Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 1 of 36 PageID #: 1507
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`HOSPIRA, INC.,
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`AMNEAL PHARMACEUTICALS LLC,
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`v.
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`Plaintiff,
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`Defendant.
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` Civil Action No. 15-697-RGA
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`HOSPIRA’S ANSWERING POST-TRIAL BRIEF ON VALIDITY
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 2 of 36 PageID #: 1508
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`TABLE OF CONTENTS
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`
`I. 
`
`II. 
`
`III. 
`
`IV. 
`
` 
`
`B. 
`
`B. 
`
`2. 
`
`3. 
`
`4. 
`
`b. 
`
`The Asserted Claims Were Not Obvious .............................................................................2 
`The prior art Precedex Concentrate product and 2010 package insert do
`A. 
`not render the claimed invention obvious. ...............................................................2 
`The examiner of the patents-in-suit already rejected Amneal’s
`1. 
`arguments. ....................................................................................................2 
`Precedex Concentrate, as disclosed in the 2010 package insert,
`does not disclose a ready to use solution in a sealed glass
`container. ......................................................................................................4 
`The prior art did not disclose a ready to use 4 µg/mL
`a. 
`dexmedetomidine solution. ..............................................................4 
`The Patent Office issued the patents-in-suit over Precedex
`Concentrate, which was considered by the examiner. .....................4 
`Amneal presented no prior art suggesting development of a ready
`to use 4 µg/ml dexmedetomidine solution. ..................................................5 
`There was no reasonable expectation of success in preparing a
`ready to use 4 µg/ml dexmedetomidine solution in a sealed glass
`container. ......................................................................................................7 
`a. 
`Glass .................................................................................................7 
`b. 
`Sealed ...............................................................................................9 
`Hospira’s internal documents may not be used as evidence for
`obviousness. ...........................................................................................................10 
`The commercial success of Precedex Premix indicates non-obviousness. ............11 
`C. 
`The Limitation “Not More Than About 2% Decrease” Is Not Inherent ............................14 
`A. 
`Amneal’s examples do not prove inherency. .........................................................15 
`B. 
`The inventors’ work may not be cited to prove inherency. ...................................19 
`C. 
`Response to Interrogatory No. 15 is not an admission of inherency. ....................20 
`Claim 6 Of The ‘106 Patent Is Not Indefinite....................................................................22 
`The intrinsic record demonstrates that the 2% limitation is measured under
`A. 
`long-term conditions. .............................................................................................22 
`The experts’ testimony confirmed that long-term conditions apply. .....................24 
`1. 
`Expert testimony explains the meaning of a term in the art. .....................24 
`2. 
`Product stability generally refers to long-term conditions. ........................26 
`The Asserted Claims Are Not Anticipated Or Rendered Obvious By Trissel ...................28 
`A. 
`Proper construction of “ready to use” precludes anticipation. ...............................28 
`
`i
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 3 of 36 PageID #: 1509
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`Trissel does not invalidate the asserted claims. .....................................................29 
`B. 
`Conclusion .........................................................................................................................30 
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`V. 
