UNITED STATES PATENT AND TRADEMARK OFFICE
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC,
`
`Petitioner
`
`V.
`
`CUBIST PHARMACEUTICALS LLC,
`
`Patent Owner
`
`CASE IPR2019-__I .
`
`U.S. PATENT NO. 9,138,456 B2
`
`DECLARATION OF RAJ SURYANARAYANAN, Ph.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`US. Patent and Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`239709551
`
`AMNEAL EX. 1003
`
`
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC,
`
`Petitioner
`
`V.
`
`CUBIST PHARMACEUTICALS LLC,
`
`Patent Owner
`
`CASE IPR2019-__I .
`
`U.S. PATENT NO. 9,138,456 B2
`
`DECLARATION OF RAJ SURYANARAYANAN, Ph.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`US. Patent and Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`239709551
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
`
`I, Raj Suryanarayanan, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of twenty-one (21) and am competent to make this
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`Declaration.
`
`I reside in the United States at 2025 Autumn Place, Roseville,
`
`Minnesota.
`
`2.
`
`1 am a Professor in the Department of Pharmaceutics in the College of
`
`Pharmacy at the University of Minnesota, where I currently hold the William &
`
`Mildred Peters Endowed Chair.
`
`1 am also an independent consultant in the field of
`
`pharmaceutics.
`
`A.
`
`Engagement
`
`3.
`
`I have been retained by counsel for Amneal Pharmaceuticals LLC in
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`the above—captioned Inter Partes Review (“IPR”) matter as an independent
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`technical expert.
`
`4.
`
`As part of this engagement, 1 have been retained to review and
`
`evaluate whether certain patents and publications disclose to a person of ordinary
`
`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 Patent issued. I expect to testify regarding the
`
`matters set forth in this declaration if asked to do so.
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`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`US. Patent No. 9,138,456 B2
`
`5.
`
`I am being compensated on an hourly basis for my work performed in
`
`connection with this case. I have received no additional compensation for my work
`
`in this case, and my compensation does not depend upon the contents of this
`
`report, any testimony I may provide, or the ultimate outcome of the case.
`
`B.
`
`6.
`
`Background and Qualifications
`
`I received my B. Pharm. and M. Pharm. degrees in 1976 and 1978,
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`respectively, from Banaras Hindu University, Varanasi, India.
`
`I subsequently
`
`received my M.Sc. and Ph.D. degrees in Pharmaceutics in 1981 and 1985,
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`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 Educator of the Year by
`
`the AAPS in 2010.
`
`I am also the past chair of the Teachers of Pharmaceutics
`
`Second of the American Association of Colleges of Pharmacy (AACP).
`
`9.
`
`I am a Morse Alumni Distinguished Teaching Professor and I was
`
`inducted into the Academy of Distinguished Teachers at the University of
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`U.S. Patent No. 9,138,456 82
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`Minnesota in 1999. In 2005, I was honored with the Award for Outstanding
`
`Contributions to Graduate and Professional Education.
`
`10.
`
`I have received a number of additional awards and honors during my
`
`career, including the following: the Distinguished Alumnus Award from Banaras
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`Hindu University in 2007', the David Grant Research Achievement Award in
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`Physical Pharmacy from AAPS in 2013; and the PhRMA (Pharmaceutical
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`Research and Manufacturers of America) Foundation Excellence Award in 2013.
`
`1 1.
`
`1 have served as a member of the United States Pharmacopeia (USP)
`
`Expert Committee (Excipicnts Test Methods).
`
`12.
`
`I am currently an associate editor for Molecular Pharmaceutics, and a
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`member of the editorial advisory board of the Journal ofPharmaceutical Sciences.
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`13. My research is in the area of pharmaceutical materials science and
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`focuses on pharmaceutical formulations, including the physical characterization of
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`drugs and excipients, phase transitions that occur during pharmaceutical
`
`processing, specifically during freeze-drying and optimization of freeze-drying of
`
`pharmaceuticals.
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`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, PhD.
`US. Patent No. 9,138,456 82
`
`14.
`
`In the past five (5) years, I have served as an expert witness in the
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`following litigations:
`
`-
`
`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,
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`Oakwood Laboratories, LLC, Maia Pharmaceuticals, Inc., et a1, Defendants.
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`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 at a trial in Ottawa, Canada, February 19, 2018.
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`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`U.S. Patent No. 9,138,456 BZ
`
`15.
