Paper No. 33
`Date Filed: March 8, 2017
`
`Filed On Behalf Of:
`
`Alkermes Pharma Ireland Limited and
`Alkermes Controlled Therapeutics, Inc.
`
`By:
`
`Scott K. Reed
`sreed@fchs.com
`212-218-2100
`
`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 and ALKERMES CONTROLLED
`THERAPEUTICS, INC.,
`Patent Owners.
`________________
`
`Case IPR2016-01096
`U.S. Patent No. 6,667,061
`________________
`
`PATENT OWNERS’ RESPONSE
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ...........................................................................................1
`
`BACKGROUND .............................................................................................4
`
`A.
`
`B.
`
`C.
`
`D.
`
`Overview of the ’061 Patent..................................................................5
`
`A Person of Ordinary Skill in the Art (“POSA”)..................................8
`
`The Claims of the ’061 Patent...............................................................8
`
`The Prosecution History......................................................................10
`
`III. CLAIM CONSTRUCTION ..........................................................................13
`
`IV.
`
`THE BOARD SHOULD FIND THAT ALL OF THE CLAIMS
`ARE PATENTABLE AND NONOBVIOUS ...............................................14
`
`A.
`
`The Board Should Find All Challenged Claims Remain
`Patentable Under Ground 1.................................................................14
`
`1.
`
`Overview of Ground 1 References ...........................................15
`
`a.
`
`b.
`
`Johnson ...........................................................................15
`
`Kino ................................................................................15
`
`2.
`
`Petitioners Fail to Establish that the Johnson
`Vehicle Inherently Has a Viscosity Within the
`Claimed Range..........................................................................16
`
`a.
`
`b.
`
`c.
`
`Testing Shows the Johnson Vehicle Falls
`Outside the Claimed Range ............................................18
`
`Petitioners Fail to Establish that CMC Alone
`is the Viscosity-Controlling Component of
`the Johnson Vehicle........................................................18
`
`Petitioners Fail to Account for the Wide
`Variety of Commercially Available Types
`and Grades of CMC........................................................20
`
`i
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`d.
`
`Petitioners Fail to Account for Many Other
`Factors that Impact Viscosity .........................................24
`
`3.
`
`Petitioners’ Ground 1 Challenge to Dependent
`Claims 4, 5, 10 and 11 Fails for Additional
`Reasons .....................................................................................28
`
`a.
`
`b.
`
`Petitioners Have Failed to Show a POSA
`Would Have Inserted the “Filler” of Kino
`into the Vehicle of Johnson to Arrive at
`Claims 4 and 5 ................................................................30
`
`Petitioners Have Failed to Show a POSA
`Would Have Inserted the “Polysorbate 80”
`Disclosure of Kino into the Vehicle of
`Johnson to Arrive at Claims 10 and 11 ..........................32
`
`B.
`
`The Board Should Find All Challenged Claims Remain
`Patentable Under Ground 2.................................................................34
`
`1.
`
`Overview of Ground 2 References ...........................................35
`
`2.
`
`3.
`
`4.
`
`a.
`
`b.
`
`c.
`
`Gustafsson.......................................................................35
`
`Ramstack.........................................................................36
`
`The Handbook ................................................................37
`
`Testing Shows the Gustafsson Vehicle Falls
`Outside the Claimed Range ......................................................37
`
`Petitioners Fail to Establish that the Gustafsson
`Vehicle Inherently Discloses a Viscosity Within
`the Claimed Range....................................................................37
`
`Ground 2 also Fails Because Petitioners Fail to
`Identify “Microparticles Comprising a Polymeric
`Binder” and Gustafsson Teaches Away from Them ................39
`
`a.
`
`Gustafsson Teaches Away from the
`Microparticles of the ’061 Patent ...................................40
`
`ii
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`b.
`
`Gustafsson Also Teaches Away From the
`PLGA- Microparticles of Claims 18, 19 and
`21 ....................................................................................42
`
`5.
`
`Petitioners’ Challenge to Claims 20-21 Fails for
`Additional Reasons ...................................................................44
`
`a. Whether Gustafsson Could be Combined
`with Ramstack is Not Legally Relevant .........................46
`
`b.