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` 
`
`ii
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 4 of 36 PageID #: 1510
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`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`AK Steel Corp. v. Sollac & Ugine,
`344 F.3d 1234 (Fed. Cir. 2003)................................................................................................24
`
`Asyst Techs, Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (2008) ...............................................................................................................14
`
`Cumberland Pharms. Inc. v. Mylan Institutional LLC,
`846 F.3d 1213 (Fed. Cir. Jan. 26, 2017) ....................................................................................2
`
`Dow Chem. Co. v. NOVA Chems. Corp.,
`803 F.3d 620 (Fed. Cir. 2015)............................................................................................25, 27
`
`Dow Chem. Co. v. NOVA Chems. Corp.,
`809 F.3d 1223 (Fed. Cir. 2015)..........................................................................................25, 28
`
`Galderma Labs, L.P. v. Tolmark, Inc.,
`737 F.3d 731 (2013) .................................................................................................................13
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................................................30
`
`Medicines Co. v. Mylan, Inc.,
`853 F.3d 1296 (Fed. Cir. 2017)................................................................................................24
`
`Merck & Co., Inc. v. Teva Pharmaceuticals USA, Inc.,
`395 F.3d 1364 (2005) ...............................................................................................................13
`
`Merck Sharpe & Dohme Corp. v. Hospira Inc.,
`221 F.Supp.3d 497, 513 (D. Del. 2016) ...................................................................................13
`
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017)................................................................................................19
`
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`134 S. Ct. 2120 (2014) .......................................................................................................22, 25
`
`Omeprazole Patent Litigation,
`483 F.3d 1364 (Fed. Cir. 2007)................................................................................................21
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. Mar. 31, 2008) .................................................................................10
`
` 
`
`iii
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 5 of 36 PageID #: 1511
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`Otsuka Pharmaceutical Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012)..........................................................................................10, 19
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`120 F. Supp. 3d 468, 475 (D. Md. July 27, 2015) ...................................................................16
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014)..............................................................................15, 16, 17, 18
`
`Proctor & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009)..................................................................................................30
`
`Retractable Techs., Inc. v. Becton, Dickinson & Co.,
`653 F.3d 1296 (Fed. Cir. 2011)................................................................................................29
`
`SRI Int’l, Inc. v. Internet Sec. Sys.,
`511 F.3d 1186 (Fed. Cir. 2008)................................................................................................11
`
`Syntex (U.S.A.) LLC v. Apotex Inc.,
`2006 WL 1530101 (N.D. Cal. June 2, 2006) .....................................................................13, 14
`
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`135 S. Ct. 831 (2015) .........................................................................................................25, 27
`
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`789 F.3d 1335 (Fed. Cir. 2015)..........................................................................................25, 26
`
`Transcend Med., Inc. v. Glaukos Corp.,
`2015 WL 5546988 (D. Del. Sept. 18, 2015) ......................................................................25, 27
`
`STATUTES
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`35 U.S.C. § 103(a) .....................................................................................................................2, 10
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` 
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`
`
`iv
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 6 of 36 PageID #: 1512
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`Amneal’s obviousness defense commits a sin in patent law. It applies hindsight to
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`attempt to show that the invention of Precedex Premix was obvious. Again and again at trial and
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`in its opening brief, Amneal does what is not permitted. It cites to and relies on the inventor’s
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`own development efforts to argue its §103 defense. Even Amneal’s inherency argument
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`regarding claim 6 of the ‘106 patent improperly depends on the inventor’s own work. Amneal’s
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`three examples that it purports show that the “2% limitation” is inherent are the work of the
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`inventors. Amneal’s argument that Hospira made an admission in an interrogatory answer also
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`refers to the inventor’s work. The interrogatory answer in question points to data showing what
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`the inventors learned about the stability of dexmedetomidine during their inventive development
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`efforts. The Federal Circuit has said repeatedly that evidence of this sort is not probative – and
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`therefore not permitted – to attempt to prove obviousness.
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`Amneal also re-argues that a ready to use solution of a diluted 4 µg/mL dexmedetomidine
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`solution was known in the prior art – an argument that the patent examiner already considered,
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`and rejected, in granting the patents-in-suit. Amneal argues that the 2010 package insert
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`discloses a ready to use solution in a sealed glass container – even though its expert, Dr.
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`Alpaslan Yaman, agreed with Hospira that there was no such disclosure. Further, Amneal argues
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`the commercial success of Precedex Premix is not probative here. But that is not the law.
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`Although the existence of a blocking patent, in some circumstances, might weaken an inference
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`of non-obviousness, the success of Precedex Premix supports that inference notwithstanding the
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`existence of the ‘214 patent—the expired patent claiming the dexmedetomidine API. When the
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`law is applied and Amneal’s improper evidence is discounted, it is plain that Amneal failed to
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`prove that the invention of the patents-in-suit was obvious.
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`
`
`1
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 7 of 36 PageID #: 1513
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`Amneal’s indefiniteness and anticipation arguments fail as well. The evidence is, and
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`Amneal’s expert agreed, that stability is measured under long term conditions and that this would
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`be known to one of ordinary skill in the art. Amneal’s anticipation argument is unpersuasive at
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`least because its supposedly anticipating reference, Trissel, lacks a “ready to use” formulation.
`
`I.
