`
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`AMNEAL PHARMACEUTICALS LLC
`Petitioner,
`
`v.
`
`CUBIST PHARMACEUTICALS LLC
`Patent Owner
`________________
`
`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`THE STATE OF THE ART & THE ’456 PATENT ...................................... 5
`
`A.
`
`B.
`
`The ’456 Patent & The Challenged Claims Unexpectedly
`Provide Long term Stability At Room Temperature and Faster
`Reconstitution Time .............................................................................. 5
`
`The Original Cubicin® Product And The Alleged Need For An
`Improved Product Capable of Room Temperature Storage .................. 7
`
`C. Methods For Improving Peptide And Protein Stability In
`Lyophilized Formulations Were Highly Unpredictable and
`Compound-Dependent .......................................................................... 9
`
`III.
`
`SCOPE AND CONTENT OF THE ART ..................................................... 11
`
`A.
`
`B.
`
`C.
`
`The Cubicin® Label (Ex. 1004) ........................................................... 11
`
`The Caspofungin (Cancidas®) Label (Ex. 1010)................................. 12
`
`Neururkar (Ex. 1005) .......................................................................... 13
`
`D. Mittal (Ex. 1007) ................................................................................. 14
`
`E.
`
`F.
`
`G.
`
`H.
`
`Sawai (Ex. 1006) ................................................................................. 18
`
`Inman (Ex. 1008) ................................................................................. 20
`
`Level of Ordinary Skill in the Art ....................................................... 21
`
`Claim Construction.............................................................................. 21
`
`IV. THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1, 2, AND 7-11 WOULD HAVE
`BEEN OBVIOUS IN VIEW OF ITS TWO ASSERTED GROUNDS ........ 21
`
`A.
`
`The Petition Fails To Provide Even A Prima Facie Motivation
`or Reason To Combine for Grounds 1 or 2 ......................................... 23
`
`1.
`
`2.
`
`Petitioner Has Not Shown That A POSA Would Be
`Motivated To Consider Caspofungin Compositions When
`Formulating Daptomycin .......................................................... 25
`
`Neururkar Does Not Teach or Disclose Any Lyophilized
`Formulations That Are Stable At Room Temperature ............. 28
`
`
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`3. Mittal Teaches That The Use Of Sucrose Will Not
`Improve Stability Above Refrigerated Temperatures ............... 31
`
`4.
`
`Sawai Does Not Disclose Any Lyophilized Formulations
`Using Sucrose That Are Stable At Room Temperature ............ 36
`
`B.
`
`Grounds 1 And 2 Also Fail For Failure To Establish Even A
`Prima Facie Basis For a Reasonable Expectation of Success ............ 38
`
`1.
`
`2.
`
`3.
`
`Petitioner’s Two-Sentence Argument Does Not Establish
`A Prima Facie Basis For An Expectation of Success .............. 39
`
`Petitioner’s Expectation Of Success Argument Conflicts
`With The Teachings Of Neururkar And Mittal ........................ 42
`
`Petitioner Also Fails To Deal With The Teachings That
`Methods Of Stabilization For One Active Ingredient
`Cannot Be Applied To Another With Any Reasonable
`Expectation Of Success ............................................................. 42
`
`C.
`
`The Additional References That Petitioner Relies Do Not
`Support Its Arguments ........................................................................ 44
`
`1.
`
`2.
`
`The Board Should Not Consider Additional References
`Cited By Petitioner .................................................................... 45
`
`The Additional References Cited By Petitioner Do Not
`Provide A Motivation Or Reasonable Expectation Of
`Success ...................................................................................... 46
`
`D. Dr. Suryanarayanan’s Conclusory Declaration Does Not
`Establish Motivation and Reasonable Expectation of Success ........... 51
`
`E.
`
`Secondary Considerations Support Non-Obviousness ....................... 53
`
`1.
`
`2.
`
`Unexpected Enhanced Stability ................................................ 54
`
`Unexpected Improved Reconstitution Time ............................. 58
`
`V.
`
`CONCLUSION .............................................................................................. 61
`
`
`
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`
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`
`ii
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`

