Case IPR2016-01096
`Patent No. 6,667,061
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`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
`__________________________________________________________________
`
`Exhibit 1024
`
`DECLARATION OF PATRICK P. DELUCA, Ph.D.
`
`
`
`
`5021449_1.docx
`
`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
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`

`

`
`
`TABLE OF CONTENTS
`
`Page
`TABLE OF EXHIBITS CITED............................................................................... iii
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 1
`
`III. CLAIM CONSTRUCTION ............................................................................ 2
`
`IV. STATE OF THE ART OF INJECTION VEHICLES ..................................... 3
`
`V.
`
`SUSPENDABILITY AND INJECTABILITY ............................................... 6
`
`VII. MICROPARTICLES OF ’061 PATENT ......................................................13
`
`VIII. COMMERCIALLY AVAILABLE CMC .....................................................15
`
`IX. ROUTINE OPTIMIZATION ........................................................................17
`
`X. DR. GEHRKE’S TESTING ..........................................................................18
`
`XI. THE TRACY DECLARATION ...................................................................20
`
`XII. THE COMBINATION OF JOHNSON IN VIEW
`OF KINO RENDERS THE CLAIMS OBVIOUS ........................................22
`
`A. Ground 1 References ..............................................................................23
`
`1. Johnson .............................................................................................23
`
`2. Kino ..................................................................................................23
`
`B. The Johnson Vehicle Has a
`Viscosity Within The Claimed Range ....................................................24
`
`1. Patent Owners’ Testing ....................................................................24
`
`2. CMC As Viscosity Controlling Component ....................................26
`
`3. Commercially Available CMC ........................................................28
`
`4. Other Viscosity Factors ....................................................................28
`
`
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
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`

`

`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`C. Dependent Claims ...................................................................................31
`
`1. Claims 4 And 5 ................................................................................31
`
`2. Claims 10 And 11 ............................................................................33
`
`D. Motivation To Combine And Reasonable Expectation Of Success .......34
`
`XIII. THE COMBINATION OF GUSTAFSSON
`IN VIEW OF RAMSTACK AND THE
`HANDBOOK RENDERS THE CLAIMS OBVIOUS .................................34
`
`A. Ground 2 References ..............................................................................35
`
`1. Gustafsson ........................................................................................35
`
`2. Ramstack ..........................................................................................35
`
`3. The Handbook ..................................................................................36
`
`B. Patent Owners’ Testing ...........................................................................36
`
`C. Gustafsson Does Not Teach
`Away And Renders Obvious Claim 1 ....................................................38
`
`D. Dependent Claims ...................................................................................41
`
`1. Claims 8-9 And 12-13 ......................................................................42
`
`2. Claims 17-19 ....................................................................................42
`
`3. Claims 20-21 ....................................................................................43
`
`E. Motivation To Combine And
`Reasonable Expectation Of Success .......................................................46
`
`XIV. OBJECTIVE INDICIA ..................................................................................48
`
`XV. CONCLUSION ..............................................................................................51
`
`
`
`ii
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`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`
`TABLE OF EXHIBITS CITED
`
`1009
`1010
`1011
`1014
`
`1015
`1016
`1017
`1018
`1019
`1020
`
`Exhibit # Reference
`1001
`U.S. Patent No. 6,667,061 (“the ’061 Patent”)
`1002
`Declaration of Dr. Patrick P. DeLuca
`Curriculum Vitae of Dr. Patrick P. DeLuca
`1003
`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. WO 199714408 (“Gustafsson”)
`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®
`Stedman’s Medical Dictionary (26th ed. 1995)
`Decapetyl components sheet
`International Publication No. WO 97/44039 (“Francois”)
`
`1021
`
`1022
`
`1023
`1026
`1027
`1028
`
`
`
`iii
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`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`
`1034
`
`1036
`1037
`1038
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`2014
`2016
`2017
`2034
`
`Exhibit # Reference
`1030
`Nutropin Label (December 1999)
`1031
`Deposition Transcript of Cory J. Berkland, Ph.D., May 26, 2017
`M.A. Macket et al., Tolerability of intramuscular injections of
`1032
`testosterone ester in oil vehicle, PubMed-NCBI, 10(4) Hum.
