28.)
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`The U.S. Pharmacopeia teaches that viscosity is typically measured at about
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`25°C and that viscosity decreases as temperature increases. (Exs.1006, at 275,
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`1840; 1002 ¶ 29.) The European Pharmacopoeia teaches that viscosity is typically
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`measured at about 20°C. (Ex.1007; 1002 ¶ 29.)
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`Kino teaches sustained release microspheres of antipsychotic drugs,
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`including risperidone. (Exs.1010, at 1:65-2:4, 2:38-41; 1002 ¶ 30.) Kino teaches
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`that such microspheres can be used in aqueous injection solutions. (Exs.1010,
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`Attorney Docket No. 9LUYE 7.1R-001
`at 4:38-40; 1002 ¶ 30.) Kino also teaches the inclusion of carboxymethylcellulose,
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`a viscosity enhancing agent, polysorbate, a wetting agent, and sodium chloride, a
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`tonicity agent. (Exs.1010, at 4:38-51; 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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`V. THE ’061 PATENT
`A. The Claims
`Independent claim 1 is directed to a composition that is suitable for injection
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`through a needle into a host, which includes microparticles with a polymeric
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`binder, and an injection vehicle. (Exs.1001 cl.1; 1002 ¶ 33.) 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. (Exs.1001 cl.1; 1002 ¶ 33)
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`Dependent claims 2 and 3 require the addition of a viscosity enhancing
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`agent, such as sodium carboxymethyl cellulose. (Exs.1001 cls.2-3, 1002 ¶ 34.)
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`Dependent claims 4 and 5 require the addition of a density enhancing agent, such
`
`as sorbitol. (Exs.1001 cls.4-5, 1002 ¶ 34.) Dependent claims 6 and 7 require the
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`addition of a tonicity adjusting agent, such as sodium chloride. (Exs.1001 cls.6-7,
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`1002 ¶ 34.) Dependent claims 8 and 9 require the addition of a wetting agent, such
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`as polysorbate 20, polysorbate 40, or polysorbate 80. (Exs.1001 cls.8-9, 1002
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`Petition for Inter Partes Review
`Attorney Docket No. 9LUYE 7.1R-001
`¶ 34.) Dependent claims 10 and 11 require the addition of a combination of a
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`density enhancing agent and a wetting agent, such as polysorbate 20, polysorbate
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`40, or polysorbate 80. (Exs.1001 cls.10-11, 1002 ¶ 34.) Dependent claims 12 and
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`13 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. (Exs.1001
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`cls.12-13, 1002 ¶ 34.) Dependent claims 17, 18, and 19 require the microparticle to
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`include an active agent encapsulated with a polymeric binder, such as
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`poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the
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`range of from about 85:15 to about 50:50. (Exs.1001 cls.2-3, 1002 ¶ 34.)
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`Dependent claims 20 and 21 require the active agent of claim 17 and 19,
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`respectively, to be risperidone, 9-hydroxyrisperidone, or a pharmaceutically
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`acceptable salt. (Exs.1001 cls.20-21, 1002 ¶ 34.) 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. (Exs.1001 cls.22-23, 1002 ¶ 34.)
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`The Family History Of The ’061 Patent
`B.
`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. (Exs. 1002 ¶ 35; 1015.)
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`Attorney Docket No. 9LUYE 7.1R-001
`The specifications of the ’164 Patent and ’061 Patent are substantially the same
`
`(Ex.1002 ¶ 35.)
`
`C. The Specification Of The ’061 Patent
`The
`’061 Patent discloses
`injectable suspensions having
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`improved
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`injectability. (Exs.1001 Abstract; 1002 ¶ 36.)
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`The Background of the Invention admits that adding viscosity enhancers to
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`injection vehicles was known. (Exs.1001, at 2:25-27; 1002 ¶ 36.) The ’061 Patent
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`also admits that this was done “in order to retard settling of the particles in the vial
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`and syringe.” (Exs.1001, at 2:25-27; 1002 ¶ 36.) The ’061 Patent provides an
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`example of known injectable pharmaceuticals. (Ex.1002 ¶ 37.) For example, the
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`’061 Patent admits that “[t]he fluid phase of a suspension of Decapeptyl . . . mean
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`particle size of 40 µm . . . when prepared as directed, has a viscosity of
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`approximately 19.7 cp.” (Exs.1001, at 2:34-37; 1002 ¶ 37.) The Background then
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`states that there is a need in the art to improve the injectability of injectables that
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`include microparticle suspensions. (Ex.1001, at 2:55-61; 1002 ¶ 37.)
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`The Summary of the Invention and the Detailed Description sections provide
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`different embodiments of the alleged invention. (Exs.1001 2:63-5:40; 1002 ¶ 38.)
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`The Method and Examples section provides various studies, such as an in vitro test
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`study, animal studies, ex vivo injectability tests, and methods of preparing the
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`injectable compositions. (Exs.1001, at 5:41-17:60; 1002 ¶ 38.)
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`Attorney Docket No. 9LUYE 7.1R-001
`D. The Pertinent Prosecution History Of The ’061 Patent
`The prosecution history of the ’061 Patent is relatively brief. The only
`
`pertinent portion of the petition is that the Examiner issued a nonfinal office action
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`on April 9, 2003, which rejected claims 1-21 and 41-42 under 35 U.S.C. § 103 as
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`being unpatentable over U.S. Patent No. 5,656,299 to Kino et al. and further in
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`view of U.S. Patent No. 5,540,912 to Roorda et al. (Exs.1016; 1002 ¶ 39)
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`In regards to Kino, the Examiner stated that Kino disclosed sustained release
`
`microsphere preparations of antipsychotic drugs that are suitable for injection.
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`(Exs.1016, at 3; 1002 ¶ 40.) 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 600cp,” it
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`would have been obvious “to determine the optimal viscosity for application.”
`
`(Exs.1016, at 4; 1002 ¶ 40.) According to the Examiner:
`
`Both