`

`TABLE OF AUTHORITIES
`
`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`Page
`
`CASES
`
`Allergan, Inc. v. Sandoz Inc.,
` 796 F.3d 1293 (Fed. Cir. 2015) ....................................................................60
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
` 676 F.3d 1063 (Fed. Cir. 2012) ....................................................................53
`
`Forest Labs., LLC v. Sigmapharm Labs., LLC,
` 918 F.3d 928 (Fed. Cir. 2019) ......................................................................22
`
`Initiative for Medicines, Access & Knowledge (I-Mak), Inc. v. Gilead
`Pharmasset LLC,
`IPR2018-00119, Paper (PTAB May 4, 2018) ...............................................52
`
`Initiative for Meds., Access & Knowledge (IMak), Inc. v. Gilead Pharmasset
`LLC,
`IPR2018-00103, Paper (PTAB June 13, 2018) ............................................52
`
`K/S Himpp v. Hear-Wear Techs., LLC,
` 751 F.3d 1362 (Fed. Cir. 2014) ....................................................................52
`
`Leo Pharm. Prods., Ltd. v. Rea,
` 726 F.3d 1346 (Fed. Cir. 2013) ....................................................................53
`
`Mylan Pharms. Inc. v. Research Corp. Techs., Inc.,
` 914 F.3d 1366 (Fed. Cir. 2019) ...................................................................... 5
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
` 520 F.3d 1358 (Fed. Cir. 2008) ....................................................................53
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
` 678 F.3d 1280 (Fed. Cir. 2012) ....................................................................26
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
` 566 F.3d 989 (Fed. Cir. 2009) ......................................................................53
`
`QuantifiCare, Inc. v. Proctor & Gamble Co.,
`IPR2017-02113, Paper (PTAB Mar. 16, 2018) ............................................34
`
`Smiths Indus. Med. Sys., Inc. v. Vital Signs, Inc.,
` 183 F.3d 1347 (Fed. Cir. 1999) ....................................................................22
`
`In re Soni,
` 54 F.3d 746 (Fed. Cir. 1995) ........................................................................53
`
`
`
`
`iii
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`

`

`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`Unified Patents Inc. v. Custom Media Techs. LLC,
`IPR2015-00516, Paper, (PTAB June 25, 2015) ............................................53
`
`Winner Int’l Royalty Corp. v. Wang,
` 202 F.3d 1340 (Fed. Cir. 2000) ....................................................................54
`
`Zetec, Inc. v. Westinghouse Elec. Co.,
`Case IPR2014-00384 (PTAB July 23, 2014) ...............................................35
`
`STATUTORY AUTHORITIES
`
`35 U.S.C. § 311(b) ...................................................................................................52
`
`35 U.S.C. § 312(a)(3) ...............................................................................................45
`
`35 U.S.C. § 314(a) ...................................................................................................46
`
`RULES AND REGULATIONS
`
`37 C.F.R. § 42.24(a) .................................................................................................62
`
`37 C.F.R. § 42.24(a)(i) .............................................................................................62
`
`37 C.F.R. § 42.24 (b)(1) ...........................................................................................62
`
`37 C.F.R. § 42.65(a) .................................................................................................52
`
`37 C.F.R. § 42.104(b)(4) ................................................................................... 45, 46
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.108(b) ..............................................................................................46
`
`ADDITIONAL AUTHORITIES
`
`November 2019, Patent Trial and Appeal Board Consolidated Trial Practice
`Guide (Ex. 2006) ...........................................................................................49
`
`
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`TABLE OF EXHIBITS
`
`2001
`
`2002
`
`2003
`
`European Medicines Agency, Annex 1 Cubicin®, first authorization
`January 19, 2006; last renewal November 29, 2010 .
`
`K.D. Roe & T.P. Labuza, Glass Transition and Crystallization of
`Amorphous Trehalose-sucrose Mixtures, 8 Int’l J. Food. Props. 559,
`published online February 7, 2007.
`
`Y. Roos & M. Karel, Differential Scanning Calorimetry Study of
`Phase Transitions Affecting the Quality of Dehydrated Materials, 6
`Biotechnol. Prog. 159-163, published 1996.
`
`2004
`
`Wang W., Review: Lyophilization and Development of Solid Protein
`Pharmaceuticals, 203 Inter’l J. Pharmaceutics 1, published 2000.
`
`2005
`
`2006
`
`Yu L et al., Determination of the Glass Properties of D-Mannitol
`Using Sorbitol as an Impurity, 87 J. Pharm. Sci. 774, published 1998.
`
`November 2019, Patent Trial and Appeal Board Consolidated Trial
`Practice Guide
`
`
`
`
`v
`
`