`
`c.
`
`d.
`
`Petitioners Have No Evidence of
`Obviousness for Claims 20 and 21.................................47
`
`A POSA Would Not Have Selected
`Gustafsson in Developing Microparticles for
`Delivering Risperidone...................................................49
`
`A POSA Would Not Have Had Any Reason
`to Combine Gustafsson and Ramstack...........................52
`
`6.
`
`Petitioners’ Challenge to Dependent Claims 8, 9,
`12 and 13 Fails for Additional Reasons....................................57
`
`V.
`
`OBJECTIVE INDICIA OF NON-OBVIOUSNESS.....................................59
`
`VI. CONCLUSION..............................................................................................62
`
`iii
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`TABLE OF AUTHORITIES
`
`Cases
`Apple, Inc. v. ITC, 725 F.3d 1356 (Fed. Cir. 2013).................................................59
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc., 725 F.3d 1341
`(Fed. Cir. 2013)..............................................................................................29
`
`Continental Can Co. U.S.A. v. Monsanto Co., 948 F.2d 1264 (Fed. Cir.
`1991) ....................................................................................................... 17, 38
`
`Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361 (Fed. Cir. 2000).................49
`
`Eisai Co. Ltd. v. Dr. Reddy's Labs., Ltd, 533 F.3d 1353 (Fed. Cir. 2008)..............53
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig., 676 F.3d 1063 (Fed. Cir. 2012)...........................................................60
`
`In re Dembiczak, 175 F.3d 994 (Fed. Cir. 1999).....................................................48
`
`In re Fine, 837 F.2d 1071 (Fed. Cir. 1988) .............................................................47
`
`In re Gordon, 733 F.2d 900 (Fed. Cir. 1984) ..........................................................46
`
`In re Kahn, 441 F.3d 977 (Fed. Cir. 2006) ..............................................................47
`
`In re Magnum Oil Tools Int'l, Ltd., 829 F.3d 1364 (Fed. Cir. 2016).......................47
`
`In re Sang Su Lee, 277 F.3d 1338 (Fed. Cir. 2002).................................................49
`
`InTouch Techs., Inc. v. VGO Communications, Inc., 751 F.3d 1327 (Fed.
`Cir. 2014).......................................................................................................46
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342 (Fed. Cir.
`2012) ..............................................................................................................47
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ......................................... 47, 48
`
`Leo Pharm. Prods. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013)............................. 52, 54
`
`Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ...........................18
`
`iv
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`Merck Sharp & Dohme Corp. v. Hospira Inc., No. 14-915, 2016 WL
`8231143 (D.Del. Oct. 7, 2016) ......................................................................61
`
`Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186 (Fed. Cir. 2014) ... 16, 17, 38
`
`PersonalWeb Techs., LLC v. Apple, Inc., No. 2016-1174, 2017 U.S. App.
`LEXIS 2544 (Fed. Cir. 2017) ........................................................................46
`
`Transocean Offshore Deepwater Drilling Inc. v. Maersk Drilling USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .....................................................................60
`
`Rules and Statutes
`
`35 U.S.C. § 103............................................................................................... 2, 4, 14
`
`37 C.F.R. § 42.65 .............................................................................................. 19, 48
`
`65 Fed. Reg. 83,041 (Dec. 29, 2000).......................................................................62
`
`Patent Trial and Appeal Board Cases
`Avaya Inc. v. Network-1 Security Solutions, Inc., IPR No. 2013-00071,
`Paper 103 (P.T.A.B. May 22, 2014)..............................................................17
`
`Coalition for Affordable Drugs VII LLC v. Pozen Inc., IPR No. 2015-01718,
`Paper 40 (P.T.A.B. Feb. 21, 2017) ................................................................60
`
`Johns Manville Corp. v. Knauf Insulation, Inc., IPR No. 2015-01633, Paper
`10 (P.T.A.B. Jan. 4, 2016)...................................................................... 19, 48
`
`v
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`I.