`
`THE ASSERTED CLAIMS WERE NOT OBVIOUS
`
`To prove that the ’158, ’470, and ’527 patents are obvious, Amneal must show, by clear
`
`and convincing evidence, that “the differences between the claimed invention and the prior art
`
`are such that the claimed invention as a whole would have been obvious before the effective
`
`filing date of the claimed invention to a person having ordinary skill in the art to which the
`
`claimed invention pertains.” 35 U.S.C. § 103(a); Cumberland Pharms. Inc. v. Mylan Institutional
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`LLC, 846 F.3d 1213, 1221-1222 (Fed. Cir. Jan. 26, 2017).
`
`A.
`
`The prior art Precedex Concentrate product and 2010 package insert do not
`render the claimed invention obvious.
`
`Amneal argues that Precedex Concentrate, as disclosed in the 2010 package insert,
`
`teaches every element of the inventive composition, except for storing the “known” ready to use
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`solution in the “known” sealed glass container. (Amneal Br. at 4-5.) Amneal is wrong.
`
`1.
`
`The examiner of the patents-in-suit already rejected Amneal’s
`arguments.
`
`The same arguments made by Amneal have previously been overcome with the examiner
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`during prosecution of the patents-in-suit. The Precedex Concentrate product, as explained in the
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`2010 package insert, consists of a 100 µg/mL dexmedetomidine solution that must be diluted
`
`prior to administration to a patient. (DTX-23 at 5014, 5016.) The examiner considered this
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`product, including the package insert, during prosecution. (PTX-5.304; PTX-6.375-6; PTX-
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`7.267-8; PTX-8.100-1.) The examiner initially rejected Hospira’s claims as anticipated or
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`obvious in view of the 2010 package insert. (PTX-5.215-7.) In response, Hospira amended its
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`
`
`2
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 8 of 36 PageID #: 1514
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`claims to specify that the 4 µg/mL dexmedetomidine solution containing 0.9% sodium chloride
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`solution covered by the patents must be a “ready to use” solution stored in a “sealed glass
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`container.” (PTX-5.229-235.) Hospira emphasized that the 2010 package insert “does not recite
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`any genus of container into which the concentrated composition is diluted.” (Id. at 230.) Thus, no
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`container of any type, either sealed or unsealed, was disclosed as containing the 4 µg/mL
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`dexmedetomidine solution to be administered per the 2010 package insert.1 (Id. at 230-31.)
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`Instead of suggesting a sealed glass container for the diluted 4 µg/mL dexmedetomidine
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`solution, the 2010 package insert merely directs that the concentrated solution be diluted prior to
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`administration to a patient. (Id. at 232.) The examiner recognized that an infusion bag would be
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`the expected container for diluting such a composition in preparation for administration to a
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`patient. (Id. at 224, 232.) Contrary to this expectation, suggesting a diluted solution was unstable
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`after 24 hours, the inventors found that storage of the ready to use solution in a sealed glass
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`container could maintain over 98% potency over a 5 month period as compared to the prior art.
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`(Id. at 233-4; PTX-71.8.)
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`The examiner allowed the claims as amended. (PTX-5.304.) In making this finding, the
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`examiner credited Hospira’s evidence that such a solution was more stable when stored in a
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`sealed glass vial relative to storage in plastic, CR3 or PVC containers, and that the prior art
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`taught away from storage of a 4 µg/mL dexmedetomidine solution for longer than 24 hours. (Id.)
`
`Thus, the examiner explicitly considered and rejected Amneal’s arguments that the 2010 package
`
`insert disclosed a “known” ready to use solution in a “known” sealed glass container.
`
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`1 Because there were other container types, either sealed or unsealed, that could store the diluted
`solution at the time of the invention, a sealed glass container is also not inherent in the reference.
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`
`
`3
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 9 of 36 PageID #: 1515
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`2.
`
`Precedex Concentrate, as disclosed in the 2010 package insert, does
`not disclose a ready to use solution in a sealed glass container.
`
`a.
`
`The prior art did not disclose a ready to use 4 µg/mL
`dexmedetomidine solution.
`
`No prior art even hinted at an answer to stably storing a ready to use 4 µg/mL
`
`dexmedetomidine solution for a standard shelf life. Both of the inventors agreed that developing
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`a stable ready to use ultra-low concentration solution was the central formulation problem. (Tr.