`
`A description of my professional qualifications, including a listing of
`
`my specialties/expertise and professional activities, is also contained in my CV, a
`
`copy of which is attached hereto as Appendix B.
`
`C.
`
`Basis of My Opinions and Materials Considered
`
`16.
`
`In forming my opinions, 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:
`
`0 U.S. Patent No. 9,138,456 (“the ‘456 Patent”; Bx. 1001), including the
`specification and claims; and
`
`o 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
`
`POSA prior to the effective filing date of the ‘456 Patent, which I have been
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`US. 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 Patent are listed below:
`
`0 Cubicin® label (downloaded on December 7, 2018 from
`https://www.accessdata.fda.gov/drugsatfda docs/nda/2003/21-
`572 Cubicin Pmtlblpdt) (Ex. 1004);
`
`0 United States Patent No. 6,136,783 (Ex. 1005; “Neururkar”);
`
`0 United States Patent No. 7,112,565 BZ (Ex. 1006; “Sawai”);
`
`0 United States Patent Application Publication No. 2010/0137197 (Ex.
`1007; “Mittal”);
`
`0 European Patent Application Publication No. EP 0 386 951 A2 (Ex.
`1008; “Inman”);
`
`0 United States Patent No. 8,835,382 (Ex. 1009); and
`
`o Caspofungini‘ label (downloaded on December 12, 2018 from
`httpszfi’wwwaccessdata.fda.gov«’drugsatfda docs/labeIEZOOSIZ1227501
`Slblpdf) (Ex. 1010).
`
`19.
`
`The documents that I have analyzed are also identified on the list of
`
`Exhibits attached hereto as Appendix A.
`
`II.
`
`PATENT PRINCIPLES
`
`20.
`
`I am a scientist and researcher by profession, and the opinions I
`
`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. I am not a
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. 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 Amneal 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 whether a patent claim
`
`under inter partes review before the United States Patent Office (PTO) is
`
`anticipated or obvious in view of the prior art, the PTO must construe the claim by
`
`giving the claim terms their “plain and ordinary meaning” as would be understood
`
`by a “person of ordinary skill in the relevant art” (a “POSA”).
`
`It is further my
`
`understanding that the “plain and ordinary meaning” of a term is “the meaning that
`
`the term would have to a person of ordinary skill in the art in question at the time of
`
`the invention.” For the purposes of this review, I have construed each claim term in
`
`accordance with its plain and ordinary meaning to a POSA.
`
`22.
`
`It is my understanding that a claim is anticipated under 35 U.S.C. §
`
`102 if each and every limitation of the claim is disclosed in a single prior art
`
`reference, either expressly or inherently. I understand inherent disclosure to mean
`
`that the claim feature necessarily flows from the disclosure of the prior art
`
`reference. I understand that a claim is unpatentable under 35 U.S.C. § 103 if the
`
`claimed subject matter as a whole would have been obvious to a POSA at the time
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`U.S. Patent No. 9,138,456 BZ
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`of the alleged invention, which I have been instructed to treat at present as the
`
`effective filing date of the ‘456 Patent. I also understand that an obviousness
`
`analysis takes into account the scope and content of the prior art, the differences
`
`between the claimed subject matter and the prior art, and the level of ordinary skill
`
`in the art at the time of the invention. Finally, I understand that I must consider any
`
`known secondary evidence that might show non-obviousness of the application,
`
`such as long felt but unfulfilled need for the claimed invention, failure by others to
`
`come up with the claimed invention, commercial success of the claimed invention,
`
`praise of the invention by others in the field, unexpected results achieved by the
`
`invention, the taking of licenses under the patent by others, expressions of surprise
`
`by experts and POSAs at the making of the invention, and the patentee proceeded
`
`contrary to the conventional wisdom of the prior art. But the secondary evidence
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`must be tied specifically to claim features that are argued to be patentable, and not
`
`those already in the public domain. I appreciate that secondary considerations must
`
`be assessed as part of the overall obviousness analysis (126., as opposed to
`
`analyzing the prior art, reaching a tentative conclusion, and then assessing whether
`
`objective indicia alter that conclusion).
`
`23.
`
`Put another way, my understanding is that not all innovations are
`
`patentable. Even if a claimed product or method is not explicitly described in its
`
`entirety in a single prior art reference, the patent claim will still be denied if the
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`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
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`claim would have been obvious to a POSA at the time of the patent application
`
`filing.
`
`24.
