UNITED STATES PATENT AND TRADEMARKOFFICE
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC,
`
`Petitioner
`
`Vv.
`
`CUBIST PHARMACEUTICALS LLC,
`
`Patent Owner
`
`CASE IPR2019-_
`
`U.S. PATENT NO.9,138,456 B2
`
`DECLARATION OF RAJ SURYANARAYANAN, Ph.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`AMNEAL EX. 1003
`
`
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC,
`
`Petitioner
`
`Vv.
`
`CUBIST PHARMACEUTICALS LLC,
`
`Patent Owner
`
`CASE IPR2019-_
`
`U.S. PATENT NO.9,138,456 B2
`
`DECLARATION OF RAJ SURYANARAYANAN, Ph.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`I, Raj Suryanarayanan, declare as follows:
`
`I.
`
`INTRODUCTION
`
`l.
`
`I am over the age of twenty-one (21) and am competent to makethis
`
`Declaration.
`
`I reside in the United States at 2025 Autumn Place, Roseville,
`
`Minnesota.
`
`2.
`
`Iam a Professor in the Department of Pharmaceutics in the College of
`
`Pharmacyat the University of Minnesota, where I currently hold the William &
`
`Mildred Peters Endowed Chair.
`
`I am also an independent consultantin the field of
`
`pharmaceutics,
`
`A.
`
`3.
`
`Engagement
`
`I have been retained by counsel for Amneal Pharmaceuticals LLC in
`
`the above-captioned Inter Partes Review (“IPR”) matter as an independent
`
`technical expert.
`
`4,
`
`Aspart of this engagement,I have beenretained to review and
`
`evaluate whethercertain patents and publications disclose to a person ofordinary
`
`skill in the art (“POSA”) the subject matter of specific claims of United States
`
`Patent No, 9,138,456 (“the ‘456 Patent”) as of the time of the filing date of the
`
`application from which the ‘456 Patentissued. 1 expectto testify regarding the
`
`matters set forth in this declaration if asked to do so.
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`5.
`
`I am being compensated on an hourly basis for my work performedin
`
`connection with this case. I have received no additional compensation for my work
`
`in this case, and my compensation does not depend uponthe contents ofthis
`
`report, any testimony I mayprovide, or the ultimate outcome ofthe case.
`
`B.
`
`6.
`
`Background and Qualifications
`
`I received my B. Pharm. and M. Pharm. degrees in 1976 and 1978,
`
`respectively, from Banaras Hindu University, Varanasi, India.
`
`| subsequently
`
`received my M.Sc. and Ph.D. degrees in Pharmaceutics in 1981 and 1985,
`
`respectively, from the University of British Columbia, Vancouver, Canada.
`
`7.
`
`I joined the faculty of the University of Minnesota in 1985.
`
`I am
`
`currently a Professor in the Department of Pharmaceutics in the College of
`
`Pharmacy, where I have held the William & Mildred Peters Endowed Chair since
`
`2006.
`
`8.
`
`I was elected a fellow of the American Association of Pharmaceutical
`
`Scientists (AAPS) in 2002 and was awarded Outstanding Educatorof the Year by
`
`the AAPSin 2010.
`
`I am also the past chair of the Teachers of Pharmaceutics
`
`Second of the American Association of Colleges of Pharmacy (AACP).
`
`9.
`
`I ama Morse Alumni Distinguished Teaching Professor and I was
`
`inducted into the Academy of Distinguished Teachersat the University of
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`Minnesota in 1999, In 2005, I was honored with the Award for Outstanding
`
`Contributions to Graduate and Professional Education.
`
`10.
`
`I have received a numberofadditional awards and honors during my
`
`career, including the following: the Distinguished Alumnus Award from Banaras
`
`Hindu University in 2007; the David Grant Research Achievement Award in
`
`Physical Pharmacy from AAPSin 2013; and the PhRMA(Pharmaceutical
`
`Research and Manufacturers of America) Foundation Excellence Award in 2013.
`
`11.
`
`Ihave served as a memberof the United States Pharmacopeia (USP)
`
`Expert Committee (Excipients Test Methods).
