throbber
Case IPR2016-01096
`Patent No. 6,667,061
`Petitioners’ Reply
`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 and
`ALKERMES CONTROLLED THERAPEUTICS, INC.,
`Patent Owners.
`
`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
`__________________________________________________________________
`
`PETITIONERS’ REPLY TO
`PATENT OWNER’S RESPONSE
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`U.S. Patent And Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`5009173_1.docx
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ................................................................................... iii
`
`EXHIBIT LIST ........................................................................................................ iv
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 2
`
`A. The Patent ................................................................................................. 2
`
`B. Person Of Skill In The Art (“POSA”) ...................................................... 3
`
`III.
`
`INJECTION VEHICLES WITH A
`VISCOSITY OVER 20 CP WERE KNOWN ................................................. 3
`
`IV.
`
`INJECTABILITY AND SUSPENDABILITY ............................................... 4
`
`V. MICROPARTICLES OF THE PATENT ....................................................... 6
`
`VI. COMMERCIALLY-AVAILABLE CMC ....................................................... 8
`
`VII. THE TRACY DECLARATION ..................................................................... 9
`
`VIII. ALKERMES’S FLAWED TESTING ...........................................................10
`
`IX. THE CHALLENGED CLAIMS ARE UNPATENTABLE ..........................11
`
`A. Ground 1: Johnson (Ex.1009) In View Of Kino (Ex.1010) ...................11
`
`1. Johnson’s Viscosity Is Within The Claimed Range ........................12
`
`a.
`
`b.
`
`c.
`
`d.
`
`Alkermes’s Testing Was Flawed ...........................................12
`
`CMC Is The Viscosity-Controlling Component ...................14
`
`Commercially-Available CMC ..............................................14
`
`Other Viscosity Factors .........................................................14
`
`
`
`i
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`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`2. The Challenged Claims Are Obvious ..............................................16
`
`a.
`
`b.
`
`Claims 1-3, 6-9, 12-13, And 22-23 ........................................16
`
`Claims 4, 5, 10, And 11 .........................................................17
`
`B. Ground 2: Gustafsson (Ex.1011) In View Of
`Ramstack (Ex.1005), And The Handbook (Ex.1008) ............................17
`
`1. Gustafsson’s Viscosity Is Within The Claimed Range ....................18
`
`a.
`
`Alkermes’s Testing Was Flawed ...........................................18
`
`2. Gustafsson Teaches The Claims
`And Does Not Teach Away .............................................................19
`
`3. The Challenged Claims Are Obvious ..............................................21
`
`a.
`
`b.
`
`c.
`
`d.
`
`Claims 1-3, 6-7, 17, And 22-23 .............................................21
`
`Claims 8-9 And 12-13 ...........................................................22
`
`Claims 18-19 ..........................................................................23
`
`Claims 20-21 ..........................................................................23
`
`X.
`
`SECONDARY CONSIDERATIONS CAN’T SAVE THE PATENT .........27
`
`XI. CONCLUSION ..............................................................................................29
`
`
`
`
`
`ii
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`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`TABLE OF AUTHORITIES
`
`
`CASES
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 29
`
`Page(s)
`
`In re DBC,
`545 F.3d 1373 (Fed. Cir. 2008) .......................................................................... 28
`
`J.T. Eaton & Co. v. Atl. Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .......................................................................... 29
`
`
`
`iii
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`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`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 Patent”)
`1001
`1002
`Declaration of Dr. Patrick P. DeLuca
`Curriculum Vitae of Dr. Patrick P. DeLuca
`1003
`1004
`Intentionally Left Blank
`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®
`Supplemental Declaration of Dr. Patrick P. DeLuca, June 9, 2017
`Intentionally left blank
`Stedman’s Medical Dictionary (26th ed. 1995)
`
`1021
`
`1022
`
`1023
`1024
`1025
`1026
`
`
`
`iv
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`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`Decapetyl components sheet
`1027
`1028
`International Publication No. WO 97/44039 (“Francois”)
`1029
`Intentionally left blank
`1030
`Nutropin Label (December 1999)
`1031
`Deposition Transcript of Cory J. Berkland, Ph.D., May 26, 2017
`1032 M.A. Macket et al., Tolerability of intramuscular injections of
`testosterone ester in oil vehicle, PubMed-NCBI, 10(4) Hum.