`
`In determining the scope and content of the prior art, it is my
`
`understanding that a reference is considered appropriate prior art if it falls within
`
`the field of the inventor’s endeavor. In addition, a reference is prior art if it is
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`reasonably pertinent to the particular problem with which the inventor was
`
`involved. A reference is reasonably pertinent if it logically would have
`
`commended itself to an inventor’s attention in considering his problem. If a
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`reference relates to the same problem as the claimed invention, that supports use of
`
`the reference as prior art in an obviousness analysis.
`
`25.
`
`To assess the differences between prior 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 that a
`
`POSA at the time of invention, confronted by the same problems as the inventor
`
`and with no knowledge of the 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 obvious at the time that the patent application was filed, by a POSA, I
`
`have been informed of several principles regarding the combination of elements of
`
`the prior art. 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, PhD.
`US. Patent No. 9,138,456 B2
`
`is likely to be obvious when it yields predictable results. Likewise, combinations
`
`involving simple substitution of one known element for another to obtain
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`predictable results, a predictable use of prior art elements according to their
`
`established fianctions, applying a known technique to a known device (method or
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`product) ready for improvement to yield predictable results, and choosing from a
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`finite number of identified, predictable solutions to solve a problem are likely to be
`
`obvious. Thus, if a POSA can implement a “predictable variation” in a prior art
`
`device, and would see the benefit from doing so, such a variation would be obvious.
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`Also, when there is pressure to solve a problem and there are a finite number of
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`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 the latter is not an innovation, but more the result of
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`ordinary skill and common sense.
`
`27.
`
`I also understand that the “teaching, suggestion, or motivation” test is
`
`a useful guide in establishing a rationale for combining elements of the prior art.
`
`This test poses the question as to whether there is an explicit teaching, suggestion,
`
`or motivation in the prior art to combine prior art elements in a way that realizes
`
`the claimed invention. Though useful to the obviousness inquiry, I understand that
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`this test should not be treated as a rigid rule. It is not necessary to seek out precise
`
`teachings; it is permissible to consider the inferences and creative steps that a
`
`11
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
`
`POSA (who is considered to have an ordinary level of creativity and is not an
`
`“automaton”) would employ.
`
`28.
`
`It is my understanding that when interpreting the claims of the ‘456
`
`Patent, I must do so based on the perspective of a POSA at the relevant priority
`
`date. My understanding is that the earliest priority date that is claimed by the ‘456
`
`Patent is November 23, 2009.
`
`III. THE ‘456 PATENT
`
`A.
`
`Technology
`
`29.
`
`The ‘456 Patent is directed to formulations of daptomycin, a cyclic
`
`lipopeptide having the following structure:
`
`12
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
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`Daptomycin
`
`0
`
`MHZ
`
`sick—f0 O
`
`NH
`
`O
`
`0
`
`N
`
`R
`
`g
`
`o
`0023—!
`
`N
`
`H
`
`N—lL-(CH2380H3
`
`/
`
`o
`
`HN
`H020\__\(=°
`H“
`
`O
`
`NH
`3:0
`HMH
`0
`N NWNPQ
`H
`0 H020
`
`30.
`
`Cyclic lipopeptides are compounds which have a ring composed of
`
`multiple peptide residues coupled to a lipid or lipophilic tail. In the structure
`
`depicted above, which is FIG. 1 of the ‘456 Patent, the peptide ring is located on
`
`the left side and the lipid or lipophilic tail extends away from it towards the right.
`
`31. Many cyclic lipopeptides have been found useful as pharmaceuticals,
`
`including as antibiotics and antifungals. Approved antifungal cyclic lipopeptides
`
`include caspofungin (approved 2001), micafungin (approved 2005), and
`
`anidulafungin (approved 2006).
`
`I3
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
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`32.
`
`Cyclic lipopeptides pharmaceuticals, like many other polypeptide and
`
`protein pharmaceuticals, are often lyophilized prior to storage in order to increase
`
`the shelf life of the active material. The cyclic lipopeptides caspofungin,
`
`micafungin, and anidulafungin, for example, are all supplied as lyophilized
`
`powders that are reconstituted prior to use.
`
`33.
`
`Lyophilization (or freeze-drying) is a process in which water is
`
`removed from a material after it is frozen and placed under a vacuum, allowing the
`
`ice to change directly from solid to vapor without passing through a liquid 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 formulation is 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 freezing is
`
`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
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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
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`temperatures ranging from -30°C to 10°C. Throughout this stage, the product is
`
`maintained in the “solid state” with retention of the structure established in the
`
`freezing step.