`

`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`
`Pursuant to 37 C.F.R. § 42.107, Patent Owner Cubist Pharmaceuticals LLC
`
`(“Cubist”) respectfully submits this Preliminary Response to the Petition for Inter
`
`Partes Review (Paper No. 2) (“the Petition”) filed by Petitioner Amneal
`
`Pharmaceuticals LLC (“Petitioner”). The Petition seeks Inter Partes Review
`
`(“IPR”) of claims 1, 2, and 7-11 (“the challenged claims”) of U.S. Patent No.
`
`9,138,456 (“the ’456 patent”) based on two obviousness grounds.
`
`I.
`
`INTRODUCTION
`
`The Board should deny institution because there was no motivation to
`
`combine the cited references, let alone for the reason asserted by Petitioner—to
`
`achieve long-term stability at room temperature. Nor does Petitioner establish a
`
`reasonable expectation of success in adding sucrose to the composition in an
`
`attempt to achieve long-term stability at room temperature. The cited references
`
`show the exact opposite.
`
`The challenged claims are directed to a solid pharmaceutical composition of
`
`the peptide daptomycin prepared by lyophilizing an aqueous solution comprising
`
`daptomycin and sucrose. The inventors discovered that adding sucrose to the
`
`lyophilization solution results in a solid composition that unexpectedly achieves
`
`long-term stability at room temperature and improved reconstitution time.
`
`Petitioner contends that it would have been obvious to add sucrose to a lyophilized
`
`daptomycin formulation to achieve room temperature storage.
`
`
`
`1
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`

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`U.S. Patent No. 9,138,456
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`
`
`Petitioner’s obviousness argument starts with the original FDA-approved
`
`product, Cubicin®, which contained only daptomycin and sodium hydroxide. The
`
`original Cubicin® product was stable for 36 months in refrigerated storage.
`
`Petitioner asserts that because the original Cubicin® product required refrigerated
`
`storage conditions, a need existed “to improve the stability of lyophilized
`
`daptomycin compositions at non-refrigerated temperatures.” Petition at 6-7.
`
`Petitioner further asserts a person of ordinary skill in the art (“POSA”) would have
`
`known “that lyophilized compositions which can be stored at room temperature are
`
`superior, both in terms of cost and ease of use, to similar compositions that require
`
`refrigeration.” Petition at 20.
`
`To support its contention that a POSA would have been motivated to add
`
`sucrose to the Cubicin® product to achieve long-term room temperature storage and
`
`would have had a reasonable expectation of success in doing so, Petitioner relies
`
`on the teachings of Neururkar, Mittal and Sawai. Neururkar and Mittal are
`
`directed to formulations containing caspofungin (a cyclic peptide different from
`
`daptomycin). Sawai is directed to formulations containing another cyclic
`
`hexapeptide that is different from daptomycin. As an initial matter, Petitioner has
`
`not met its burden to show that a POSA would have had a reason to rely on
`
`caspofungin-related and/or cyclic hexapeptide-related references when seeking to
`
`improve existing daptomycin formulations. Caspofungin and daptomycin are two
`
`
`
`2
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`

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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`distinct chemical entities with different stability characteristics and degradation
`
`pathways. Petitioner makes no attempt to show that a POSA would have been
`
`motivated, in view of these chemical and physical differences, to apply the
`
`caspofungin teachings to daptomycin.
`
`But assuming that a POSA would look to Neururkar, Mittal or Sawai when
`
`formulating daptomycin, Petitioner’s argument is fundamentally flawed.
`
`Following the teachings of Neururkar, Mittal or Sawai, a POSA would not have
`
`been motivated to add sucrose to achieve a daptomycin product capable of room
`
`temperature storage. The cited references explicitly teach that lyophilized
`
`formulations with sucrose do not achieve room temperature storage. In fact, each
`
`and every lyophilized cyclic peptide-sucrose formulation disclosed in the cited
`
`references requires refrigerated storage.
`
`Neururkar teaches that lyophilized formulations of caspofungin with sucrose
`
`(in combination with mannitol and acetic acid) require refrigerated storage.
`
`Similarly, Mittal teaches that the mere addition of sucrose will not result in a
`
`lyophilized composition that can be stored at room temperature and uses sucrose-
`
`containing formulations as comparative examples that do not achieve room
`
`temperature stability. Finally, Sawai provides no teaching, disclosure or
`
`suggestion that lyophilized peptide formulations containing sucrose can achieve
`
`room temperature storage. Thus, based on Neururkar, Mittal and Sawai, a POSA
`
`
`
`3
`
`