`Reprod. 862-5 (April 1995)
`USP 23 NF 18, Suspensions, The U.S. Pharmacopeia, The Nat’l
`Formulary, Jan. 1, 1995
`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 (“Gombotz”)
`Declaration of Dr. Cory J. Berkland, Mar. 8, 2017
`Patrick DeLuca Dep., Feb. 22, 2017
`Remington’s Pharmaceutical Sciences (17th ed. 1985)
`AQUALON Sodium Carboymethycellulose, Physical and Chemical
`Properties (Hercules 1999) (250-10H Rev. 4-02)
`Carboxymethylcellulose, Industrial Specialties (1995-2017),
`http://www.dow.com/dowwolff/en/industrial solutions/polymers/carb
`oxymethylcellulose/
`Performance Specialties Reference Guide
`Specification Sheet, Sigma-Aldrich
`Safety Data Sheet, Spectrum Chemical Mfg. Corp., Preparation Date:
`1/22/2015, Rev. 1/22/2015, Rev. No. G1
`Clinical Pharmacology and Biopharmaceutics Reviews(s), Center for
`Drug Evaluation and Research, Application No. 21-346
`
`2036
`
`2038
`2039
`2040
`
`2041
`
`
`
`iv
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`Case IPR2016- 01096
`Petition for Inter Partes Review
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`
`Exhibit # Reference
`2059
`Declaration of Professor Stevin Gehrke, Mar. 8, 2017
`2067
`Procedure for Preparing CMC Water Solution,
`Nippon Paper Indus. (2013)
`Brookfield DV-II+Pro Programmable Viscometer, Operating
`Instructions, Manual No. M/03-165-C0508
`
`2068
`
`
`
`v
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`Case IPR2016-01096
`Patent No. 6,667,061
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Attorney Docket No. 9LUYE 7.1R-004
`
`I.
`
`INTRODUCTION
`I, PATRICK P. DELUCA, hereby declare as follows:
`
`1.
`
`I am the same Patrick P. DeLuca, Ph.D., who submitted a declaration
`
`in support of Petitioner’s Petition for Inter Partes Review (“Preliminary
`
`Declaration”) on May 31, 2016.
`
`2. My background, education, training, compensation, and professional
`
`experiences are set forth in my Preliminary Declaration, and are incorporated by
`
`reference herein.
`
`3.
`
`I have reviewed the Declarations of Cory J. Berkland, Ph.D.,
`
`Robson F. Storey, Ph.D., Scott Spears, and the amended declaration of Professor
`
`Stevin Gehrke submitted by the Patent Owners in support of their Response.
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`In my Preliminary Declaration, I proposed that a POSA would have at
`4.
`
`least a bachelor’s degree and a number of years of industry training or experience
`
`in one or more the following fields: pharmaceutical formulation, chemistry,
`
`pharmaceutical science, polymer chemistry, pharmaceutics, pharmaceutical
`
`technology, pharmacokinetics, and/or pharmacology. During my deposition, I
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`stated that by a “number of years” I meant two to four years. (Ex.2016,
`
`79:18-80:1.) I understand Alkermes proposed to define a POSA as having “a
`
`bachelor’s degree in one or more 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).” (Paper 33, 8.) Although I am of
`
`the opinion that my definition of a POSA is more accurate, I believe the challenged
`
`claims are obvious under either definition.
`
`5.
`
`I believe I am a person of at least ordinary skill in the art and that I
`
`know who a POSA was, and what they would have known and understood at the
`
`time of the filing of this patent. I am also aware of what a POSA would appreciate
`
`at the time of the invention, which allows me to give an opinion about the
`
`qualifications of a POSA at the time of the invention as well as interpret the prior
`
`art from the perspective of a POSA.
`
`III. CLAIM CONSTRUCTION
`I understand that the Board determined that “none of the claim terms
`6.
`
`require explicit construction.” (Paper 13, 6.) Furthermore, I have reviewed
`
`Dr. Berkland’s discussion of how terms of the ’061 Patent should be construed and
`
`understand he believes that the claims should be given their broadest reasonable
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`interpretation, based on the specification. I understand this is the proper standard in
`
`Inter Partes Review, and I agree with his assessment. Regardless of how the terms
`
`are construed, the patent is still obvious.