`
`INTRODUCTION
`
`U.S. Patent No. 6,667,061 (“the ’061 patent”) “relates to injectable
`
`suspensions having improved injectability, and to methods for the preparation of
`
`such injectable suspensions.” (Exh. 1001 at 1:11-14.) Prior to the invention that
`
`led to the ’061 patent, it was widely believed that the viscosity of the injection
`
`vehicle should be kept low in order to overcome injectability problems. (Id. at
`
`2:26-54, 4:60-62; Exh. 2016 at 96:19-97-1; Exh. 2014 at ¶¶ 32-33, 57, 84, 157; see
`
`also Exh. 1014 at 287, 298-99.) Because of their larger particle size and higher
`
`solid concentration, keeping viscosity low was believed to be particularly
`
`important for suspensions containing microparticles. (Exh. 1001 at 2:41-54; Exh.
`
`2014 at ¶ 31.) Contrary to this conventional wisdom, the invention of the ’061
`
`patent overcame injectability problems by “increasing [rather than decreasing] the
`
`viscosity of the fluid phase of [the] injectable suspension.” (Exh. 1001 at 4:57-60
`
`(emphasis added).) The inventors’ solution to these problems allowed for the
`
`commercialization of highly successful injectable medications including
`
`Risperdal® Consta®, a long-acting injection of risperidone microparticles used to
`
`treat schizophrenia.1
`
`1 Risperdal® Consta® is a successful product. Risperdal® Consta® had $893 million
`
`in sales in 2016. (Exh. 2049 at 10.)
`
`1
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`Petitioners requested inter partes review (“IPR”) of claims 1-13 and 17-23
`
`of the ’061 patent based on two grounds under 35 U.S.C. § 103. Under both
`
`grounds, Petitioners admit, and the Board recognized, that the claimed viscosity
`
`limitation is not expressly disclosed in the cited art. (Petition at 25, 39; Institution
`
`Decision at 9-10, 23.) Nevertheless, Petitioners argue that the injection vehicle
`
`formulations disclosed in the primary references of both grounds, Johnson and
`
`Gustafsson, would inherently have viscosities between 20 cp and 600 cp at 20ºC as
`
`claimed in the ’061 patent. (Petition at 25-26, 39-40.) Petitioners have failed,
`
`however, to satisfy the high burden to establish inherency for the claimed viscosity
`
`limitation. Petitioners have failed to show that the viscosity of the injection
`
`vehicles of Johnson and Gustafsson can be determined based only on the
`
`concentration of carboxymethyl cellulose (“CMC”) in the vehicle. Petitioners have
`
`also failed to establish that the type or grade of CMC used in the Johnson or
`
`Gustafsson vehicles would necessarily have achieved the claimed viscosity, or that
`
`the additional ingredients and method of preparing the vehicles would not have
`
`caused the viscosity to fall outside the claimed range. Nor could they have.
`
`Johnson and Gustafsson provide insufficient information to ascertain the viscosity
`
`of their vehicles or to determine that it necessarily falls within the claimed range,
`
`and there is evidence showing that, using certain CMCs, the viscosity would fall
`
`outside the claimed range. Moreover, the references provide no teaching that
`
`2
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`would suggest selection of a viscosity within the claimed range, particularly where
`
`conventional wisdom at the time suggested against increasing viscosity.
`
`Petitioners’ challenge to the ’061 patent based on Gustafsson fails for an
`
`additional and independent reason. Gustafsson teaches away from the invention
`
`claimed in the ’061 patent: its coated microparticles do not meet the definition of
`
`microparticles in the ’061 patent. Gustafsson also expressly teaches away from
`
`encapsulating active substances in a polymeric binder and in a poly(d,l-lactide-co-
`
`glycolide) (“PLGA”) polymer in particular.
`
`Additionally, with respect to Petitioners’ reliance on the combination of
`
`Johnson and Kino, and the combination of Gustafsson and Ramstack, in order to
`
`challenge various dependent claims, Petitioners fail to explain why a POSA would
`
`have combined the references, much less particular components of the references,
`
`to arrive at the claimed invention. At most, Petitioners assert that the references
`
`could be combined, which is legally irrelevant to an obviousness analysis. All the
`
`combinations are a product of hindsight using the claimed invention as a guide to
`
`pluck components from the references. For example, there is no reason, other than
`
`hindsight, that a POSA would have plucked risperidone microparticles formed with
`
`a PLGA binder from Ramstack and inserted them into the injection vehicle of
`
`Gustafsson, which expressly teaches away from such microparticles, to arrive at
`
`claims 20 and 21 of the ’061 patent.