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`68:7-69:20, 74:24-75:24 (Rowchowdhury), 853:17-855:15 (Cedergren).) This is because the
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`stability of the diluted 4 µg/mL solution was unknown after 24 hours, and at the same time,
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`formulations at ultra-low concentrations were known to present challenges. (Id.; PTX-71.8.)
`
`b.
`
`The Patent Office issued the patents-in-suit over Precedex
`Concentrate, which was considered by the examiner.
`
`The development of the patents-in-suit expressly sought to produce a ready-to-use
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`alternative to Precedex Concentrate, and the parties’ experts all agree that Precedex Concentrate,
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`per the 2010 package insert, was not a ready to use 4 µg/mL dexmedetomidine solution.
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`Dr. Roychowdhury, one of the inventors of the patents-in-suit, explained that Precedex
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`Concentrate required ad-mixing, and that her work in developing the patents was focused on
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`eliminating that step. (Tr. 73:1-7.) She testified that Precedex Concentrate had a concentration of
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`100 µg/mL, and Hospira had identified disadvantages with the admixing step required for
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`administration of that product, including safety concerns, cost, and waste of the drug. (Tr. 62:18-
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`63:5; 63:13-17; 68:7-70:8.) Admixing of Precedex Concentrate requires five steps, collecting
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`Precedex Concentrate and a 50 mL bottle of 0.9% sodium chloride, removal of 2 mL of the
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`sodium chloride solution, removal of the 2 mL of 100 µg/mL dexmedetomidine from its bottle,
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`injection of the dexmedetomidine into the prepared 48 mL sodium chloride solution, and finally
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`mixing of the solutions. (Tr. 70:18-71:13.) Dr. Roychowdhury worked to eliminate the admixing
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`
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`4
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`

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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 10 of 36 PageID #: 1516
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`step, and ultimately developed a ready to use formulation of dexmedetomidine as an alternative
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`to Precedex Concentrate. (Tr. 63:13-24; 65:6-10; 73:1-7.)
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`Dr. Yaman explained that Precedex Concentrate was extemporaneously compounded
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`from its original 100 µg/mL concentration down to 4 µg/mL for administration. (Tr. 617:19-
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`620:9.) He explained that solutions requiring “extemporaneous compounding,” such as Precedex
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`Concentrate, are not ready to use. (Tr. 618:19-620:9) According to Amneal’s own expert, Dr.
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`Yaman, Precedex Concentrate was not a ready to use pharmaceutical.
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`Dr. Linhardt agrees with Dr. Yaman that Precedex Concentrate was not ready to use. Dr.
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`Linhardt explained that to be ready to use, a solution must be ready to administer to a patient
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`without additional manipulation. (Tr. 262:3-12.) Dr. Linhardt reviewed the specification and
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`prosecution history of the patents-in-suit, and found that these patents were directed at
`
`elimination of the dilution step required for Precedex Concentrate. (Tr. 262:17-23; 263:24-
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`265:15.) Thus, Dr. Linhardt explained that the ready to use formulation claimed in the patents-in-
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`suit contrasted with Precedex Concentrate, at least because it does not require dilution prior to
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`administration to patients. (Id.) Dr. Ramsay also confirms from the perspective of a clinician that
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`Precedex Concentrate was not ready to use. He elaborated that clinicians are concerned with the
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`use of Precedex Concentrate because it requires dilution, which can lead to medical errors,
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`including dosage errors, and contamination. (Tr. 863:3-864:6.) By contrast, the patents describe a
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`ready to use 4 µg/mL product administered directly to patients. (Tr. 864:7-21.)
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`Dr. Yaman, Dr. Linhardt, and Dr. Ramsay all confirm that the development of the
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`patents-in-suit shows that Precedex Concentrate was never considered a ready-to-use product.
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`3.
`
`Amneal presented no prior art suggesting development of a ready to
`use 4 µg/ml dexmedetomidine solution.
`
`Amneal has not presented any evidence of motivation known to persons of ordinary skill,
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`
`
`5
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`

`

`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 11 of 36 PageID #: 1517
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`or recounted in publically available literature, to make a ready to use 4 µg/mL dexmedetomidine
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`solution prior to Hospira’s invention. (Amneal Br. at 7.) Instead, Amneal argues that Dr. Cain’s
`
`article provides motivation. (Id.) Dr. Cain could have stated in his article that a manufacturer-
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`prepared ready to use 4 µg/mL dexmedetomidine formulation should be developed; he did not.