`
`IV. STATE OF THE ART OF INJECTION VEHICLES
`To “inject” means to introduce a fluid into the body. (Ex.1026, 874.)
`7.
`
`An injection is defined as the introduction of a medical substance or nutrient
`
`material into the tissues, canals, or cavities of the body. (Id.) If the material is
`
`injected into the vein, it is considered an intravenous injection. (Id.) If the material
`
`is injected to merely be placed under the skin, it is considered subcutaneous
`
`injection. (Id.) If the material is to be injected into the muscular tissue, it is
`
`considered an intramuscular injection. (Id.) All of these would be considered
`
`parenteral. (Id. 1300.)
`
`8.
`
`As I stated in my Preliminary Declaration, the general principles for
`
`developing injectable formulations by May 25, 2000, were well known and well
`
`understood. (Ex.1002 ¶17.) Injectable suspensions are heterogeneous systems that
`
`include a solid phase (such as microparticles) and an aqueous or nonaqueous liquid
`
`phase (or
`
`injection vehicle). (Exs.1014, 285; 1001, 1:17-25.) Injectable
`
`suspensions are usually administered subcutaneously or intramuscularly. (Ex.1014,
`
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`285.) One advantage of utilizing injectable suspensions is the possibility of
`
`controlled release or depot action. (Id.) A depot injection is used when the
`
`substance in the fluid is intended to be kept at the injection site for a prolonged
`
`period of time. (Ex.1026, 874.)
`
`9.
`
`Patent Owners did not invent injection vehicles or injectable
`
`suspensions. Patent Owners did not invent adding various excipients to an injection
`
`vehicle to improve its injectability or suspendability. (Exs.1009 12:42-45; 1008,
`
`78.) And Patent Owners most certainly did not invent an injection vehicle with a
`
`viscosity range outside of what was already known. (Exs.1008, 135, 137, 329, 420,
`
`481; 1028, 6:37-7:3.) For example, Decapeptyl has a viscosity of 19.7cp, per the
`
`Patent Owners’ admission, and includes microparticles of triporelin in d,l-lactide
`
`co-glycolide polymers and an injection vehicle of mannitol, CMC, and polysorbate
`
`80 in water for injection. (Exs.1001 2:34-37; 1027) Patent Owners also did not
`
`invent microparticles or microparticles that are encapsulated. (See Exs.2041 (FDA
`
`stating that similar depot injections with PLGA were approved ____ Nutropin Depo,
`
`Lupron Depot, Trelstar, and Sandostatin LAR Depot); 1030; 1031, 255:22-257:21.)
`
`And finally, the ’061 Patent does not purport or suggest or claim the invention of
`
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`risperidone or even risperidone microparticles. (Exs.1001; 1005, 35:1-36:26,
`
`Examples 2, 3.)
`
`10. Against this knowledge, Patent Owners argue that it was against the
`
`conventional wisdom to increase viscosity of injectable suspensions. (Paper 33, 3.)
`
`But as I mentioned in my Preliminary Declaration, numerous nonaqueous vehicles
`
`used for intramuscular injections, including corn oil, cottonseed oil, peanut oil,
`
`sesame oil, and soybean oil, all provide a viscosity within the claimed range.
`
`(Exs.1008, 135, 137, 329, 420, 481; 1014, 290-91.) So it was actually well known
`
`at the time of the invention that viscosities in the claimed range were injectable.
`
`11.
`
`It was well known at the time of the invention that aqueous
`
`suspensions having a viscosity in the claimed range were injectable. As noted
`
`above, Patent Owners admitted that Decapeptyl has a viscosity of 19.7cp.
`
`(Ex.1001, 2:34-37.) The Brookfield manual states that it is accurate in measuring
`
`viscosity to ±1.0%. (Ex.2068, 7.) So, assuming that the Decapeptyl’s viscosity was
`
`taken using a Brookfield viscometer as disclosed in the specification of the
`
`’061 Patent, the Decapeptyl that Patent Owners describe as being known would
`
`appear to overlap with and be encompassed by Patent Owners’ claimed range.
`
`(Ex.2068, 7.) Decapeptyl’s viscosity range would be 19.5-19.9cp (i.e., 19.7 ±1% =
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`19.5 to 19.9), and the bottom end of Patent Owners’ claimed range would be
`
`19.8-20.2cp (i.e., 20 ±1% = 19.8 to 20.2).