`
`12.
`
`lamcurrently an associate editor for Molecular Pharmaceutics, and a
`
`memberof the editorial advisory board of the Journal ofPharmaceutical Sciences.
`
`13. My researchis in the area of pharmaceutical materials science and
`
`focuses on pharmaceutical formulations, including the physical characterization of
`
`drugs andexcipients, phase transitions that occur during pharmaceutical
`
`processing, specifically during freeze-drying and optimization of freeze-drying of
`
`pharmaceuticals.
`
`I have published extensively in the area of freeze-drying
`
`(lyophilization).
`
`I have written over 165 papers for publication in peer-reviewed
`
`journals, which are listed on the copy of my curriculum vitae (CV)attached hereto
`
`as Appendix B.
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`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`14.
`
`In the past five (5) years, I have served as an expert witnessin the
`
`followinglitigations:
`
`°
`
`Janssen Inc. v. *Teva Canada Limited, et al., Court File No. T-2195-12,
`
`Feb. 24, 2014 (deposition).
`
`°
`
`Pfizer Inc.; Wyeth, LLC; Wyeth Pharmaceuticals Inc. and PF Prism
`
`C.V., vs. *Anchen Pharmaceuticals, Inc., et al., June 11, 2014 (deposition).
`
`°
`
`Otsuka Pharmaceutical Co., Ltd., Plaintiff v. *Amneal Pharmaceuticals
`
`LLC, and Amneal Pharmaceuticals India Pvt. Ltd., Defendants. Civil Action
`
`No. 1:15-cv-1585-JBS-KMW,United States District Court, District of New
`
`Jersey, September 29, 2016 (deposition)
`
`°
`
`Fresenius Kabi USA, LLC,Plaintiff v. *Fera Pharmaceuticals, LLC,
`
`Oakwood Laboratories, LLC, Maia Pharmaceuticals,Inc., et al, Defendants.
`
`United States District Court for the District of New Jersey, Court File No.
`
`2:15-cv-03654-KM-MAH,February 14, 2017 (deposition)
`
`°
`
`Janssen Inc Applicant and - Teva Canada Limited and Minister Of
`
`Health Respondents and - Millenium Pharmaceuticals, Inc. Respondent
`
`Licensee and Sub-Licensor and United States of America Represented by the
`
`Secretary, Department of Health and Human Services Court File No. T-2195-
`
`12 — Testimony ata trial in Ottawa, Canada, February 19, 2018.
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`15.
`
`A description of my professional qualifications, including a listing of
`
`my specialties/expertise and professionalactivities, is also contained in my CV, a
`
`copy of which is attached hereto as Appendix B.
`
`C.
`
`16.
`
`Basis of My Opinions and Materials Considered
`
`In forming myopinions,I have relied upon my education, knowledge
`
`and experience with the lyophilization of materials intended for pharmaceutical
`
`use, including products intended to be reconstituted and then administered via
`
`intravenous injection. I have also relied upon my education, knowledge and
`
`experience with pharmaceuticals.
`
`17.
`
`For this work, I reviewed and considered the following materials:
`
`e US. Patent No. 9,138,456 (“the ‘456 Patent”; Ex. 1001), including the
`specification and claims; and
`
`e The prosecution history of United States Patent Application No.
`14/096,346(“the ‘346 Application”), i.e., the prosecution history of
`the ‘456 Patent (Ex. 1002).
`
`18.
`
`I have also been asked to review the subject matter disclosed by
`
`various patents and publications that are prior art to the “456 Patent, and have been
`
`further asked to compare the subject matter disclosed by those patents and
`
`publications to claims 1, 2, and 7-11 of the ‘456 Patent and determine whether
`
`those patents and printed publications disclosed the claimed subject matter to a
`
`POSApriorto the effective filing date of the ‘456 Patent, whichI have been
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`instructed to assume is November 23, 2009 for purposes of my analysis. The
`
`principal documents that I have analyzed with regard to their teachings of subject
`
`matter claimed in the ‘456 Patentare listed below:
`
`Cubicin® label (downloaded on December7, 2018 from
`https://www.accessdata.fda.gov/drugsatfda docs/nda/2003/21-
`572 Cubicin Prmtlbl.pdf) (Ex. 1004);
`
`United States Patent No. 6,136,783 (Ex. 1005; “Neururkar’),
`
`United States Patent No. 7,112,565 B2 (Ex. 1006; “Sawai”);
`
`United States Patent Application Publication No. 2010/0137197 (Ex.