`

`
`would not have been motivated to add sucrose because doing so would not result in
`
`an improved composition over the original Cubicin® formulation—the need for
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`refrigerated storage would still remain.
`
`Likewise, Neururkar, Mittal and Sawai all fail to establish a reasonable
`
`expectation of success that adding sucrose to daptomycin would result in a
`
`lyophilized composition capable of long-term room temperature stability. If
`
`anything, they teach the exact opposite. Based on the cited references, a POSA
`
`would have expected that a daptomycin-sucrose composition would require
`
`refrigerated storage just like the other formulations with sucrose disclosed in
`
`Neururkar, Mittal and Sawai. And Petitioner’s reasonable expectation of success
`
`argument fails for a second reason. Petitioner’s own references teach that one
`
`cannot apply the method of stabilization for one active ingredient to a completely
`
`different active ingredient with any reasonable expectation of success.
`
`Accordingly, Petitioner has not demonstrated a reasonable likelihood that
`
`any of the challenged claims is unpatentable.1 The Board should deny institution.
`
`
`1 This preliminary response addresses Petitioner’s arguments concerning
`
`claim 1, the sole independent claim of ’456 patent claims being challenged.
`
`Because the Petition fails to show that claim 1 is obvious, the dependent claims are
`
`
`
`4
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`

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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`II. THE STATE OF THE ART & THE ’456 PATENT
`
`A. The ’456 Patent & The Challenged Claims Unexpectedly Provide
`Long term Stability At Room Temperature and Faster
`Reconstitution Time
`
`The challenged claims of the ’456 patent are directed to new lyophilized
`
`formulations of daptomycin. Daptomycin is a cyclic lipopeptide having the
`
`following formula:
`
`
`
`
`also not obvious for at least the same reasons. Mylan Pharms. Inc. v. Research
`
`Corp. Techs., Inc., 914 F.3d 1366, 1376 (Fed. Cir. 2019) (“Likewise, because we
`
`find that Appellants did not meet their burden to show that claims 1-9 would have
`
`been obvious over Kohn 1991 and Silverman, we conclude that the Board did not
`
`err in concluding that Appellants failed to meet their obviousness burden regarding
`
`claims 10-13, which depend therefrom. Dependent claims, with added limitations,
`
`are generally not obvious when their parent claims are not.”).
`
`
`
`5
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
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`Ex. 1001 at FIG. 1. Daptomycin is a powerful antibiotic indicated for the
`
`treatment of complicated skin and skin structure infections.
`
`The challenged claims each require the presence of sucrose in the pre-
`
`lyophilization solution. Claim 1, which is the only independent claim challenged,
`
`reads as follows:
`
`1. A solid pharmaceutical daptomycin composition,
`
`wherein said composition is prepared by lyophilizing an
`
`aqueous daptomycin solution comprising daptomycin and
`
`sucrose.
`
`Ex. 1001 at 27:2-5. The dependent claims add further limitations, such as the pH
`
`of the pre-lyophilization solution and the molar ratio of daptomycin to sucrose.
`
`The inventors discovered that adding sucrose to the pre-lyophilization
`
`solution as described in the ’456 patent unexpectedly resulted in a solid lyophilized
`
`daptomycin product capable of long-term storage at room temperature. There are
`
`three major degradation products are produced during the purification of
`
`daptomycin. Ex. 1001 at 1:51-56 and FIGS. 2-4. Different parameters, particularly
`
`pH, affect these individual degradation pathways, and there was no single
`
`formulation as of the priority date of the ’456 patent that could control the
`
`formation of the three major degradation products.
`
`
`
`6
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`