`
`12. And it was well known at the time of the invention that aqueous
`
`suspensions of risperidone with a viscosity in the claimed range were injectable.
`
`(See, e.g., Ex.1028 (“Francois”).) Francois teaches that a depot injection of a
`
`risperidone prodrug can be accomplished with aqueous suspensions having a
`
`viscosity of “75 mPas (cp) or below.” (Id. 6:37-7:3.)
`
`13. A POSA also knows that an aqueous injection vehicle may require
`
`additional components, such as suspending agents, wetting agents, preservatives,
`
`buffers, and isotonizing agents. (Ex.1028, 6:1-5.) This concept would be readily
`
`apparent to any formulator. (See Ex.1014, 288-93.)
`
`V.
`
`SUSPENDABILITY AND INJECTABILITY
`14. Suspendability (or resuspendability) refers to the use of various
`
`components to assist in keeping solid particles in a state of suspension and is an
`
`important concept for a POSA to consider when formulating an injectable
`
`pharmaceutical suspension. (Ex.1014, 26.) Suspensions, by nature, include
`
`particulate matter that will settle to the bottom of a container if left standing for too
`
`long. (Ex.1034, 1949.) If the sedimentation is allowed to solidify, it becomes much
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`more difficult to resuspend. (Id.) To avoid the sedimentation issue in a
`
`pharmaceutical suspension, the skilled artisan will add suitable pharmaceutically
`
`acceptable excipients to increase the viscosity of the suspension. (Id.)
`
`15. As I discussed in detail in my Preliminary Declaration, 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 syringe into the tissue
`
`of a patient at the injection site). (Exs.1002 ¶¶17-19; 1014, 285, 298-99; 1001,
`
`1:53-60.) Syringeability is incredibly important to injectable suspensions. If a
`
`composition cannot flow through the needle from a vial and be collected in the
`
`syringe, it cannot be injected. (Exs.1002 ¶¶21-22; 1014, 285, 298-99.) Likewise, a
`
`composition cannot be expelled from the syringe and passed easily through the
`
`needle and into the tissue of a patient if it does not have adequate syringeability
`
`and injectability.
`
`16. As admitted by Dr. Berkland and would be known to any POSA,
`
`suspendability is extremely important for an injectable suspension. (Exs.2016,
`
`105:6-15; 1031, 101:18-103:11.) A POSA will balance both suspendability and
`
`injectability in developing an injectable suspension. A POSA will increase the
`
`viscosity of the injectable suspension to redisperse the particles and thus improve
`
`
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
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`the suspendability. (Ex.1034, 1949.) But a POSA knows that if viscosity is too
`
`high, it would lead to injectability problems. Adjusting and optimizing viscosity is
`
`well within the normal routine of any POSA and one of the easiest factors for a
`
`formulator to control and measure. (Ex.1014, 33.)
`
`17. Syringeability and injectability are directly related to the particular
`
`mode of administration. For example, a POSA would not formulate an injectable
`
`suspension having a viscosity over of 40cps intravenously as this could potentially
`
`induce a pulmonary embolism. But a pulmonary embolism would not be a concern
`
`when injecting a viscous substance intramuscularly. And as was well known,
`
`intramuscular injections using castor oil (1000cp), which would be classified as a
`
`“high” viscosity according to the Patent Owners’ standard, was “safe and well
`
`tolerated” by patients. (Ex.1032.)
`
`18. Patent Owners and Dr. Berkland also argue that “conventional
`
`wisdom” was to keep viscosity low to make the suspension easier to inject.
`
`(Paper 33, 5.) And I agree. (Ex.2016, 96:19-97:2.) But Patent Owners do not
`
`quantify the meaning of “low” in any of their papers or exhibits. It would be
`
`readily apparent to a POSA that “low” means, as I stated in my deposition, low
`
`enough to be injected but yet viscous enough to suspend the microparticles in a
`
`
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`IPR2016-01096
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`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`vehicle. (Ex.2016, 96:19-21.) Low enough to be injected is a consistency that is
`
`capable of being pushed through the needle. (Paper 33, 5.) Patent Owners’ and
`
`Dr. Berkland assume this 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; 1032.) So although a formulator may not want an
`
`injection vehicle to have too “high” a viscosity it is well within conventional
`
`wisdom to provide an injection vehicle within the range claimed in the ’061 Patent.