`
`3
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`Finally, any showing of obviousness is overcome by compelling evidence of
`
`objective indicia of non-obviousness such as the unexpected nature of the claimed
`
`invention and the market entry and subsequent commercial success of Risperdal®
`
`Consta®.
`
`For at least these reasons, Petitioners have failed to show that any challenged
`
`claim of the ’061 patent is unpatentable under 35 U.S.C. § 103.
`
`II.
`
`BACKGROUND
`
`Injectability, or the performance of a formulation during injection, is a
`
`critical performance parameter of injectable suspensions. (Exh. 1001 at 1:39-64;
`
`Exh. 2014 at ¶¶ 29-30.) It includes factors such as the pressure or force required
`
`for injection, evenness of flow and freedom from clogging. (Exh. 1001 at 1:39-
`
`64.) In order to be effective, pharmaceutically acceptable, and commercially
`
`viable, a suspension must achieve a certain level of injectability. (Id.) Indeed, too
`
`many injectability failures can directly impact the commercial viability of a
`
`product or even block its commercial entry entirely. Furthermore, issues related to
`
`injectability, like pain at the injection site, can influence a patient’s compliance.
`
`(See Exh. 2050 at 922.)
`
`Before the invention of the ’061 patent, many injectable suspensions,
`
`particularly those containing microparticles, were susceptible to injectability
`
`4
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`problems. (Exh. 1001 at 2:41-61; Exh. 2014 at ¶ 31.) Conventional wisdom, at
`
`that time, was to keep viscosity of injectable suspensions low in order to make
`
`suspensions easier to inject. (Exh. 1001 at 2:26-54, 4:60-62; Exh. 1014 at 287,
`
`298-99; Exh. 2014 at ¶¶ 32-33, 57, 84, 157.) Dr. Patrick DeLuca, Petitioners’
`
`declarant, also admitted the same:
`
`In the injectables, you try to keep the viscosity as low as
`possible or low enough to be injected. Because the more
`materials you add to the parenteral, then you're going to
`increase the viscosity, because of more viscous that then
`you do -- you get to a point where it becomes difficult to
`push the plunger and get the -- the suspension through
`the needle.
`
`(Exh. 2016 at 96:19-97:2; see also id. at 98:9-14 (“The goal is not to use a
`
`viscosity-enhancing agent or to . . . enhance the viscosity”.) Surprisingly, the
`
`invention of the ’061 patent addressed injectability problems by increasing the
`
`viscosity of injectable microparticle compositions. (Exh. 1001 at 4:57-60; Exh.
`
`2014 at ¶ 33.)
`
`A.
`
`Overview of the ’061 Patent
`
`The ’061 patent specification describes a series of tests to evaluate
`
`injectability and determine the key factors affecting injectability. (Exh. 1001 at
`
`Examples 2-4.) These tests included measuring the viscosity of different
`
`5
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`formulations including formulations comprising varying amounts of CMC,
`
`sorbitol, saline, and polysorbate 20 (also called Tween® 20). (Id. at Example 3,
`
`Tables 4 and 5.) The tests show the importance of the viscosity limitation to the
`
`invention because they demonstrated that “injectability [was] improved, and in
`
`vivo injectability failures [were] significantly and unexpectedly reduced, by
`
`increasing the viscosity of the fluid phase of an injectable suspension.” (Id. at
`
`4:47-60, Examples 1-4.) The inventors concluded that “[v]iscosities of at least
`
`about 20 cp are necessary for successful and medically acceptable injectability
`
`rates” and that viscosities of up to about 600 cp could be used in the invention. (Id.
`
`at 10:64-65, Examples 3-4.)
`
`This was in direct contrast to “conventional teachings that an increase in the
`
`viscosity hinders injectability and syringeability.” (Id. at 4:60-62; see also Exh.