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`Instead at trial Dr. Cain commented on the need for ready to use medications generally, without
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`addressing the formulation challenges faced by the inventors here. (DTX-003 at 63184; Tr.
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`750:23-751:6.) The article merely discloses the preparation of Precedex Concentrate according to
`
`its label. (DTX-003 at 63184; Tr. 740:13-23, 798:5-803:3.) Similarly, Amneal points to Dr.
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`Yaman’s testimony that a person of ordinary skill in the art would have been motivated by the
`
`“voice of the customer” to prepare a ready to use dexmedetomidine product, (Amneal Br. at 7,)
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`but Yaman provided no actual evidence for support. (Tr. 520:14-521:17.)
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`Amneal then retreats “[m]ore generally” to literature describing the need for ready to use
`
`products other than diluted dexmedetomidine. (Amneal Br. at 7.) At best these articles
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`demonstrate a long-felt need for ready to use products generally, even though the market had not
`
`realized its need for a ready to use 4 µg/mL dexmedetomidine solution prior to Hospira’s
`
`patented invention. Dr. Cain admitted that these articles call for manufacturers to provide ready
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`to use formulations when possible, but that they did not refer to dexmedetomidine specifically.
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`(DTX-43 at 4843, Tr. 818:6-9, 819:10-820:17; DTX-44 at 56, Tr. 809:9-24, 810:10-16, 811:13-
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`813:22; DTX-46, Tr. 756:16-757:20.)
`
`Precedex Concentrate was not new to the market when the articles cited by Amneal were
`
`published in 2010, 2011, 2010, respectively. (PTX-43, PTX-44, PTX-46.) If a ready to use 4
`
`µg/mL dexmedetomidine was obvious, then these articles could have noted it specifically, as
`
`they did for other medications. (PTX-43 (calling for manufacturers to prepare ready to use
`
`
`
`6
`
`

`

`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 12 of 36 PageID #: 1518
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`medications generally), PTX-44 (calling for a manufacture to prepare a ready to use amiodarone
`
`IV), PTX-46 (calling for manufacturers to prepare ready to use medications generally).) Despite
`
`the lack of articles calling specifically for a ready to use dexmedetomidine product, the market’s
`
`desire for a ready to use 4 µg/mL dexmedetomidine product was ignited when Hospira brought
`
`its patented ready to use product to market, as discussed below.
`
`4.
`
`There was no reasonable expectation of success in preparing a ready
`to use 4 µg/ml dexmedetomidine solution in a sealed glass container.2
`
`Precedex Concentrate, as disclosed in the 2010 package insert, does not disclose a sealed
`
`glass container containing 4 µg/mL dexmedetomidine solution. Amneal focuses instead on
`
`Precedex Concentrate’s 2 mL glass vial with its coated stopper, (Amneal Br. at 4,) without
`
`acknowledging that the 2010 Package insert does not disclose any container or seal for the
`
`diluted 4 µg/mL dexmedetomidine solution. (DTX-23 at 5014, 5016, 5023.) The issue is whether
`
`the 2010 package insert discloses or suggests to a person having ordinary skill in the art, that a
`
`“sealed” or a “glass container” should be used to store a ready to use 4 µg/mL dexmedetomidine
`
`solution. It does not do either. (Id. at 5014, 5016-17, 5032.)
`
`a.
`
`Glass
`
`Amneal’s conflation of Precedex Concentrate with the vial claimed here containing
`
`Precedex Premix matters because not every vial will work to store the solution. Precedex
`
`2 The parties now appear to agree with the Court’s proposal that the plain and ordinary meaning
`of the “sealed” claim term is a glass container that is “closed tightly to maintain sterility.”
`(Comp. D.I. 101 at fn. 3 and Amneal Br. at 29.) This construction is supported by the intrinsic
`evidence cited in Hospira’s opening brief (at fn. 3) and also the prosecution history quoted by
`Amneal (discussing use of a “sealed container… to maintain the sterility of the
`composition….”). (PTX 5.216.)