`
`19. Although a POSA would have known that viscosity impacts
`
`syringeability and injectability, a POSA is not concerned about formulating a
`
`vehicle to achieve a particular viscosity. Instead, a formulator preparing an
`
`injection vehicle focuses on suspendability and injectability. In meeting these
`
`goals, viscosity is a consequence.
`
`20. As mentioned above, viscosity is a necessary attribute of injectable
`
`formulations and the easiest for a formulator to control. (Exs.1002 ¶22; 1014,
`
`33-34.) 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). (Exs.1002 ¶22; 1014, 33-34.)
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`9
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
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`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`And an injectable formulation containing microspheres or microparticles will
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`necessarily include viscosity enhancing or suspending agents, such as sodium
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`carboxymethylcellulose (CMC), to properly suspend the particles for injection.
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`(Exs.1008, 78-81; 1022, 305.) This was all well known at the time of the invention.
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`(Exs.1002 ¶22; 1014, 33-34.)
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`21. As I discussed during my deposition, viscosity becomes important, to
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`some extent, when suspending the active agent so that the agent does not settle,
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`which could then lead to clogging. (Ex.2016, 97:7-11.) So something like water,
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`which has a relatively negligible viscosity of 1cp, will allow settling of the agent
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`quickly. An agent placed in honey, with an approximate viscosity of 10,000cp, or
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`USP simple syrup with an approximate viscosity of 5,000cp, would take much
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`longer to settle. (Id.)
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`22. Clogging refers to the blockage of the syringe needle while
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`administering a suspension. It may occur because of a single large particle, or an
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`aggregate that blocks the lumen of the needle due to a bridging effect of the
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`particles. (Ex.1001, 1:65-2:1.) At the time of the invention, a POSA would know
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`that settling and agglomeration was an issue, which could lead to clogging.
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`Clogging at or near the needle end may be caused by restrictions to flow from the
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`10
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`suspension. This may involve a number of factors, such as the injection vehicle,
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`wetting of particles, particle size and distribution, particle shape, viscosity, and
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`flow characteristics of the suspension. (Exs.1014, 299; 1001, 1:65-2:6.)
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`23. A POSA would know that a viscosity that is too low, such as that of
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`water alone, would cause sedimentation and agglomeration of particles and that
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`this could lead to clogging of the needle. At the time of the invention, it would be
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`readily apparent to a POSA that an increase in viscosity of the vehicle to prevent
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`settling and potential needle clogging and would lead to a decrease in injection
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`failures caused by clogging.
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`24. An injectable suspension that includes a higher concentration of solids
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`(or solids having a larger particle size) is more difficult to successfully inject than
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`one with a lower concentration of solids or one having smaller particles.
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`Nevertheless, a POSA would know from the teachings of similar suspensions that
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`even a viscosity of 75cp is injectable. (Ex.1028, 7:3.) So a POSA formulating a
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`vehicle for an
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`injectable suspension having a higher concentration of
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`microparticles would know that viscosity could be raised as high as 75cp and
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`expect to achieve proper suspendablity and injectability.
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
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`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`VI. POLYMERS
`25. A polymer is defined as a macromolecule formed by the chemical
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`union of five or more identical combining units called monomers. (Ex.1036, 1993)
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`Polymers can be inorganic or organic. (Id.) Organic polymers can be naturally
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`occurring, synthetic, or semisynthetic. (Id.) Examples of naturally occurring
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`polymers are polysaccharide starches, cellulose, and proteins. (Id.) Examples of
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`synthetic polymers are thermoplastic and thermosetting elastomers. (Id.)
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`26. A copolymer
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`is an elastomer produced by
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`the simultaneous
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`polymerization
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`of
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`two
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`or more
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`dissimilar monomers.
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`(Id. 309)
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`Poly(lactic-co-glycolic acid) or PLGA is a well-known synthetic copolymer.