`
`2016 at 96:19-97:2; Exh. 1014 at 33 (“Increases in the following characteristics
`
`tend to reduce syringeability or make material transfer through the needle more
`
`difficult: [t]he viscosity of the vehicle . . . Probably the most important of these
`
`factors is viscosity.”), 287 (“[M]ost parenteral suspensions are usually dilute and
`
`have practical limitations for viscosity because of syringeability and injectability
`
`constraints.”), 299 (“Increase in the viscosity, density, particle size, and
`
`concentration of solids in suspension hinders the syringeability of suspension.”),
`
`Therefore, the conventional wisdom was to keep viscosity of injectable
`
`6
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`suspensions low in order to make suspensions easier to inject. (Exh. 1001 at 2:26-
`
`54, 4:60-62; Exh. 1014 at 287, 298-99; Exh. 2014 at ¶¶ 32-33, 57, 84, 157; Exh.
`
`2016 at 96:19-97:2.) Even the in vitro studies conducted by the inventors
`
`supported the conventional wisdom. (Exh. 1001 at Example 1.) But the inventors’
`
`in vivo injectability studies showed “a dramatic improvement in injectability with
`
`increased injection vehicle viscosity.” (Id. at 7:38-40; see also id. at Examples 2-
`
`3.) The in vivo studies also revealed that including a density enhancing agent, such
`
`as sorbitol, in the injection vehicle may improve injectability. (Id. at 11:1-11.)
`
`The injectable formulations of the ’061 patent also require specific
`
`microparticles. The patent defines “microparticles” as “particles that contain an
`
`active agent or other substance dispersed or dissolved within a polymer that serves
`
`as a matrix or binder of the particle.” (Id. at 5:15-18.) The patent therefore
`
`employs a matrix-type—as opposed to the reservoir form—of drug delivery
`
`system. (Exh. 2054 at ¶¶ 30-31, 66, 73.) In matrix systems, the active agent is
`
`dispersed or dissolved throughout the polymer material. (Id. at ¶¶ 30, 68, 74.) As
`
`a “matrix or binder,” the polymer encapsulates the active agent and is intimately
`
`associated with it as opposed to providing a polymer film on the outside of a drug
`
`core as in a reservoir system. (Id. at ¶¶ 30, 32, 33, 44, 66, 84.) In the patent
`
`examples, the active agent is dispersed in a PLGA polymeric matrix using organic
`
`solvent. (Id. at ¶ 30; Exh. 1001 at 17:4-59.)
`
`7
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`B.
`
`A Person of Ordinary Skill in the Art (“POSA”)
`
`The ’061 patent “relates to injectable suspensions having improved
`
`injectability, and to methods for the preparation of such injectable suspensions.”
`
`(Exh. 1001 at 1:11-14.) In particular, the injectable compositions of the ’061
`
`patent comprise microparticles suspended at a particular concentration in an
`
`injection vehicle, wherein the fluid phase of such compositions has a particular
`
`viscosity when measured at 20ºC. (See, e.g., id. at claim 1.) As such, a POSA
`
`would have a bachelor’s degree in one of the following fields: pharmaceutical
`
`formulation, chemistry, polymer science, or a related field, and one or two years of
`
`industry training or experience in those field(s). (Exh. 2014 at ¶ 21; Exh. 2054 at ¶
`
`27.)
`
`The challenged claims are patentable under either Patent Owners’ or
`
`Petitioners’ definition.
`
`C.
`
`The Claims of the ’061 Patent
`
`Claim 1, the sole independent claim of the ’061 patent, recites:
`
`1. A composition suitable for injection through a needle into a host,
`comprising:
`microparticles comprising a polymeric binder; and
`
`an injection vehicle, wherein said microparticles are
`suspended in said injection vehicle at a
`concentration of greater than about 30 mg/ml to
`
`8
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`form a suspension, wherein a fluid phase of said
`suspension has a viscosity greater than about 20 cp
`and less than about 600 cp at 20º C, wherein the
`viscosity of said fluid phase of said suspension
`provides injectability of the composition through a
`needle ranging in diameter from 18-22 gauge.