`
`This construction is similar to the construction Hospira proffered pre-trial, “a glass container
`closed to maintain sterility by having a seal or other closure that passes closure integrity
`testing.” As such, Hospira’s arguments do not depend on whether the Court’s or Hospira’s
`previously proposed construction govern.
`
`
`
`7
`
`

`

`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 13 of 36 PageID #: 1519
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`Concentrate was only sold in a 2 mL vial, rather than the 50 or 100 mL vial used for Precedex
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`Premix. (Tr. 70:18-71:13, 124:8-125:13.) In fact, the inventors knew they had to use a different
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`vial, and had concerns about the container material from the beginning of their formulation
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`development. (Tr. 82:3-10.) Through extensive testing, the inventors discovered that numerous
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`types of containers were unsuitable, including plastic flexible containers and various glass vials
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`that could not be sealed. (Tr. 82:11-83:14; 84:15-87:17; 89:11-105:20; 107:2-126:24.) As
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`illustrated by the extensive problems Hospira’s inventors had finding an appropriate container
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`for the ready to use 4 µg/mL dexmedetomidine solution, the specific vial chosen is important.
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`The inventors were motivated to use a material other than glass as it was not the preferred
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`container closure, and Hospira sought to avoid issues such as glass particles. (Tr. 80:20-81:12.).
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`Dr. Yaman explained that glass fissures can be imparted into the glass during manufacturing,
`
`(Tr. 636:6-637:12,) and Dr. Ramsay confirmed from the perspective of a clinician that glass is
`
`avoided when possible. (Tr. 874:10-875:10.) Dr. Linhardt elaborated, noting glass breakage can
`
`cause problems in hospital settings and that glass is more likely to lead to adsorption of drug
`
`product in situations, such as with dexmedetomidine, where the molecule is positively charged.
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`(Tr. 940:18-945:4; PTX-95.) Dr. Yaman also confirmed that a person of ordinary skill in the art
`
`should consider plastics as an option, and that the voice of the customer at the time of Hospira’s
`
`invention called for products in plastic containers, rather than glass. (Tr. 536:1-4, 674:3-21.)
`
`Therefore, because glass may not seal, as Hospira found out during its extensive testing,
`
`and glass may adsorb too much of the drug molecule to be a viable container, Amneal’s
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`conflation of a vial for Precedex Concentrate with a vial for the diluted solution cannot be
`
`sufficient to show a reasonable expectation of success in preparing a sealed glass container with
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`4 µg/mL dexmedetomidine solution, especially considering the advantages of avoiding glass.
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`8
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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 14 of 36 PageID #: 1520
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`b.
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`Sealed
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`Similarly, the 2010 package insert does not disclose a sealed container for the 4 µg/mL
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`dexmedetomidine solution. (DTX-23 at 5014, 5016, 5023.) Dr. Roychowdhury testified that
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`there were three different vial sizes being tested for the ready to use product, 20, 50, and 100 mL,
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`each of which required container closure and stability testing. (Tr. 124:8-125:13.) Although
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`Amneal argues that the 2010 package insert taught the exact type of packing claimed in these
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`patents, they are wrong. (Amneal Br. at 4.) This is clear, as Hospira’s initial container closure
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`and stability testing failed because the glass vial elastomeric combination would not work to seal
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`the container. (Tr. 125:14-22; PTX-40.12.) This problem took months to resolve, and required
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`identifying and testing alternative stoppers as well as alternative glass containers. (Tr. 125:19-
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`126:24; PTX-40.12-13.)
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`Hospira’s failures prove that, contrary to Amneal’s arguments, glass vials are not
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`interchangeable. (Id.) Numerous vial properties potentially differ, including the material used
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`(again, the 2010 package insert does not disclose a glass container for the ready to use 4 µg/mL
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`dexmedetomidine solution), as well as size characteristics, each requiring testing for every
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`potential vial configuration. (Tr. 124:17-126:2.)
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`Moreover, it was understood by persons of ordinary skill at the time that once Precedex
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`Concentrate was diluted down to 4 µg/mL, that this diluted solution was potentially unstable
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`after 24 hours. The examiner understood this, (PTX-5.304; PTX-71.8,) as did the inventors, (Tr.