`1007; “Mittal’’);
`
`European Patent Application Publication No. EP 0 386 951 A2 (Ex.
`1008; “Jaman’’);
`
`United States Patent No. 8,835,382 (Ex. 1009); and
`
`Caspofungin® label (downloaded on December12, 2018 from
`https://www.accessdata.fda.gov/drugsatfda docs/label/2005/21227s01
`Slbl.pdf) (Ex. 1010).
`
`19,
`
`The documents that I have analyzed are also identified on the list of
`
`Exhibits attached hereto as Appendix A.
`
`Il.
`
`PATENT PRINCIPLES
`
`20.
`
`I am a scientist and researcher by profession, and the opinions|
`
`express in this declaration involve the application of my knowledge and experience
`
`to the evaluation of certain prior art with respect to the ‘456 Patent. [ am not a
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`lawyer and have not been trained in the law of patents. Therefore, the attorneys
`
`from Dickinson Wright PLLC, who represent Amnea! Pharmaceuticals LLC,
`
`provided me with guidance as to the applicable patent law in this matter. The
`
`paragraphs below express my understanding of how I must apply current legal
`
`principles related to patent validity to my analysis.
`
`21.
`
`It is my understanding that in determining whethera patent claim
`
`underinter partes review before the United States Patent Office (PTO)is
`
`anticipated or obvious in view ofthe prior art, the PTO must construe the claim by
`
`giving the claim termstheir “plain and ordinary meaning” as would be understood
`
`by a “person ofordinary skill in the relevant art” (a “POSA”).
`
`It is further my
`
`understandingthat the “plain and ordinary meaning”ofa term is “the meaning that
`
`the term would have to a person ofordinary skill in the art in question at the time of
`
`the invention.” For the purposesofthis review, I have construed each claim term in
`
`accordance with its plain and ordinary meaning to a POSA.
`
`22.
`
`It is my understandingthat a claim is anticipated under 35 U.S.C.§
`
`102 if each and every limitation ofthe claim is disclosed in a single prior art
`
`reference,either expressly or inherently. ] understand inherent disclosure to mean
`
`that the claim feature necessarily flows from the disclosure ofthe prior art
`
`reference. I understand that a claim is unpatentable under 35 U.S.C. § 103if the
`
`claimed subject matter as a whole would have been obviousto a POSAatthe time
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`of the alleged invention, which I have been instructed to treat at present as the
`
`effective filing date of the ‘456 Patent. I also understandthat an obviousness
`
`analysis takes into accountthe scope and contentofthepriorart, the differences
`
`betweenthe claimed subject matter andthe priorart, and the level of ordinary skill
`
`in the art at the timeof the invention.Finally, ] understand that 1 must consider any
`
`known secondary evidence that might show non-obviousnessof the application,
`
`such as long felt but unfulfilled need for the claimed invention,failure by others to
`
`comeupwith the claimed invention, commercial success ofthe claimed invention,
`
`praise ofthe invention by othersin the field, unexpected results achieved by the
`
`invention,the taking oflicenses underthe patent by others, expressions of surprise
`
`by experts and POSAsat the making ofthe invention, and the patentee proceeded
`
`contrary to the conventional wisdom ofthepriorart. But the secondary evidence
`
`mustbe tied specifically to claim features that are argued to be patentable, and not
`
`those already in the public domain.| appreciate that secondary considerations must
`
`be assessed as part of the overall obviousnessanalysis(i.¢., as opposed to
`
`analyzing theprior art, reaching a tentative conclusion, and then assessing, whether
`
`objective indicia alter that conclusion).
`
`23.