`
`All other claims of the ’061 patent depend from claim 1. All the claims,
`
`therefore, require a particular viscosity for improved injectability and
`
`microparticles. While some of the claims of the ’061 patent recite particular
`
`components of the composition, none of the claims of the ’061 patent recite a
`
`specific formulation for the injection vehicle required to practice the invention.
`
`Instead, the claims are directed to formulations where the fluid phase has a
`
`viscosity that achieves improved injectability. It was precisely this discovery of
`
`the relationship between injectability and viscosity that forms the crux of the
`
`invention. Thus, in order to show that any challenged claim is obvious over the
`
`prior art, Petitioners must show that the formulations disclosed in Johnson or
`
`Gustafsson necessarily and always have viscosities within the claimed range.
`
`Petitioners fail to show that the dependent claims are obvious for additional
`
`reasons.
`
`9
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`D.
`
`The Prosecution History
`
`The ’061 patent issued on December 23, 2003 from U.S. Patent Application
`
`No. 10/259,949, which was filed on September 30, 2002 as a continuation of U.S.
`
`Patent Application No. 09/577,875 (“the ’875 application,” Exh. 2053). The ’875
`
`application was filed on May 25, 2000 and issued as U.S. Patent No. 6,495,164 on
`
`December 17, 2002.
`
`During prosecution, the Examiner considered multiple prior art references
`
`including Kino (cited in Ground 1) and Ramstack (cited in Ground 2). (See, e.g.,
`
`Exh. 1001 at References Cited.) The Examiner rejected pending claims over Kino
`
`for obviousness stating that, although “Kino does not disclose the viscosity to be
`
`greater than about 60 cp and less than about 600 cp . . . absent unexpected results
`
`regarding the criticality of viscosity, Kino discloses all the limitations of the instant
`
`claims.” (Exh. 1016 at 4.)
`
`In response to the rejection, the Applicants submitted the declaration of
`
`Mark Tracy, Ph.D. (“the Tracy Declaration”).1 Dr. Tracy explained that Kino
`
`“does not provide any information about injectability, or the relationship between
`
`injectability and viscosity of the injection vehicle.” (Exh. 1018 at ¶ 3.) The
`
`1 The Tracy Declaration was originally filed during the prosecution of the ’875
`
`application.
`
`10
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`Applicants also pointed to portions of the application’s specification to support a
`
`showing of the criticality of viscosity. (Exh. 1017 at 3-4.)
`
`Dr. Tracy also explained that Test Examples 1, 3 and 4 of Kino use
`
`physiological saline as the injection vehicle and that the viscosity of saline alone is
`
`approximately 1 cp at 20º C. (Exh. 1018 at ¶ 4.) As to the remaining example
`
`(Test Example 2), which used a 0.5% CMC solution isotonized with mannitol as
`
`the injection vehicle, Dr. Tracy explained that “CMC is the viscosity-controlling
`
`component of the injection vehicle of Test Example 2.” (Id. 1018 at ¶ 5 (emphasis
`
`added); Exh. 1010 at 6:29-31.) Dr. Tracy based his conclusion on the viscosity
`
`measurements of two vehicle formulations disclosed in the ’875 application (which
`
`comprise CMC, sorbitol and 0.2% Tween® 20) where CMC was also the viscosity-
`
`controlling component. (Exh. 1018 at ¶ 5.) Dr. Tracy then found that “the
`
`viscosity of the CMC injection vehicle as the fluid phase of a suspension
`
`containing the microspheres of Test Example 2 of the Kino patent is less than 7 cp
`
`at 20ºC.” (Id.) Table 1 summarizes the information Dr. Tracy relied upon in
`
`reaching his conclusions regarding Kino Test Example 2.
`
`11
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`Table 1: Vehicles of the ’875 Application and Kino Test Example 2
`’875 Application
`’875 Application
`Kino Test Example 2
`(Formula 1)
`(Formula 2)
`
`1.5% by volume CMC,
`30% by volume sorbitol,
`0.2% by volume Tween
`20
`
`0.75% by volume CMC,
`15% by volume sorbitol,
`0.2% by volume Tween
`20
`
`0.5% CMC isotonized
`with mannitol
`
`Viscosity: 27 cp at 20ºC
`
`Viscosity: 7 cp at 20ºC
`
`No viscosity disclosed.