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`U.S. Patent No. 9,138,456
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`
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`In addition, the invention also achieved faster reconstitution times. Both
`
`characteristics were significant improvements over the original daptomycin
`
`product, Cubicin®, which required refrigerated storage and took up to 45 minutes
`
`to reconstitute prior to use. Ex. 1001 at 1:44-46.
`
`The invention of the ’456 patent resulted in the Cubicin RF® product.
`
`B.
`
`The Original Cubicin® Product And The Alleged Need For An
`Improved Product Capable of Room Temperature Storage
`
`The original Cubicin® product, which was approved in the U.S. in 2003 and
`
`in Europe in 2006, consists of daptomycin lyophilized with sodium hydroxide for
`
`pH adjustment. Ex. 1004; Ex. 1016. Sodium hydroxide is the only inactive
`
`ingredient in the original Cubicin® product. Ex. 1004 at 1. The lyophilized
`
`Cubicin® product achieved long-term shelf stability of 36 months at refrigerated
`
`temperatures of 2 to 8° C (36 to 46° F). Ex. 1004 at 18; Ex. 2001 at 18.
`
`Based on the requirement for refrigerated storage of Cubicin®, Petitioner
`
`alleges that a need existed for a daptomycin product capable of long-term storage
`
`at room temperature. Specifically, Petitioner claims:
`
`It is, and was at the relevant time, known to a POSA that
`
`storing and shipping lyophilized materials at room
`
`temperature is easier and cheaper than storing and
`
`shipping the same materials at low temperature. For
`
`example, when a product can be stored and shipped at
`
`room temperature, there is no longer a need for expensive
`
`
`
`7
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
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`
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`cooling equipment and no requirements for special
`
`handling. There was, therefore, a need in the art to
`
`improve the stability of lyophilized daptomycin
`
`compositions at non-refrigerated temperatures.
`
`Petition at 6-7 (citations omitted)2. Petitioner does not identify any other existing
`
`need regarding the stability of Cubicin®, other than the need to achieve long-term
`
`room temperature storage. Notably, the Cubicin® product already achieved 36-
`
`month stability under refrigerated conditions. Petitioner therefore does not allege
`
`any need or desire to extend the shelf stability at refrigerated temperatures.3
`
`Rather, Petitioner asserts that a POSA would have been motivated to modify
`
`the Cubicin® product to achieve long-term room temperature storage. Petitioner
`
`specifically asserts that based on prior art teachings for the antifungal caspofungin
`
`
`2 Unless otherwise noted, all emphases are added.
`
`3 Indeed, Petitioner also does not articulate the length of room temperature
`
`storage that formed the alleged need in the art. To the extent Petitioner alleges
`
`there was a need for having room temperature stability for a period less than 36
`
`months, Petitioner has not articulated any reason why a POSA would view that
`
`product as superior to the existing Cubicin® product, which achieved 36-month
`
`stability under refrigerated conditions.
`
`
`
`8
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`

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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`and sulfate-substituted cyclic peptides, a POSA would be motivated to add sucrose
`
`to the Cubicin® product to achieve that goal. E.g., Petition at 21-22. In addition,
`
`Petitioner asserts, again based on the prior experience with caspofungin and
`
`sulfate-substituted cyclic peptides, a POSA would expect that the mere addition of
`
`sucrose would satisfy the alleged need for the desired room temperature stability.
`
`Id.
`
`C. Methods For Improving Peptide And Protein Stability In
`Lyophilized Formulations Were Highly Unpredictable and
`Compound-Dependent
`
`At the time the ’456 patent was filed and to this day, however, formulating a
`
`stable pharmaceutical product is an unpredictable process, especially in the case of
`
`peptide and proteins. Peptides and proteins are susceptible to multiple different
`
`types of degradation. For example, three major degradation products are produced
`
`during the purification of daptomycin: anhydro-daptomycin, a β-isomer, and a
`
`lactone hydrolysis product. Ex. 1001 at 1:51-56 and FIGS. 2-4. Other cyclic
`
`peptides, like caspofungin, are different chemical compounds and therefore
`
`undergo chemical degradation via different pathways than daptomycin. See Ex.
`
`1011 at 974. While different parameters, such as excipients and pH, affect
`
`degradation pathways, there was no single formulation that could control each type
`
`of degradation product for the various peptides and proteins.
`
`
`
`9
`
`