`
`37.
`
`The secondary drying stage involves removing the relatively 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 lead to a large number of
`
`small ice crystals, which in turn presents a large ice- water interface. Exposure of
`
`proteins and peptides to this ice—water interface can cause denaturation and/or
`
`degradation.
`
`In addition, small ice crystals can result in pores with high surface to
`
`volume ratios, resulting in lower diffusive flux and slower sublimation rates, both
`
`of which can affect the drying rate as well as the structure of the final dried cake.
`
`Damage during the drying stages can result from removal of the hydration shell
`
`from a protein or peptide, which destabilizes the structure in the absence of one or
`
`more appropriate stabilizers.
`
`15
`
`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
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`39. Among the 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 POSAs that sucrose is 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:
`
`o The water replacement hypothesis: Disaccharides have been found
`
`to interact with these products by hydrogen bonding similarly to the
`
`replaced water.
`
`0 The vitrification 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
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`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`U.S. Patent No. 9,138,456 B2
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`function (or fimctions). Buffers (also referred to as pH adjusters) and bulking
`
`agents are two common excipients.
`
`42.
`
`Buffers are used in pharmaceutical formulations to maintain the pH in
`
`the desired range, before and after reconstitution. In the development of a
`
`lyophilized formulation, it is preferable to use low concentrations of buffer to
`
`avoid selective crystallization of a buffer component leading to pH changes during
`
`freezing.
`
`43.
`
`The desired pH range, and by extension the buffer selection, must take
`
`into consideration the other formulation components, including the active
`
`ingredient and stabilizer, 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. This is
`
`important in cases in which low concentrations of the active ingredient are used.
`
`Crystalline bulking agents such as mannitol are frequently used, since they are
`
`known by POSAS to produce an elegant cake with desired mechanical properties.
`
`45. Daptomycin was first approved for human use by the US. Food &
`
`Drug Administration in 2003. Much like many other approved cyclic lipopeptide
`
`pharmaceuticals, including caspofungin (Cancidasm), micafungin (Mycaminei‘),
`
`and anidulafungin (Eraxisj‘), the approved daptomycin product (Cubicinw) is
`
`lyophilized daptomycin (which also contains a small amount of sodium hydroxide
`
`17
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`AMNEAL EX. 1003
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`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
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`to adjust pH). Ex. 1004 at 14—18. When used, the lyophilized daptomycin cake is
`
`first reconstituted with 0.9% sodium chloride injection to be administered by
`
`intravenous infusion. Ex. 1004 at 486-490.
`
`46.
`
`As noted in the label, the Cubicin‘g product’s lyophilized cake,
`
`however, must be stored at reduced temperature (2”C - 89C). Ex.1004 at 514—5 15.
`
`Based on my experience, it is my understanding that this is done to prevent
`
`degradation of the active ingredient. The label of the Cubicin” product also
`
`specifically notes the need to avoid exposing the drug product to excessive heat
`
`(Le. temperatures above 40°C). 1d.
`
`47.
`
`It is, and was at the relevant time, known to POSAs that storing and
`
`shipping lyophilized materials at room temperature is easier and cheaper than
`
`storing and shipping the same materials at low (Le. less than ambient) temperature.
`
`When a product can be stored at room temperature, there is no longer a need for
`
`expensive cooling equipment, such as refrigerators or cold rooms, and no
`
`requirements for special handling. Similarly, shipping at room temperature
`
`eliminates the need for refrigerated packaging, such as dry ice packs and insulated
`
`boxes, and for refrigerated transportation, such as refrigerated 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.
`US. Patent No. 9,138,456 BZ
`
`maintained.
`
`B.
`
`The Claimed Invention
`
`48.
`
`The ‘456 Patent claims pharmaceutical formulations of daptomycin, the
`
`structure of which has been reproduced above.
`
`49.
`
`Independent claims 1 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 molar ratio 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 aqueous solution. Claims 10 and 1 1
`
`claim a pharmaceutical product containing the solid pharmaceutical daptomycin
`
`composition of claim 1 plus a pharrnaceutically acceptable diluent, such as sterile
`
`water for 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 process recited 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 121.12 to about 1:8.98. Claim 3-6 require a third component in the
`
`aqueous daptomycin solution, viz. a buffering agent (claims 4-6 further define that
`
`19
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. 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 processes recited in claims 12-14 and 15 of the ‘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 about 6.5 to about
`
`7.5; and (iii) converting the daptomycin sugar formulation into a solid
`
`pharmaceutical daptomycin composition. Claims 12-14 recite that the aqueous
`
`daptomycin solution 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 CubicinE product was first approved for commercial sale by the FDA.