`
`(Exh. 2053 at 12:10-14.)
`
`(Exh. 2053 at 12:14-17.)
`
`(Exh. 1010 at 6:29-31.)
`
`Because Kino did not disclose the viscosity of its Test Example 2, in order to
`
`make a comparison between Kino Test Example 2 and the ’875 application, Dr.
`
`Tracy had to assume that the Kino CMC was the same as that used in the ’875
`
`application. (Exh. 2014 at ¶¶ 83-85; see also Exh. 2016 at 176:2-24.) Under that
`
`assumption, and consistent with the conventional teachings that an increase in
`
`viscosity hinders injectability, the conclusion was that the viscosity of Kino Test
`
`Example 2 was far below the claimed viscosity range of the ’061 patent. That
`
`assumption and conclusion were also consistent with Kino’s use of physiological
`
`saline alone in three of the four exemplified vehicles, all of which had a viscosity
`
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`Paper No. 33
`Date Filed: March 8, 2017
`
`of 1 cp—far below the claimed viscosity range. (Exh. 1010 at 6:19, 6:43-44, 7:8-
`
`9; Exh. 2014 at ¶¶ 78-85.)2
`
`Because Kino Test Example 2 and the particular formulations of the ’875
`
`application that Dr. Tracy considered do not contain sodium chloride or 1%
`
`polysorbate 20, Dr. Tracy did not comment on the impact of sodium chloride or
`
`1% polysorbate 20 on the viscosity of a vehicle with CMC. (Exh. 2014 at ¶¶ 80-
`
`81, 86.)
`
`Upon consideration of this evidence, the Examiner withdrew all rejections
`
`and allowed the claims of the ’061 patent. (Exh. 1019.)
`
`III. CLAIM CONSTRUCTION
`
`The Board determined that “none of the claim terms require explicit
`
`construction.” (Institution Decision at 6.) At this time, Patent Owners agree that
`
`there is no need to construe any of the claim terms because, regardless of how the
`
`2 Given Kino’s teachings and the conventional wisdom at the time, Dr. Tracy could
`
`have reasonably assumed that an even lower grade of CMC than that used in the
`
`formulas of the ’875 application should be used in Kino Test Example 2. (Exh.
`
`2014 at ¶ 84; Exh. 1001 at 2:26-54, 4:60-62; Exh. 2016 at 96:15-97:2; Exh. 1014 at
`
`287, 298-9.)
`
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`
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`

`Paper No. 33
`Date Filed: March 8, 2017
`
`terms are construed, there is sufficient evidence that Petitioners have not satisfied
`
`their burden.
`
`IV. THE BOARD SHOULD FIND THAT ALL OF THE CLAIMS ARE
`PATENTABLE AND NONOBVIOUS
`
`Petitioners challenge claims 1-13 and 17-23 of the ’061 patent on two
`
`grounds. In Ground 1, Petitioners argue that these claims are obvious under § 103
`
`over Johnson in view of Kino. In Ground 2, Petitioners challenge the same claims
`
`as obvious under § 103 over Gustafsson in view of Ramstack and the Handbook of
`
`Pharmaceutical Excipients (“Handbook”). The Board instituted IPR under Ground
`
`1 for claims 1-13, 22 and 23 and instituted IPR under Ground 2 for claims 1-3, 6-9,
`
`12, 13, and 17-23. As described below, Petitioners have failed to establish that any
`
`challenged claim of the ’061 patent is unpatentable under either ground.
`
`A.
`
`The Board Should Find All Challenged Claims Remain
`Patentable Under Ground 1
`
`Petitioners’ challenge to claims 1-13, 22 and 23 under Ground 1 fails
`
`because Johnson does not expressly or inherently meet the viscosity limitation of
`
`the claims. Petitioners’ challenge to dependent claims 4, 5, 10, and 11 fails for
`
`additional reasons.
`
`14
`
`

`

`Paper No. 33
`Date Filed: March 8, 2017
`
`1.
`
`Overview of Ground 1 References
`
`a.