`

`
`
`Indeed, the prior art Carpenter reference, cited by Petitioner, explains that
`
`the formulation and resulting stability of proteins is entirely dependent on the
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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`specific protein being formulated:
`
`For many proteins the advice given above will probably
`
`lead to a successful lyophilized formulation. However,
`
`every protein has unique physicochemical properties and,
`
`hence, unique stabilization requirements. Thus, the
`
`formulation will have to be “customized” for every
`
`protein drug.
`
`Ex. 1011 at 974. In other words, what might work for one protein , does not
`
`predict what will work for another.4
`
`Thus, formulation of proteins frequently required trial and error because
`
`there was no established pathway for making these formulations:
`
`Although significant progress has been made in the past
`
`decade in protein formulation, there is still no single
`
`pathway to follow in formulating a solid protein product.
`
`
`4 In addition, formulation issues for proteins differ from peptides in that
`
`proteins require particular three-dimensional folding to function, whereas peptides
`
`do not. Thus, protein formulation techniques that involve methods designed to
`
`stabilize the three-dimensional structure are wholly inapplicable to peptides.
`
`
`
`10
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`

`

`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`
`In most cases, solid protein products have been
`
`developed on a trial-and-error basis.
`
`Ex. 2004 at 44. Wang explains that there are a number of different types of
`
`excipients that should be considered “[t]o achieve successful formulation of solid
`
`protein products by lyophilization,” including buffering agents, bulking agents,
`
`protein stabilizers, and antimicrobial agents. Id. Accordingly, Wang notes that:
`
`In summary, development of a lyophilized protein
`
`product usually takes an enormous amount of time, labor,
`
`and effort, simply because there is no single, short, and
`
`mature pathway to follow in formulating such a product,
`
`and many experiments are done on a trial-and-error basis.
`
`This trend will continue until a breakthrough is achieved
`
`in understanding the basic behavior of proteins and their
`
`stabilization.
`
`Id. at 51.
`
`Thus, as of the priority date of the ’456 patent, protein and peptide formulation
`
`was an unpredictable and challenging art, and required bespoke “trial and error”
`
`solutions for each new protein or peptide to be formulated.
`
`III. SCOPE AND CONTENT OF THE ART
`
`A. The Cubicin® Label (Ex. 1004)
`
`The Cubicin® Label describes the Cubicin® product that was approved by
`
`the FDA in 2003. The product described in the Cubicin® Label is lyophilized
`
`
`
`11
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`