`Reprod. 862-5 (April 1995)
`Intentionally left blank
`USP 23 NF 18, Suspensions, The U.S. Pharmacopeia, The Nat’l
`Formulary, Jan. 1, 1995.
`Intentionally left blank
`Hawley’s Condensed Chemical Dictionary (12th ed. 1993)
`(Ch.19) Organic Chemistry (2nd ed. 1998)
`U.S. Patent No. 5,417,982
`Biochemicals and Reagents for Life Science Research,
`Sigma-Aldrich 1998
`Biochemicals and Reagents for Life Science Research,
`Sigma-Aldrich 1999
`Biochemicals and Reagents for Life Science Research,
`Sigma-Aldrich 2000/2001
`Lupron Label, Center for Drug Evaluation and Research, Application
`No. NDA 19732/S012
`International Publication No. WO 99/013780
`Deposition Transcript of Robson Storey, Ph.D., May 3, 2016
`
`1033
`1034
`
`1035
`1036
`1037
`1038
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`1044
`
`
`
`v
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`

`

`Case IPR2016-01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`I.
`
`INTRODUCTION
`Claims 1-13 and 17-23 of the Patent are obvious. Nothing in Alkermes’s
`
`responses (Papers 11, 33) or supporting declarations (Exs.2014, 2054, 2059)
`
`changes this. Alkermes contends that it was outside conventional wisdom to
`
`increase the viscosity of an injectable suspension and that it was thought that
`
`viscosity should be kept low to overcome injectability issues. (Paper 33, 1.)
`
`Alkermes alleges that the viscosity of the compositions of each of Petitioners’
`
`primary references, Johnson and Gustafsson, would not inherently be within the
`
`claimed range and that the conventional wisdom taught against the range. (Id.)
`
`Alkermes also contends that Gustafsson teaches away from the claimed invention
`
`and that a POSA would not combine Johnson and Kino or Gustafsson and
`
`Ramstack to arrive at the claimed invention. (Id. 2.)
`
`Alkermes’s statements fail to appreciate key facts. The challenged claims
`
`use known microparticles in a known concentration in combination with a known
`
`injection vehicle with known excipients to prepare an injectable suspension having
`
`a viscosity that was known to be injectable and suspendable. (Ex.1024 ¶¶7-24.)
`
`Alkermes statements that increasing the viscosity of a suspension was an
`
`unexpected improvement in injectability and reduced in vivo injection failures fails
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`to appreciate that numerous references already taught viscosities squarely within
`
`the claimed range. (Exs.1024 ¶9; 1028, 6:37-7:3.)
`
`Finally, as to alleged secondary considerations, Alkermes fails to establish
`
`anything unexpected about the invention or provide relevant evidence of
`
`commercial success. Alkermes has similarly failed to show any nexus.
`
`II. BACKGROUND
`Alkermes alleges that injectable suspensions that included microparticles
`
`had known injectability problems before the Patent. (Paper 33, 5.) Interestingly,
`
`Alkermes provides no evidence to support this contention. And although it was
`
`known to keep viscosity “low” to improve injectability, Alkermes provides no
`
`evidence that “low” is less than 20cps. (Ex.1024 ¶¶17-18.)
`
`A. The Patent
`The Background admits that adding viscosity enhancers to injection vehicles
`
`was known. (Exs.1001, 2:25-27.) The Patent also admits that this was done “in
`
`order to retard settling of the particles in the vial and syringe.” (Exs.1001,
`
`2:25-27.) The Patent provides an example of a known commercial product whose
`
`viscosity was within the margin of error of that claimed in the Patent. (Ex.1024
`
`¶11.) Specifically, the Patent describes Decapeptyl as having a viscosity of
`
`approximately 19.7cp. (Exs.1001, 2:34-37; 1024 ¶9.) And the Patent also
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`specifically states that its vehicle is not “the aqueous injection vehicle that consists
`
`of 3% by volume carboxymethyl cellulose, 1% by volume polysorbate 20, 0.9% by
`
`volume sodium chloride.”
`
`(Ex.1001, 3:4-7.)
`
`Interestingly enough,
`
`this
`
`“disclaimed” injection vehicle is exactly that described in Johnson. (Ex.1024 ¶¶56,
`
`70.)
`
`Person Of Skill In The Art (“POSA”)
`B.
`Although the parties disagree on the definition of a POSA, the claims are
`
`obvious regardless of which definition is used. (Ex.1024 ¶¶4-5.)1
`
`III.