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`27. A polysaccharide is a macromolecule formed by the chemical union
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`of monosaccharides. (Ex.1036, 941 (“polysaccharide. A combination of nine or
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`more monosaccharides, linked together by glycosidic bonds. Examples: starch,
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`cellulose, glycogen.”) And as admitted by Patent Owners’ expert, Dr. Berkland, a
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`polysaccharide is a polymer. (Ex.1031, 81:15-82:3) Starch is a polysaccharide.
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`(Ex.1036, 941.) Thus, starch is a polymer. (Exs.1036, 1085-1086 (“starch . . . a
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`carbohydrate polymer” and “starch-based polymer . . . A reactive polyol derived
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`from a mixture of a starch with dibasic acids, hydrogen-donating compounds, and
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`12
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`catalysts dissolved in water the slurry is subjected to high temperatures and
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`pressures, yielding a low viscosity polymer in a 50% solids aqueous solution.”);
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`1037, 871 (“Plants convert excess D-glucose into a polymer known as starch.”).)
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`VII. MICROPARTICLES OF ’061 PATENT
`28. Although the ’061 Patent is directed to a particular “injection
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`vehicle”, as evidenced from its title (“Preparation of Injectable Suspensions
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`Having Improved Injectability”), Patent Owners appear to argue that their
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`microparticles should in some way distinguish their claims from that of the prior
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`art. But this argument fails to appreciate that microparticles are not the goal or
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`even alleged aspect of novelty of the ’061 Patent. In fact, the ’061 Patent
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`specifically states, on numerous occasions, that any microparticle will work with
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`their invention and that it is not limited to biodegradable or other types of
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`sustained-release microparticles. (Ex.1001, 4:27-30, 14:33-3, 16:11-24.) A POSA
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`would agree with this interpretation.
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`29. The Board acknowledged, and I agree, that the ’061 Patent defines
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`microparticle itself as a particle that requires “an active or other agent dispersed or
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`dissolved within a polymer that serves as a matrix or binder of the particle.”
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`(Paper 13, 25-26, Ex.1001, 5:15-18.) As the ’061 Patent does not limit the
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`
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`13
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`polymers for use in conjunction with forming microparticles or microspheres, a
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`POSA would appreciate that any polymer can satisfy this requirement. (Paper 13,
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`25-26, Ex.1001, 5:15-18.) It would be readily apparent to a POSA that starch is
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`one example of a polymer capable of serving as a matrix or binder of particles.
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`(Exs.1036, 1085-86; 1038, Abstract, 1:37-49 (“The polymer matrix . . . starch.”).)
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`30. The specification of
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`the ’061 Patent
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`later describes
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`that
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`the
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`microparticles may preferably include a polymeric binder. (Ex.1001, 14:10-11.)
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`But the specification describes the polymeric binder material in such a way that the
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`material is not required to be the same as the polymer used to form a matrix or bind
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`the microparticle. In other words, the specification does not require that the
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`polymeric binder material has any sort of function. Thus, although the polymeric
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`binder material may have binding qualities due to the nature of the component, it is
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`not required for the formation of the microparticle based on reading the claims in
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`light of the specification. The polymeric binder material is exemplified as being a
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`variety of substances, that include biodegradable, sustained-release polymers, such
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`as poly(d,l-lactic-co-glycolic acid) (“PLGA”). (Id. 14:10-32.) But, the specification
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`clearly states that the microparticles are not limited to biodegradable and sustained
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`release microparticles. (Id. 14:36-37.) So the examples of polymeric binder
`
`
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`14
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`LUYE1024
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`Case IPR2016-01096
`Supplemental Declaration of Patrick P. DeLuca, Ph.D.
`Patent No. 6,667,061
`Attorney Docket No. 9LUYE 7.1R-004
`
`materials, which include PLGA, are clearly not meant to be an exhaustive list. The
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`’061 Patent then goes on to describe how the polymeric binder material should
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`have a molecular weight high enough to form a polymer coating. (Id. 14:37-43.)
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`VIII. COMMERCIALLY AVAILABLE CMC
`31. Patent Owners argue that Petitioner’s inherency argument based on
`
`the Tracy Declaration relied on by Patent Owners to secure allowance of the
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`’061 Patent is incorrect because other CMCs were allegedly available on the
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`market at the time of the invention. But Patent Owners have not offered any
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`evidence that any of the CMCs allegedly outside of the scope of the invention were
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`actually available at the time of the appl