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`Case IPR2020-00193
`U.S. Patent No. 9,138,456
`
`
`daptomycin. Ex. 1004 at 1. The “only inactive ingredient [in Cubicin®] is sodium
`
`hydroxide which is used in minimal quantities for pH adjustment.” Id.
`
`The original Cubicin® product required storage at refrigerated temperatures
`
`of 2 to 8° C (36 to 46° F). Ex. 1004 at 18. It was known that the original Cubicin®
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`product achieved long-term shelf stability of 36 months at such refrigerated
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`temperatures. Ex. 1016 at 4; Ex. 2001 at 18.
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`It was also known that during the development of the Cubicin® product,
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`lyophilized formulations containing mannitol, a non-reducing sugar, as bulking
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`agent had been tested in early batches. However, as described in the EPAR
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`publication for the original Cubicin® product, the use of mannitol during
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`lyophilization “became unnecessary as the dose for clinical use increased.” Ex.
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`1016 at 3. The EPAR publication noted that the presence of mannitol used as
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`bulking agent was “not expected to have any impact on the product performance
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`based on the type of molecule and the mode of administration.” Id. at 3.
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`B.
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`The Caspofungin (Cancidas®) Label (Ex. 1010)
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`The Cancidas® Label is directed to a lyophilized formulation containing
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`caspofungin. Caspofungin is a cyclic hexapeptide that is chemically and
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`physically distinct from daptomycin. The Cancidas® Label states that “[i]n addition
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`to the active ingredient caspofungin acetate, CANCIDAS contains the following
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`inactive ingredients: sucrose, mannitol, acetic acid, and sodium hydroxide.” Ex.
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`12
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`1010 at 1. The acetate present in the formulation serves as a buffer and to stabilize
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`the formulation in the solid state.
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`Despite containing sucrose, the approved Cancidas® product required
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`refrigerated storage at 2 to 8° C (to 46° F)—the same refrigerated storage
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`temperature of the original Cubicin® product. Id. at 11. Thus, a POSA would
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`understand that the presence of sucrose in the lyophilized caspofungin product did
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`not result in a product capable of long-term storage at room temperature.
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`C. Neururkar (Ex. 1005)
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`The Neururkar patent is an Orange Book-listed patent for the Cancidas®
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`product and is solely directed to lyophilized formulations containing caspofungin.
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`Neururkar does not disclose caspofungin formulations that are suitable for room
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`temperature storage, let alone any such sucrose-containing formulations. Rather,
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`Neururkar teaches that its caspofungin-sucrose formulations require refrigerated
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`storage. Ex. 1005 at 3:36-50 (“The compositions of the invention are generally
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`prepared as follows: . . . lyophilized vials are stoppered and stored at about 5° C.”).
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`Accordingly, Neururkar discloses that the formulations of the examples were
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`stored at a refrigerated temperature:
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`The formulations were stored in the lyophilized state at
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`5° C. and tested at about 4 week intervals for stability.
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`Stability and formation of degradates was determined by
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`gradient HPLC using standard methods known to one
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`skilled in the art.
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`Id. at 8:60-64.
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`Moreover, Neururkar attributes the stability of its disclosed formulations to
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`the acetate buffer, rather than the sucrose. Indeed, Neururkar discloses that
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`Formulation 6, a caspofungin formulation with sucrose but without the acetate
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`buffer, was unstable. Id. at 8:65-68 and Table 1. Neururkar explains that bulking
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`agents like sucrose “provide an aesthetically suitable lyophilized cake, solid
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`dilution of the active ingredient, and sorption of available moisture.” Id. at 3:20-23.
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`But Neururkar teaches that acetate is critical to stability. Neururkar teaches that
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`“[b]y switching [from tartrate buffered formulation] to an acetate buffer, the
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`lyophilized product is more stable, contains less of unwanted degradates while
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`extending the shelf life of the composition” as compared to formulations that
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`contain no acetate. Id. at 2:66-3:1.
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`In any event, at bottom, the resulting formulations of caspofungin were
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`shown to be long-term stable at refrigerated temperatures, not room temperature.
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`D. Mittal (Ex. 1007)
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`The Mittal reference also relates solely to caspofungin formulations. Mittal
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`discloses that caspofungin compositions containing trehalose can supposedly
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`achieve some stability at room temperature. Notably, Mittal uses sucrose-
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`containing formulations as comparative examples that do not achieve improved
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`room temperature storage stability.
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`Mittal discloses various formulations containing caspofungin together with
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`acetate buffer and a non-reducing sugar. Ex. 1007 at [0005]-[0008]. Mittal
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`characterizes the desired non-reducing sugars as “having a glass transition
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`temperature Tg(s) of at least about 90° C” in combination with an acetate buffer.
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`Id. at [0007]-[0008]. The resulting pharmaceutical composition “has a glass
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`transition temperature Tg(c)5 of at least about 55° C,” which results in “good
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`chemical and storage stability at and below room temperature (i.e., at or below
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`about 30° C.).” Id. at [0012]-[0013]. Mittal then explicitly contrasts these new
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`caspofungin formulations as having “stability exceeding that of known lyophilized
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`caspofungin-containing compositions which employ sucrose and mannitol.” Id.
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`at [0013]. Mittal explains these prior art formulations lacked the required Tg(c),
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`and thus only had “good storage stability at low temperature (e.g., 2° C. to 8° C.).”
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`Id. at [0004], [0013]. The only caspofungin compositions disclosed by Mittal as
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`achieving improved room temperature stability contain trehalose, not sucrose.
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`5 Mittal uses the term “Tg(s)” to refer to the glass transition temperature of
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`the sugar(s) and the term “Tg(c)” to refer to the glass transition temperature of the
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`entire formulation.
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`Trehalose is a non-reducing sugar with a Tg above the 90° C threshold for
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`allegedly achieving improved stability. In contrast, sucrose has a Tg of 50-60° C,
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`far below the 90° C threshold. Ex. 2002 at Abstract (“The Tg of pure dry trehalose
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`was found to be 106 °C…”); Ex. 2002 at Abstract (“sucrose had a Tg of 60 °C”);
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`Ex. 2003 at Table 1 (showing Tg of sucrose of about 56° C).
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`Mittal discloses that while trehalose can be combined with other sugars, it
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`mandates that “the Tg(s) value of the sugars together in a mixture (after
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`lyophilization) must be at least about 90° C” and that “[t]ypically, however, each
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`of the non-reducing sugars employed in the lyophilized composition has an
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`individual [Tg] of at least about 90° C”:
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`When more than one