`
`Accordingly, in describing the BACKGROUND of the invention, the specification
`
`of the ‘456 Patent notes that Cubicin‘l" “is supplied as a lyophilized powder that 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 fipm the lyophilized cake by
`
`“combination with a medically appropriate amount of pharmaceutical diluent (e. g. ,
`
`0.9% aqueous sodium chloride)” Id. at 1:37-41.
`
`20
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 BZ
`
`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 compositions that 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
`
`chemical stability .
`
`.
`
`. (i.e., higher total percent daptomycin purity over time),
`
`providing advantages of longer shelf life, increased tolerance for more varied
`
`storage conditions (e.g., higher temperature or humidity) .
`
`. ..” Id. at 2:51-58.
`
`54.
`
`As originally 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. Nor did 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 examiner at the PTO on
`
`various grounds. Among those grounds, the examiner rejected certain claims as
`
`being identically disclosed by Inman (Ex. 1008).
`
`55.
`
`In response to the rejection over Inman, 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 REMARKS that accompanied that amendment, applicant’s representative
`
`21
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
`
`argued that this distinguished the claims from Inman because “Inman fails to
`
`disclose solid pharmaceutical formulations, the subject-matter of Applicants’
`
`claims.
`
`In addition, Inman discloses buffered solutions of dextrose, not sucrose, as
`
`required by the instant claims.” Id. at 61 (emphasis in original).
`
`In addition, in
`
`response to the examiner’s rejection of the pending claims for obviousness,
`
`applicant’s representative argued that the cited prior art
`
`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 shown in 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 over time at elevated temperature.
`
`Id. at 63. Applicant’s representative also contended that the prior art did not “teach
`
`or suggest the surprising rapid reconstitution of solid daptomycin compositions
`
`containing sucrose.” Id. at 64.
`
`56.
`
`Following applicant’s amendment, the examiner allowed the claims of
`
`the ‘346 Application on the grounds that “[a] solid pharmaceutical daptomycin
`
`composition comprising daptomycin and sucrose recited in [the] instant claims .
`
`.
`
`.
`
`is free of prior art.” Ex. 1002 at 34. The examiner further stated that “Applicant
`
`has presented unexpected results of surprising rapid reconstitution of solid
`
`daptomycin compositions comprising sucrose and increased chemical stability of
`
`22
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, Ph.D.
`US. Patent No. 9,138,456 B2
`
`such composition [sic] .
`
`. ..” Id. The ‘346 Application subsequently issued as the
`
`‘456 Patent. Id. at 1.
`
`IV.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`57.
`
`I have been informed that a “person of ordinary skill in the art” (a
`
`“POSA”) is a hypothetical person to whom an expert in the relevant field could
`
`assign a routine task with reasonable confidence that the task would be
`
`successfully carried out. I have been informed that the level of skill in the art is
`
`evidenced by prior art references. In this case, the ‘456 Patent is directed to a
`
`particular lyophilized formulation of daptomycin and processes of making the
`
`same. Accordingly, a POSA in the field of the ‘456 Patent as of November 23,
`
`2009, would have had at least a bachelor of science degree in one or more of the
`
`pharmaceutical sciences, including pharmaceutical chemistry and/or
`
`pharmaceutics, or a related technical field, 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 area relating to lyophilized pharmaceutical formulations.
`
`58.
`
`Based on my experience, I have an understanding of the capabilities
`
`of a POSA.
`
`I have supervised and directed many such persons over the course of
`
`my career. Further, I had those capabilities myself at the time the application for
`
`the ‘456 Patent was effectively filed. That is, at least by 2009, when the earliest
`
`23
`
`AMNEAL EX. 1003
`
`
`
`Declaration of Raj Suryanarayanan, PhD.
`US. Patent No. 9,138,456 B2
`
`priority application was filed, I was already in possession of multiple advanced
`
`degrees (masters and doctorate) in one of the pharmaceutical sciences and I had
`
`considerably more than the requisite 3-5 years of work experience in areas relating
`
`to lyophilized pharmaceutical formulations.
`
`In fact, by 2009, 1 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
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