`
`Johnson
`
`Johnson relates to a sustained release composition for delivering “stabilized
`
`human growth hormone (hGH).” (Exh. 1009 at 1:42-45.) Johnson describes the
`
`subcutaneous injection of hGH microspheres into monkeys using an injection
`
`vehicle containing “3% w/v Carboxymethyl Cellulose (sodium salt), 1% v/v
`
`Tween 20 (Polysorbate 20) and 0.9% sodium chloride.” (Id. at 12:42-45.) Johnson
`
`does not describe the viscosity of any of its injection vehicles or how they are
`
`prepared or teach that its injection vehicles would benefit from stabilization or an
`
`increase in density.
`
`b.
`
`Kino
`
`Kino relates to “a sustained release microsphere preparation which contains
`
`a hydrophobic antipsychotic drug” (Exh. 1010 at 1:8-11), such as risperidone (id.
`
`at 2:38-49; 6:7-13). Kino teaches two injection vehicles for delivering the
`
`microspheres: “0.5% sodium carboxymethyl-cellulose solution isotonized with
`
`mannitol” (id. at 6:28-32), and “physiological saline” (id. at 6:17-21, 6:41-46, 7:7-
`
`8). Kino also teaches that its microspheres “can be made into sustained release
`
`injections by preparing an aqueous suspension together with a dispersing agent.”
`
`(Id. at 4:38-47.)
`
`15
`
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`Paper No. 33
`Date Filed: March 8, 2017
`
`2.
`
`Petitioners Fail to Establish that the Johnson Vehicle
`Inherently Has a Viscosity Within the Claimed Range
`
`Petitioners rely only on Johnson for the viscosity limitation of the challenged
`
`claims. (Petition at 4, 24-26; Exh. 2016 at 222:14-17.) Petitioners and the Board
`
`both acknowledge, however, that Johnson does not specifically teach the claimed
`
`viscosity limitation. (Petition at 25; Institution Decision at 9-10.) Instead,
`
`Petitioners argue that, based only on the amount of CMC, Johnson’s injection
`
`vehicle would inherently have a viscosity within the claimed range when measured
`
`at 20ºC. (Petition at 24-26.) Petitioners also argue that the Johnson injection
`
`vehicle inherently has substantially the same viscosity as a preferred embodiment
`
`of the ’061 patent. (Id. at 25.) Johnson, however, never provides any
`
`measurements of viscosity and provides insufficient information to ascertain the
`
`viscosity of its injection vehicle or to conclude that it is necessarily the same as
`
`that of a preferred embodiment of the ’061 patent. (Exh. 2014 at ¶¶ 81, 87.)
`
`The Federal Circuit has held that “the use of inherency, a doctrine originally
`
`rooted in anticipation, must be carefully circumscribed in the context of
`
`obviousness.” Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1195 (Fed.
`
`Cir. 2014). “[T]he concept of inherency must be limited when applied to
`
`obviousness” and “the limitation at issue necessarily must be present.” Id. at
`
`1195-96 (emphases added). Inherency “may not be established by probabilities or
`
`16
`
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`

`Paper No. 33
`Date Filed: March 8, 2017
`
`possibilities. The mere fact that a certain thing may result from a given set of
`
`circumstances is not sufficient.” Continental Can Co. U.S.A. v. Monsanto Co., 948
`
`F.2d 1264, 1269 (Fed. Cir. 1991); see also Avaya Inc. v. Network-1 Security
`
`Solutions, Inc., IPR No. 2013-00071, Paper 103 at 24-28 (P.T.A.B. May 22, 2014)
`
`(rejecting inherency argument where Petitioner made assumptions in order to
`
`interpret cited art but Patent Owner made other reasonable assumptions to interpret
`
`the cited art another way).
`
`Thus, even if the Board only finds that “it may be true” that Johnson’s
`
`injection vehicle results in a viscosity within the claimed range under a certain set
`
`of assumptions, Petitioners have failed to prove that Johnson meets the exacting
`
`standard for proving inherency in an obviousness analysis. Par Pharm., 773 F.3d
`
`at 1196 (emphasis in original).
`
`As discussed be