`
`INJECTION VEHICLES WITH A
`VISCOSITY OVER 20 CP WERE KNOWN
`With respect to the Patent, Alkermes did not invent any of the following:
`
`injection vehicles, using excipients in an injection vehicle to improve injectability
`
`or suspendability, microparticles or microparticles
`
`that are encapsulated,
`
`risperidone or risperidone microparticles, or injection vehicles with a viscosity
`
`1 While Alkermes’s experts, Drs. Berkland or Storey, are both experts in polymer
`
`chemistry and the formation of microparticles, microparticles are merely the
`
`workpiece of the Patent. Neither have significant experience in the preparation and
`
`formulation of injection vehicles. (Exs.1031, 64:14-66:12; 1044, 11:24-22:17.)
`
`Accordingly, their testimony should be accorded little weight.
`
`3
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`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`range outside of what was already known. (Exs.1009, 12:42-45; 1008, 78, 135,
`
`137, 329, 420, 481; 1001, 2:34-37; 1028, 6:37-7:3; 2041; see also 1030; 1031,
`
`255:22-257:21; 1005, 35:1-36:26, Examples 2, 3; 1024 ¶9.)
`
`In fact, it was well known at the time of the invention that aqueous
`
`suspensions of microparticles with a viscosity in the claimed range were injectable.
`
`(Ex.1024 ¶11) And it was well known that aqueous suspensions of risperidone
`
`prodrug with a viscosity in the claimed range could be used as a depot injection.
`
`(Ex.1028, 6:37-7:3; 1024 ¶12.)
`
`Alkermes’s arguments that “conventional wisdom” was to keep viscosity
`
`low to make the suspension easier to inject fail to appreciate that “low” is an
`
`entirely relative term. (Ex.2016, 96:19-97:2.) “Low” to a POSA means low enough
`
`to be injected but yet viscous enough to adequately suspend the microparticles in a
`
`vehicle. (Ex.1024 ¶18.) Alkermes appears to believe that “low” means lower than
`
`the claimed range, but this assumption fails to appreciate the numerous references
`
`that teach injection vehicles having viscosities within the claimed range. (See, e.g.,
`
`Exs.1008, 135, 137, 329, 420, 481; 1014, 290-91; 1028, 6:37-7:3; 1024 ¶¶10, 18.)
`
`IV.
`
`INJECTABILITY AND SUSPENDABILITY
`An injectable suspension must be syringeable (capable of flowing through a
`
`needle from a vial) and injectable (capable of flowing through a needle from a
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`syringe into the tissue of a patient at the injection site). (Exs.1002 ¶¶17-19; 1014,
`
`285, 298-99; 1001, 1:53-60; 1024 ¶15.) Syringeability is important since if a
`
`composition cannot flow through the needle from a vial and be collected in the
`
`syringe, it cannot be injected. (Exs.1002 ¶¶20-25; 1014, 285, 298-99; 1001,
`
`1:53-60; 1024 ¶15.) Likewise, a composition cannot be expelled from the syringe
`
`and passed easily through needle if it does not have adequate injectability.
`
`(Ex.1024 ¶15.)
`
`As explained in detailed by Dr. DeLuca, a POSA knew that viscosity
`
`impacts injectability and suspendability, but a POSA’s goal was not to formulate
`
`an injection vehicle to achieve a particular viscosity. Instead, a formulator focuses
`
`on balancing the dual goals of injectability and suspendability of the product, with
`
`viscosity being a consequence of achieving that balance. (Ex.1024 ¶16.)
`
`Viscosity becomes important, to some extent, when suspending the active
`
`agent so that the agent does not settle, which could then lead to agglomeration
`
`and/or clogging as a result of caking or sedimentation, which will adversely affect
`
`resuspension. (Exs.1034, 1949; 2016, 97:7-11; 1024, ¶16.) So something like
`
`water, with a negligible viscosity of 1cp, will allow particles to settle quickly,
`
`whereas particles suspending in honey, with a viscosity of about 10,000cp, would
`
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`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`take much longer to settle. (Exs.2016, 97:7-11; 1024 ¶17.) To prevent such
`
`problems, a POSA knows that suitable ingredients that increase viscosity of the
`
`suspension should be added. (Ex.1024 ¶¶14-24.)