`
`Put another way, my understandingis that notall innovationsare
`
`patentable. Evenif a claimed product or method is not explicitly described in its
`
`entirety in a single prior art reference, the patent claim willstill be denied if the
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`claim would have been obvious to a POSAatthe timeof the patent application
`
`filing.
`
`24.
`
`In determining the scope and contentofthe priorart, it is my
`
`understanding that a reference is considered appropriate priorart if it falls within
`
`the field of the inventor’s endeavor. In addition, a referenceis prior art if it is
`
`reasonably pertinentto the particular problem with whichthe inventor was
`
`involved. A reference is reasonably pertinentif it logically would have
`
`commendeditself to an inventor’s attention in considering his problem.Ifa
`
`referencerelates to the same problem as the claimedinvention, that supports use of
`
`the reference asprior art in an obviousness analysis.
`
`25.
`
`To assess the differences betweenprior art and the claimed subject
`
`matter, it is my understanding that 35 U.S.C. § 103 requires the claimed invention
`
`to be considered as a whole. This “as a whole” assessment requires showing thata
`
`POSA atthe time of invention, confronted by the same problemsas the inventor
`
`and with no knowledgeofthe claimed invention, would have selected the elements
`
`from the prior art and combined them in the claimed manner.
`
`26.
`
`In determining whether the subject matter as a whole would have been
`
`considered obviousat the time that the patent application was filed, by a POSA,I
`
`have been informedofseveral principles regarding the combination of elements of
`
`the priorart. First, a combination of familiar elements according to known methods
`
`10
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`is likely to be obvious whenit yields predictable results. Likewise, combinations
`
`involving simple substitution of one known elementfor anotherto obtain
`
`predictable results, a predictable use ofprior art elements accordingto their
`
`established functions, applying a knowntechnique to a knowndevice (method or
`
`product) ready for improvementto yield predictableresults, and choosing from a
`
`finite numberofidentified, predictable solutions to solve a problem arelikely to be
`
`obvious. Thus,if a POSA can implementa “predictable variation”in a prior art
`
`device, and would see the benefit from doing so, such a variation would be obvious.
`
`Also, whenthere is pressure to solve a problem andthereare a finite number of
`
`identifiable, predictable solutions, it would be reasonable for a POSA to pursue
`
`those options that fall within his or her technical grasp. If such a process leads to
`
`the claimed invention,then thelatter is not an innovation, but more the result of
`
`ordinary skill and common sense.
`
`27.
`
`1 also understandthat the “teaching, suggestion, or motivation”test is
`
`a useful guide in establishing a rationale for combining elements of the priorart.
`
`This test poses the question as to whetherthere is an explicit teaching, suggestion,
`
`or motivation in the prior art to combinepriorart elements in a way that realizes
`
`the claimed invention. Though useful to the obviousness inquiry,| understand that
`
`this test should not betreated asa rigid rule.It is not necessary to seek out precise
`
`teachings;it is permissible to consider the inferences and creative steps that a
`
`1]
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`POSA(whois considered to have an ordinary level of creativity and is not an
`
`“automaton”) would employ.
`
`28.
`
`It is my understanding that wheninterpreting the claimsof the ‘456
`
`Patent, I must do so based on the perspective of a POSAatthe relevantpriority
`
`date. My understandingis thatthe earliest priority date that is claimed by the ‘456
`
`Patent is November 23, 2009,
`
`IH. THE ‘456 PATENT
`
`A.
`
`29,
`
`Technology
`
`The ‘456 Patentis directed to formulations of daptomycin, a cyclic
`
`lipopeptide having the followingstructure:
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`Daptomycin
`
`Q
`
`NH,
`
`NH
`
`0.
`
`°
`
`0
`
`:
`
`\
`
`8
`
`°
`
`NH
`
`HO,C
`HN
`HOa 0
`
`NH
`
`oO
`
`HN
`
`HOAC
`
`°
`
`0
`
`HN
`
`N
`H
`© 10,0
`
`HN
`
`H
`N
`
`0
`
`CORN
`.
`
`H
`
`H
`
`o
`N(CH)gCHs
`
`/
`
`H
`
`O
`CO,H
`
`NH
`
`30.