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`68:7-69:20, 74:24-75:24.) Because the diluted solution was to be used within 24 hours of
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`dilution, and it was expected that this step would be performed in a pharmacy, there had been no
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`previous need by Hospira to do testing on containers for the diluted solution. (Id.) Contrary to
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`Amneal’s characterization that the 2010 package insert taught the exact type of packaging
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`claimed in the patents, Hospira had not performed testing on container systems for
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`9
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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 15 of 36 PageID #: 1521
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`dexmedetomidine diluted to 4 µg/mL. (Id.) Hospira’s testing failures led to months of costly
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`development work, proving that the exact type of packaging required was, in fact, not known to
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`Hospira at the time of the invention. Thus, just as above, Amneal’s conflation of Precedex
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`Concentrate’s vial with a vial for the diluted solution cannot be sufficient to show a reasonable
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`expectation of success in preparing a sealed container with 4 µg/mL dexmedetomidine solution.
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`B.
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`Hospira’s internal documents may not be used as evidence for obviousness.
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`Amneal’s arguments that the asserted claims are obvious based on Hospira’s internal
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`development process amounts to improper hindsight. In an obviousness analysis, “[p]atentability
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`shall not be negatived by the manner in which the invention was made.” 35 U.S.C § 103(a). “The
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`inventor's own path itself never leads to a conclusion of obviousness; that is hindsight.” Otsuka
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`Pharmaceutical Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1296 (Fed. Cir. 2012). Instead, “[w]hat
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`matters is the path that the person of ordinary skill in the art would have followed, as evidenced
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`by the pertinent prior art.” Id.
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`In Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., “Mylan’s expert, Dr. Anderson,
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`simply retraced the path of the inventor with hindsight, discounted the number and complexity of
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`the alternatives, and concluded that the invention of topiramate was obvious.” 520 F.3d 1358,
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`1364 (Fed. Cir. Mar. 31, 2008). On appeal, the Federal Circuit held that, “this reasoning is
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`always inappropriate for an obviousness test based on the language of Title 35 that requires the
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`analysis to examine ‘the subject matter as a whole’ to ascertain if it ‘would have been obvious at
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`the time the invention was made.’” Id. (citing 35 U.S.C. § 103(a)). Thus, “[i]n retrospect, Dr.
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`Maryanoff’s pathway to the invention, of course, seems to follow the logical steps to produce
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`these properties, but at the time of invention, the inventor’s insights, willingness to confront and
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`overcome obstacles, and yes, even serendipity, cannot be discounted.” Id.
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`10
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`Case 1:15-cv-00697-RGA Document 106 Filed 10/10/17 Page 16 of 36 PageID #: 1522
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`Here, Amneal improperly relies on the inventor’s own path in its attempt to prove
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`obviousness. Amneal’s opening argument focused extensively on Hospira’s internal documents.
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`(Tr. 40:17-43:12, 46:5-47:1.) Amneal explained that these documents showed a clear internal
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`development pathway, and revealed a clear likelihood of success in developing a ready to use 4
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`µg/ml dexmedetomidine solution in a sealed glass container. (Id.) Amneal continues to argue that
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`Hospira’s internal development showed that the invention was obvious. (See, e.g., Amneal Br. at
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`5, 8, 14, 15.) This argument should be rejected as improper.
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`Moreover, Hospira’s internal development documents are not prior art that may be
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`considered, because they were not public at the time of invention. SRI Int'l, Inc. v. Internet Sec.
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`Sys., 511 F.3d 1186, 1194 (Fed. Cir. 2008). No such showing has been made concerning
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`Hospira’s internal development documents.
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`Because hindsight is prohibited, and Hospira’s internal development documents were not
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`publically disclosed, this evidence may not support Amneal’s attempted obviousness defense.
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`C.
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`The commercial success of Precedex Premix indicates non-obviousness.
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`Precedex Premix is a commercial success. It sells for a premium price because of the
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`invention in a uniformly generic market and enjoys significant market share. Mr. David Engels,
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`an employee of Pfizer, described Precedex Premix’s success.
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`Precedex Concentrate has been on the market since 1999. (See, e.g., Tr. 510:19-24.)
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`Precedex Premix launched in 2013 following numerous generic concentrate products to market.
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`(See, e.g., Tr. 213:9-12, 1055:14-1057:1.) The vast majority of Hospira’s current sales of
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`Precedex are for it