`
`V. Microparticles Of The Patent
`The challenged claims all require microparticles. (Ex.1001 cl.1.) Alkermes
`
`would have us believe that its use of known microparticles distinguishes over the
`
`prior art. But as the title of the Patent makes clear, the alleged invention is directed
`
`to an improved injectable suspension. The Patent repeatedly states that any
`
`microparticle works. (Exs.1001, 4:27-30, 14:33-3, 16:11-24; 1024 ¶28.)
`
`The Board correctly acknowledged, and Dr. DeLuca agrees, that the Patent
`
`defines microparticles as particles that require “an active or other agent dispersed
`
`or dissolved within a polymer that serves as a matrix or binder of the particle.”
`
`(Paper 13, 25-26, Ex.1001, 5:15-18.)
`
`The Patent does not limit the polymers used in forming microparticles. A
`
`polymer is a macromolecule formed by the chemical union of five or more
`
`identical combining units called monomers. (Exs.1036, 936; 1024 ¶25.) A
`
`polysaccharide is one example of a polymer. (Exs.1036, 941; 1031, 81:15-82:3;
`
`1024 ¶27.) Starch is a polysaccharide polymer. (Exs.1036, 941, 1085-86; 1037,
`
`871; 1024 ¶27.) Therefore, for purposes of forming the microparticles, any
`
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`polymer, such as starch, can satisfy this requirement. (Paper 13, 25-26, Exs.1001,
`
`5:15-18; 1024 ¶¶27, 29.)
`
`Claim 1 recites a “polymeric binder” in such a way that this polymer need
`
`not be the same as the polymer that forms the microparticles. (Ex.1024 ¶30.) While
`
`the polymeric binder need not serve any particular function, the Patent teaches that
`
`for the sustained-release microparticles of one embodiment, “the molecular weight
`
`of the polymeric binder material . . . should be high enough to permit the formation
`
`of satisfactory polymer coatings, i.e., the polymer should be a good film former.”
`
`(Ex.1001, 14:33-43.) This is not to say that the “polymeric binder” of claim 1 can’t
`
`be the same as the polymer used to form the microparticles ____ only that it doesn’t
`
`have to be. Instead, the polymeric binder may be an additional component of the
`
`microparticle. This is clear from the specification. The definition of microparticle
`
`simply requires it to include a polymer that acts as a binder or matrix. (Ex.1001,
`
`5:15-18.)
`
`In
`
`later describing
`
`the previously-defined microparticles,
`
`the
`
`specification states that they “preferably comprise a polymeric binder” and
`
`provides a list of suitable “polymeric binder materials.” (Exs.1001, 14:10-32; 1024
`
`¶30.)
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`While the polymeric binder of claim 1 is not functionally defined, claim 17
`
`requires that the active agent be “encapsulated within” the polymeric binder of
`
`claim 1. But again, the polymeric binder serving as the encapsulating material need
`
`not be one and the same as the “polymer that serves as a matrix or binder of the
`
`particle” to form the microparticle. (Exs.1001, 5:15-18; 1024 ¶¶94, 100.)
`
`VI. COMMERCIALLY-AVAILABLE CMC
`Alkermes argues that Petitioners’ inherency argument based on the Tracy
`
`Declaration is incorrect because other CMCs were allegedly commercially
`
`available at the time of the invention. But Alkermes offered no evidence that any
`
`of the CMCs that would allegedly yield viscosities outside of the claimed range
`
`were actually available at the time of the application. Nor did Alkermes provide
`
`any evidence that these types of CMC were pharmaceutical grade and would have
`
`been used by a POSA at the relevant time.
`
`For example, the Aqualon brochure (Ex.2034) has a revision date of April
`
`2002, “[s]upercedes all previous editions,” and is not prior art, so it is unclear if
`
`any of its CMCs were available at the time of the invention (id., 29; Ex.1024 ¶32).
`
`The Dow brochure has a copyright date of 2017, while the Ashland catalog’s is
`
`2016. (Exs.2036; 2038; 1024 ¶32.) Neither are prior art or prove availability at the
`
`relevant time. Similarly, the Spectrum CA193 Safety Data Sheet has a revision
`
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`date of January 22, 2015, and Alkermes has provided no evidence that the product
`
`was actually available at the time of the invention. (Exs.2040; 1024 ¶32.) And
`
`Alkermes’s Sigma-Aldrich reference (Ex.2039), which describes an ultra-low
`
`viscosity CMC, was also not available at the time of the invention, as evidenced by
`
`its absence from the 1998, 1998, and 2000/2001 Sigma-Aldrich catalogs.