`
`Cyclic lipopeptides are compounds which havea ring composed of
`
`multiple peptide residues coupledto a lipid or lipophilic tail. In the structure
`
`depicted above, whichis FIG. 1 of the ‘456 Patent, the peptide ring is located on
`
`the left side andthelipid or lipophilic tail extends away from it towardsthe right.
`
`31.
`
`Manycyclic lipopeptides have been found useful as pharmaceuticals,
`
`includingas antibiotics and antifungals. Approved antifungal cyclic lipopeptides
`
`include caspofungin (approved 2001), micafungin (approved 2005), and
`
`anidulafungin (approved 2006).
`
`13
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`32.
`
`Cyclic lipopeptides pharmaceuticals, like many other polypeptide and
`
`protein pharmaceuticals, are often lyophilized prior to storage in orderto increase
`
`the shelf Jife of the active material. The cyclic lipopeptides caspofungin,
`
`micafungin, and anidulafungin, for example, are all supplied as lyophilized
`
`powdersthat are reconstituted priorto use.
`
`33.
`
`Lyophilization (or freeze-drying) is a process in which wateris
`
`removed from a materialafter it is frozen and placed under a vacuum,allowing the
`
`ice to changedirectly from solid to vapor without passing throughaliquid phase.
`
`This use of sublimation avoids the need to raise the temperature of the material, as
`
`is required for evaporation.
`
`34.
`
`Generally, the lyophilization process consists of three stages: freezing,
`
`primary drying, and secondary drying.
`
`35. During the freezing stage, the liquid formulationis cooled.
`
`Crystalline ice forms from the liquid, thereby resulting in a progressive freeze
`
`concentration of the liquid. Ultimately, this highly concentrated and viscous
`
`solution solidifies, yielding an amorphous,crystalline, or a partially crystalline
`
`phase.
`
`36. During the primary drying stage, the ice formed during freezingis
`
`removed by sublimation under vacuum at temperatures below room temperature.
`
`This step traditionally is carried out at chamber pressures of 40-400 Torr and shelf
`
`14
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`temperatures ranging from -30°C to 10°C. Throughoutthis stage, the productis
`
`maintained in the “solid state” with retention ofthe structure established in the
`
`freezing step.
`
`37.
`
`The secondary drying stage involves removing therelatively small
`
`amount of bound water remaining in the product by desorption. During this stage,
`
`the temperature is increased to promote adequate desorption rates and achieve the
`
`desired residual moisture.
`
`38.
`
`Despite being a milder way of removing water than evaporation,
`
`lyophilization can still damage the material being processed. Freezing damage, for
`
`example, can occur with labile proteins and peptides. Rapid nucleation and growth
`
`rate resulting from a high degree of super-cooling can leadto a large number of
`
`small ice crystals, which in turn presents a large ice—waterinterface. Exposure of
`
`proteins and peptidesto this ice—water interface can cause denaturation and/or
`
`degradation.
`
`In addition, small ice crystals can result in pores with high surface to
`
`volumeratios, resulting in lower diffusive flux and slower sublimation rates, both
`
`of which can affect the drying rate as well as the structure ofthe final dried cake.
`
`Damageduring the drying stages can result from removalof the hydration shell
`
`from a protein or peptide, which destabilizes the structure in the absence ofoneor
`
`more appropriate stabilizers.
`
`15
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`39.
`
`Amongthe potential stabilizers, disaccharides have proven to be most
`
`effective in stabilizing products such as proteins and peptides during
`
`lyophilization. Sucrose and trehalose are both “inert” and have been used
`
`successfully in stabilizing protein and peptide formulations. When choosing
`
`between these two disaccharides,it is known by POSAsthat sucroseis less
`
`expensive and generally more readily available than trehalose. Lactose, on the
`
`other hand, is a reducing disaccharide and so can degrade proteins and peptides by
`
`means of the Maillard reaction.
`
`40.
`
`Two hypotheses have been postulated to explain the stabilizing effects
`
`of disaccharides:
`
`@ The water replacement hypothesis: Disaccharides have been found
`
`to interact with these products by hydrogen bondingsimilarly to the
`
`replaced water.
`
`@ Thevitrification hypothesis: Disaccharides form sugar glasses of
`
`extremely high viscosity, immobilizing the drug and water molecules.
`
`41,
`
`The design of an optimized lyophilized formulation is dependent on
`
`the properties of the active pharmaceutical ingredient and intended route of
`
`administration. Consequently, in addition to the active protein or peptide and the
`
`stabilizer, a formulation may also include one or more excipients with a specific
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`function (or functions). Buffers (also referred to as pH adjusters) and bulking
`
`agents are two commonexcipients.
`
`42.
`
`Buffers are used in pharmaceutical formulations to maintain the pH in
`
`the desired range, before and after reconstitution. In the development ofa
`
`lyophilized formulation,it is preferable to use low concentrations of buffer to
`
`avoid selective crystallization of a buffer componentleading to pH changes during
`
`freezing.
`
`43,
`
`The desired pH range, and byextensionthe buffer selection, musttake
`
`into consideration the other formulation components, includingthe active
`
`ingredient andstabilizer, and their stability as a function of pH. Sucrose, for
`
`example, is hydrolyzed at pH less than 4.
`
`44,
`
`Bulking agents are used to provide bulk to the formulation. Thisis
`
`important in cases in which low concentrationsofthe active ingredient are used.
`
`Crystalline bulking agents such as mannitolare frequently used, since they are
`
`known by POSAsto produce an elegant cake with desired mechanical properties.
`
`45. Daptomycin wasfirst approved for human use bythe US. Food &
`
`Drug Administration in 2003. Muchlike many other approved cyclic lipopeptide
`
`pharmaceuticals, including caspofungin (Cancidas*), micafungin (Mycamine*),
`
`and anidulafungin (Eraxis*), the approved daptomycin product (Cubicin*) is
`
`lyophilized daptomycin (which also contains a small amount of sodium hydroxide
`
`17
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`to adjust pH). Ex. 1004 at 14-18. When used, the lyophilized daptomycin cakeis
`
`first reconstituted with 0.9% sodium chloride injection to be administered by
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`intravenousinfusion. Ex. 1004 at 486-490.
`
`46. Asnoted in the label, the Cubicin® product’s lyophilized cake,
`
`however, mustbe stored at reduced temperature (2°C - 8°C). Ex.1004 at 514-515.
`
`Based on my experience,it is my understanding that this is done to prevent
`
`degradationof the active ingredient. Thelabel of the Cubicin” productalso
`
`specifically notes the need to avoid exposing the drug productto excessive heat
`
`(ie. temperatures above 40°C). Id.
`
`47.
`
`It is, and was at the relevant time, known to POSAsthatstoring and
`
`shipping lyophilized materials at room temperature is easier and cheaper than
`
`storing and shipping the same materials at low (i.e. less than ambient) temperature.
`
`Whena product can bestored at room temperature,there is no longer a need for
`
`expensive cooling equipment, suchasrefrigerators or cold rooms, and no
`
`requirements for special handling. Similarly, shipping at room temperature
`
`eliminates the needfor refrigerated packaging, such as dry ice packsand insulated
`
`boxes, and for refrigerated transportation, such asrefrigerated trucks and train cars.
`
`Moreover, storing and shipping lyophilized materials at room temperature
`
`eliminates the need for expensive temperature monitoring equipment and labor-
`
`AMNEAL EX. 1003
`
`
`
`intensive protocols for confirming that the requisite temperature has and is being
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`maintained.
`
`B.
`
`The Claimed Invention
`
`48.
`
`The ‘456 Patent claims pharmaceutical formulations ofdaptomycin,the
`
`structure of which has been reproduced above.
`
`49,
`
`Independent claims | and 15 recite a solid pharmaceutical daptomycin
`
`composition prepared by lyophilizing an aqueous solution of daptomycin and
`
`sucrose. Claims 2-9 depend from claim 1, with claim 2 limiting the molarratio of
`
`daptomycin to sucrose, claims 3-6 requiring the presence of a buffer in the aqueous
`
`solution, and claims 7-9 limiting the pH of the aqueoussolution. Claims 10 and 11
`
`claim a pharmaceutical product containing the solid pharmaceutical daptomycin
`
`composition of claim | plus a pharmaceutically acceptable diluent, such as sterile
`
`waterfor injection. Claims 12-14 claim a solid pharmaceutical daptomycin
`
`composition prepared by lyophilizing an aqueous solution of daptomycin, sucrose,
`
`and a buffering agent.