`
`(Exs.1039; 1040; 1041.)
`
`Alkermes has simply done nothing to refute Petitioners arguments regarding
`
`the inherency of the viscosity limitation of the Patent claims.
`
`VII. THE TRACY DECLARATION
`During prosecution of the Patent, the Examiner stated that although “Kino
`
`does not disclose the viscosity to be greater than about 60 cp and less than about
`
`600 cp,” it would have been obvious “to determine the optimal viscosity for
`
`application.” (Exs.1016, 4; 1002 ¶41.) Petitioners agree.
`
`Alkermes did not test the formulation of Kino (Ex.1010), nor did it provide
`
`testing that compared its formulation with Kino (Exs.1018; 1002 ¶44; 1024
`
`¶¶46-52). Instead, Applicants submitted the Tracy Declaration to compare their
`
`injection vehicle, described as a composition having 1.5% CMC and a viscosity of
`
`27cps, with an injection vehicle having 0.75% CMC and a viscosity of 7cps.
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`(Exs.1018, 5; 1002 ¶44; 1024 ¶47.) More importantly, Applicants didn’t address
`
`the Examiner’s request for evidence of unexpected results. (Ex.1018.)
`
`In seeking IPR to show that these claims are obvious based on the prior art,
`
`Petitioners used, and the Board accepted, the very logic that allowed Alkermes to
`
`obtain the challenged claims in the first place. What is sauce for the goose is sauce
`
`for the gander.
`
`VIII. ALKERMES’S FLAWED TESTING
`Alkermes instructed Dr. Gehrke to prepare the injection vehicles of both
`
`Johnson and Gustafsson using currently available CMC. But Alkermes failed to
`
`demonstrate the specific types and grades of CMC used ____ ultra-low and extra-low
`
`viscosity ____ were available at the time of the invention and for use in a
`
`pharmaceutical parenteral formulation. Alkermes’s experts did not choose these
`
`CMCs, and Dr. Berkland admitted that he did not know if they were available at
`
`the time of the invention. (Exs.1024 ¶43; 1031, 217:18-218:10, 2059 ¶6.)
`
`A POSA would choose commercially-available pharmaceutical-grade
`
`CMC ____ not a special-order non-pharmaceutical-grade CMC ____ in preparing an
`
`injection vehicle. (Ex.1024 ¶44.) As explained by Dr. DeLuca, it would be
`
`nonsensical for an experienced formulator to use anything other than a readily
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`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`available pharmaceutical-grade CMC to develop a parenteral formulation. (Id.)
`
`Dr. Gehrke’s tests are of no relevance.
`
`IX. THE CHALLENGED CLAIMS ARE UNPATENTABLE2
`A. Ground 1: Johnson (Ex.1009) In View Of Kino (Ex.1010)
`Johnson teaches a microparticle concentration greater than 30 mg/ml and an
`
`injection vehicle that includes 3% CMC (low viscosity). (Exs.1009, 10:17-18,
`
`10:67-11:1, 12:38-45; 1024 ¶54.) Johnson further teaches incorporating a wetting
`
`agent, such as polysorbate, and a tonicity agent, such as sodium chloride, into the
`
`vehicle. (Exs.1009, 12:39-45; 1024 ¶54.) Johnson teaches that such formulation
`
`may be injected through a 20 gauge needle. (Exs.1009, 12:40-42; 1024 ¶54.)
`
`Johnson specifically identifies “low viscosity” CMC in the examples, and a POSA
`
`would appreciate that this implies the same CMC was used by Johnson
`
`
`2 Although the Board instituted for review dependent claims 2-3, 6-9, 12-13,
`
`and 22-23 with respect to Ground 1 and claims 2-3, 6-7, 17, and 22-23 with respect
`
`to Ground 2, Alkermes set forth no specific arguments as to these claims in its
`
`Response. Petitioners respectfully submit that these claims are unpatentable based
`
`on the arguments set forth in their Petition.
`
`11
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`throughout.3 And Johnson specifically teaches an injection vehicle that is 3%
`
`CMC, 1% polysorbate 20, and 0.9% sodium chloride. (Exs.1009, 10:17-18,
`
`10:67-11:1, 12:42-45; 1024 ¶54.)
`
`Kino teaches sustained release microspheres that include risperidone.
`
`(Exs.1010, 1:65-2:4, 2:38-41; 1024 ¶55.) Kino teaches that such microspheres can
`
`be used in aqueous injections that include CMC. (Exs.1010, 4:38-41; 1024 ¶55.)
`
`Kino teaches a vehicle using CMC, polysorbate, and sodium chloride. (Exs.1010,
`
`38-51; 1024 ¶55.) Kino also teaches the addition of sorbitol to an injection vehicle.
`
`(Exs.1010, 4:52:55; 1024 ¶55.)
`
`1.
`
`Johnson’s Viscosity Is
`Within The Claimed Range
`Alkermes’s Testing Was Flawed
`a.
`As discussed in the original Petition, the Patent includes a recitation in the
`
`Summary of the Invention that specifically disclaims the very vehicle disclosed in
`
`Johnson, “3% by volume carboxymethyl cellulose, 1% by volume polysorbate 20,
`
`3 It’s worth noting that Johnson is a named inventor of the Patent. If Johnson’s
`
`prior art vehicle used something else ____ like the extra- or ultra-low that Dr. Gehrke
`
`used ____ Alkermes should have said so through Johnson. Alkermes failed to do so
`
`in either of its responses, and it’s too late now.
`
`12
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`0.9% by volume sodium chloride,” but the claims include no such disclaimer.
`
`(Exs.1001 3:4-7; 1024 ¶56.) Applying the logic Alkermes used in Tracy to
`
`determine inherent viscosities, the issued claims of the Patent read directly on the
`
`Johnson injection vehicle. (Ex.1024 ¶60.)
`
`Faced with this dilemma, Alkermes now attempts to argue that Johnson’s
`
`vehicle would have a viscosity outside of the claimed range based on Dr. Gehrke’s
`
`selective testing. Alkermes is wrong. Dr. Gehrke did not test low viscosity CMC,
`
`which
`
`is clearly a
`
`requirement of Johnson.
`
`Instead, he only
`
`tested
`
`non-pharmaceutical grade ultra- and extra-low viscosity CMCs, chosen by
`
`Alkermes to ensure the desired results. A POSA would not use either to formulate
`
`an injection vehicle at the time of the invention assuming these products were even
`
`available. (Ex.1024 ¶¶57-58.)
`
`And even if they were available, neither Kino nor the Patent describes the
`
`type and grade of CMC used. (Ex.1024 ¶¶51, 59.) If the CMC mattered, then
`
`Alkermes should not have been able to rely upon Tracy to overcome Kino. (Id.)
`
`The Patent never would have been allowed without Alkermes’s reliance on Tracy.
`
`Alkermes litigation-driven attempt to disavow Tracy’s methodology should be
`
`rejected.
`
`13
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`CMC Is The Viscosity-Controlling Component
`b.
`Alkermes argues that a POSA could not predict the viscosity of Johnson
`
`based solely on the amount of CMC used, which is particularly interesting
`
`considering that is exactly how Alkermes overcame the Kino reference during
`
`prosecution.
`
`It would be obvious to a POSA that Johnson’s CMC impacts viscosity more
`
`than any other component. To say otherwise either misrepresents basic scientific
`
`principles or lacks understanding of the components typically used in parenteral
`
`formulations. (Exs.1024 ¶¶61-63, 69; 1031, 178:21-186:21.)
`
`Commercially-Available CMC
`c.
`Alkermes alleges that it is “impossible” to establish Johnson’s viscosity
`
`because the particular grade and type of CMC are not specified. How convenient
`
`for Alkermes that this is only now a concern. Neither Tracy nor the Patent
`
`addresses the grade or type of CMC. (Exs.1024 ¶64-66; 1031, 125:4-21.)
`
`d. Other Viscosity Factors
`Alkermes now alleges that other factors, such as method of dissolution or
`
`mixing, sterilization, the addition of tonicity and wetting agents, and the order of
`
`such additions, would dramatically impact the overall viscosity of the injection
`
`14
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`vehicle. (Paper 33, 24; Ex.1024 ¶67.) This is ironic given that neither Tracy nor the
`
`Patent address any of these factors.
`
`Alkermes’s own expert admitted that the Patent does not disclose or suggest
`
`the type of CMC used or how the vehicles are prepared. So although Alkermes
`
`attempts to focus now on the importance of the CMC grade and the steps for how
`
`the vehicle is prepared, it’s clear that these were not a concern when drafting the
`
`Patent or when Tracy prepared his declaration. (Exs.1024 ¶64; 1031, 125:4-21,
`
`128:25-132:13.)