`
`50.
`
`The processrecited in claims 1-9 of the ‘456 Patent involves
`
`lyophilizing an aqueous daptomycin solution containing daptomycin and sucrose.
`
`Claim 2 is directed to the molar ratio of daptomycin to sucrose, and recites a range
`
`of about 1:1.12 to about 1:8.98. Claim 3-6 require a third componentin the
`
`aqueous daptomycin solution,viz. a buffering agent (claims 4-6 further define that
`
`19
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`buffering agent). Claims 7-9 are directed to the pH of the aqueous daptomycin
`
`solution and recite particular ranges (claims 7 and 8) or a value(claim 9).
`
`51.
`
`The processesrecited in claims 12-14 and 15 ofthe ‘465 Patent
`
`involve the same three steps: (i) adding sucrose to an aqueous daptomycin solution
`
`to form a daptomycin sugar formulation; (ii) adjusting the pH to about6.5 to about
`
`7.5; and(iii) converting the daptomycin sugar formulationinto a solid
`
`pharmaceutical daptomycin composition. Claims 12-14 recite that the aqueous
`
`daptomycinsolution has an initial pH between about 4.5 and about 5.0 and also
`
`include the additional step of adding a buffering agent to that aqueous daptomycin
`
`solution prior to the step of adding sucrose (claims 13 and 14 further define the
`
`buffering agent).
`
`52.
`
`The ‘346 Application, from which the ‘456 Patent issued, was filed
`
`after the Cubicin® product wasfirst approved for commercial sale by the FDA.
`
`Accordingly, in describing the BACKGROUNDofthe invention,the specification
`
`of the ‘456 Patent notes that Cubicin® “is supplied as a lyophilized powderthat is
`
`reconstituted and compounded as a pharmaceutical composition for parenteral
`
`administration.” Ex. 1001 at 1:33-37. The specification further notes that the
`
`reconstituted formulation can be prepared from the lyophilized cake by
`
`“combination with a medically appropriate amount of pharmaceutical diluent(e.g.,
`
`0.9% aqueous sodium chloride).” Jd. at 1:37-41.
`
`20
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`53. Although not expressly stating that there are problems and/or
`
`limitations associated with Cubicin®, the specification nevertheless states that “[t]
`
`here is a need for solid lipopeptide compositionsthat rapidly reconstitute (e.g., in
`
`less than about 5 minutes) .. ..” Ex. 1001 at 2:39-43. The specification further
`
`states that “[t]here is also a need for solid daptomycin compositions with improved
`
`chemicalstability ... (i.e., higher total percent daptomycinpurity over time),
`
`providing advantages of longershelflife, increased tolerance for more varied
`
`storage conditions(e.g., higher temperature or humidity) .
`
`. ..” /d. at 2:51-58.
`
`54.
`
`Asoriginally filed, the broadest claim of the ‘346 Application was
`
`directed to solid pharmaceutical daptomycin compositions having certain
`
`dissolution characteristics, but was not limited to any particular process of
`
`preparation. See Ex. 2 at 606, 640. Nordid that claimed composition rquire
`
`sucrose (instead, just “one or more sugars”). See id. While the ‘346 Application
`
`was pending, however,this claim was rejected by the examinerat the PTO on
`
`various grounds. Amongthose grounds, the examinerrejected certain claims as
`
`being identically disclosed by Inman (Ex. 1008).
`
`55.
`
`In responseto the rejection over Jaman, the applicant amended the
`
`claim to require that the solid pharmaceutical daptomycin solution be prepared by
`
`lyophilizing an aqueous solution of daptomycin and sucrose. Ex. 1002 at 55.