`
`As POSA focuses on suspendability and injectability when preparing
`
`parenteral suspensions. (Exs.1002 ¶19; 1024 ¶¶19, 66-69.) It would have been
`
`obvious to a POSA to adjust the viscosity to determine what is needed to achieve
`
`injectability and suspendability. (Ex.1024 ¶¶20, 71.) A POSA would know that the
`
`vehicle would have to be viscous enough to prevent settling of the particles prior to
`
`injection into the host. (Id. ¶¶21-24, 69.) The factors that Alkermes alleges would
`
`dramatically impact the viscosity would not be an issue for any POSA and would
`
`have an insignificant impact on viscosity. (Id. ¶¶67-71.)
`
`15
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`2.
`
`The Challenged Claims Are Obvious
`Claims 1-3, 6-9, 12-13, And 22-23
`a.
`Alkermes’s entire basis to uphold claims 1-3, 6-9, 12-13, and 22-23 rests
`
`upon its flawed argument that Johnson’s viscosity is not within the claimed range.
`
`While Johnson is silent as to the viscosity of the vehicle, based on Alkermes’s
`
`admission in Tracy and what would be known to a POSA, Johnson’s
`
`vehicle ____ having 3% CMC (low viscosity) ____ would be expected to have a
`
`viscosity greater than 27cp and certainly within the claimed range of 20-600cp.
`
`(Id. ¶60.) And as discussed above, Johnson not only teaches microspheres
`
`suspended in an aqueous injection vehicle of 3% CMC (Ex.1001 cls.2-3 (“a
`
`viscosity enhancing agent”)), but also sodium chloride (id. cls.6-7 (“a tonicity
`
`adjusting agent”)) and polysorbate 20 (id. cls.8-9, 12-13 (“a wetting agent”)) in a
`
`vehicle suitable for injection into a patient via a 20 gauge needle (Ex.1009,
`
`12:39-45). Interestingly, Johnson’s vehicle, allegedly “disclaimed” in the Patent,
`
`differs from Vehicle C of the Patent only in the amount of polysorbate (1% versus
`
`0.1%). (Compare Ex.1001, 3:4-7, 9:46 with Ex.1009, 12:39-42; Exs.1002 ¶¶55, 59;
`
`1024 ¶¶56, 70.) In the Patent, Vehicle C has a viscosity of at least 56. (Ex.1001,
`
`10:24-26, 52.) This difference in polysorbate between Vehicle C and Johnson has
`
`minimal impact on viscosity, furthering the conclusion that Johnson’s viscosity
`
`16
`
`

`

`Case IPR2016- 01096
`Petitioners’ Reply
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`falls within the claimed range. (Ex.1024 ¶¶60, 70.) Johnson therefore teaches every
`
`limitation of claims 1-3, 6-9, and 12-13. (Ex.1002 ¶¶60-61, 63.)
`
`Claims 4, 5, 10, And 11
`b.
`Like Johnson, Kino also teaches incorporating polysorbate 80 (Ex.1001
`
`cls.8-9, 12-13 (“a wetting agent”)) into an aqueous suspension (Exs.1010, 4:38-40;
`
`1002 ¶¶56, 62). Kino also teaches that fillers, such as sorbitol (Ex.1001 cls.4-5 (“a
`
`density enhancing agent”)), are useful for enhancing the stability of a microparticle
`
`suspension (Exs.1010, 4:52-56; 1002 ¶¶56, 62). A POSA, reading Kino, would
`
`appreciate that sorbitol would increase the density of an injectable suspension.
`
`(Ex.1002 ¶62.) Increasing the density may be desirable to stabilize the formulation
`
`(id.) or to minimize the difference between the densities of the particles and the
`
`vehicle to reduce sedimentation (or settling). (Ex.1024 ¶¶73-76.) A POSA would
`
`therefore be motivated to combine the teachings of Kino with Johnson for
`
`suspendability and resuspendability purposes. (Id. ¶¶79-80.)
`
`B. Ground 2: Gustafsson (Ex.1011) In View Of
`Ramstack (Ex.1005), And The Handbook (Ex.1008)
`Gustafsson teaches a sustained release formulation that: includes polymer
`
`microparticl

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