`
`In
`
`the REMARKSthat accompanied that amendment, applicant’s representative
`
`21
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`argued that this distinguished the claims from Jnman because “Inmanfails to
`
`disclose solid pharmaceutical formulations, the subject-matter of Applicants’
`
`claims.
`
`In addition, Inman discloses buffered solutions of dextrose, not sucrose, as
`
`required bythe instant claims.” /d. at 61 (emphasisin original).
`
`In addition, in
`
`response to the examiner’s rejection of the pending claims for obviousness,
`
`applicant’s representative argued that the cited priorart
`
`does not teach the surprising stabilizing effect of sucrose on solid
`daptomycin as discovered by the instant inventors, as shown in Table
`4... and in Table 9 (Figure 8) of the application as filed. For
`example, as shownin Table 4, combining 15-20% sucrose with
`daptomycin in a lyophilized composition increases daptomycin
`stability by about 78-96% .
`.
`.. In addition, Table 9 (Figure 8) shows
`that sucrose increases the chemical stability of solid daptomycin
`compositions overtime at elevated temperature.
`
`Id. at 63. Applicant’s representative also contended that the priorart did not “teach
`
`or suggest the surprising rapid reconstitution of solid daptomycin compositions
`
`containing sucrose.” Jd. at 64.
`
`56.
`
`Following applicant’s amendment, the examiner allowed the claims of
`
`the ‘346 Application on the groundsthat “[a] solid pharmaceutical daptomycin
`
`composition comprising daptomycin and sucrose recited in [the] instant claims...
`
`is free of prior art.” Ex. 1002 at 34. The examinerfurther stated that “Applicant
`
`has presented unexpected results of surprising rapid reconstitution ofsolid
`
`daptomycin compositions comprising sucrose and increased chemicalstability of
`
`22
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`such composition [sic] ....” Jd. The ‘346 Application subsequently issued as the
`
`‘456 Patent. Jd. at 1.
`
`IV.
`
`PERSON OF ORDINARYSKILL IN THE ART
`
`57.
`
`[have been informedthat a “person of ordinary skill in the art” (a
`
`“POQSA”) is a hypothetical person to whom anexpert in the relevantfield could
`
`assign a routine task with reasonable confidencethatthe task would be
`
`successfully carried out. I have been informedthatthe level ofskill in the art is
`
`evidencedby prior art references. In this case, the ‘456 Patentis directed to a
`
`particular lyophilized formulation of daptomycin and processes of making the
`
`same. Accordingly, a POSAinthefield of the ‘456 Patent as of November23,
`
`2009, would have hadatleast a bachelorof science degree in one or more of the
`
`pharmaceuticalsciences, including pharmaceutical chemistry and/or
`
`pharmaceutics, or a related technicalfield, and either an advanced degree (such as
`
`a masters or doctorate) or an equivalent amount of work experience,i.e. 3-5 years,
`
`in an arearelating to lyophilized pharmaceutical formulations.
`
`58.
`
`Based on my experience,I have an understanding ofthe capabilities
`
`ofa POSA.I have supervised and directed many suchpersons overthe course of
`
`my career. Further, I had those capabilities myself at the time the application for
`
`the ‘456 Patent waseffectively filed. That is, at least by 2009, when the earliest
`
`23
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
`
`priority application wasfiled, I was already in possession of multiple advanced
`
`degrees (masters and doctorate) in one of the pharmaceutical sciences and I had
`
`considerably more thanthe requisite 3-5 years of work experiencein areas relating
`
`to lyophilized pharmaceutical formulations.
`
`In fact, by 2009, J already had over
`
`fifteen (15) years of actual, hands-on experience with lyophilized pharmaceutical
`
`formulations and had not only received multiple advanced degrees in the
`
`pharmaceutical sciences myself, but had also mentored over a dozen Ph.D.
`
`students to completion of their doctorates in one of the pharmaceutical sciences.
`
`Vv.
`
`CLAIM CONSTRUCTION
`
`59.
`
`I concur with Petitioner that none of the terms used in the claims of
`
`the ‘456 Patent appears to be expressly defined anywherein the specification.
`
`Consequently, counsel for Petitioner has informed methatal
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