`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`
`EVERGREEN THERAGNOSTICS, INC.,
`
`Petitioner,
`
`v.
`
`ADVANCED ACCELERATOR APPLICATIONS S.A.,
`
`Patent Owner.
`
`______________________
`
`Case PGR2021-00001
`
`U.S. Patent No. 10,596,278
`______________________
`
`
`PRELIMINARY PATENT OWNER RESPONSE
`
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
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`
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`TABLE OF CONTENTS
`
`PRELIMINARY STATEMENT ............................................................................ 1
`FACTS ...................................................................................................................... 7
`
`A. Radionuclide Cancer Therapy Prior to July 2018 .................................. 7
`1. Therapeutic Rationale ............................................................................ 7
`2. Problem of Stability ............................................................................... 9
`3. Advanced Accelerator Applications S.A. ............................................15
`4. The Invention .......................................................................................15
`5. Prosecution ..........................................................................................16
`
`
`
`B. Evergreen’s Petition .................................................................................18
`ARGUMENT ..........................................................................................................20
`
`A. Evergreen Fails to Show That the Protocol Is Prior Art ......................20
`1. Strosberg and Protocol Are Two Separate Documents .......................22
`2. Evergreen Has Failed to Carry Its Burden of Proving the
`Protocol Is Prior Art ............................................................................25
`
`B. Evergreen Fails to Show That the Protocol Anticipates Any
`Claim ..........................................................................................................39
`1. The Protocol Does Not Explicitly Disclose the Required
`Stability Characteristics .......................................................................39
`2. The Protocol Does Not Inherently Disclose the Required
`Stability Characteristics .......................................................................46
`
`C. Maus Was Overcome in Prosecution and Evergreen Presents
`Substantially the Same Arguments .........................................................52
`1. Substantially the Same Art, and Substantially the Same
`Arguments Were Presented to the PTO ..............................................55
`a) Becton factor (a): the similarities and material differences
`between the asserted art and the prior art involved during
`examination and Becton factor (b): the cumulative nature of
`the asserted art and the prior art evaluated during
`examination ...................................................................................55
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`i
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`b) Becton factor (d): the extent of the overlap between the
`arguments made during examination and the manner in
`which Petitioner relies on the prior art .........................................56
`2. Evergreen Fails to Sufficiently Point Out Material Error by the
`PTO ......................................................................................................57
`a) Becton factor (c): the extent to which the asserted art was
`evaluated during examination, including whether the prior
`art was the basis for rejection .......................................................57
`b) Becton factor (e): whether Petitioner has pointed out
`sufficiently how the Examiner erred in its evaluation of the
`asserted prior art ...........................................................................60
`c) Becton factor (f): the extent to which additional evidence
`and facts presented in the petition warrant reconsideration
`of the prior art or arguments .........................................................62
`
`D. Obviousness ...............................................................................................66
`1. Evergreen’s Petition Improperly Multiplies Its Obviousness
`Grounds. ..............................................................................................66
`2. Evergreen’s Petition Offers Only Pro Forma Statements
`Concerning Motivation to Combine ....................................................68
`3. Evergreen’s Putative Expert Is Not a Person of Ordinary Skill,
`Which Is a Team Including both Radiochemists and Individuals
`Skilled in Administering Radiopharmaceuticals .................................70
`
`E. Evergreen’s Contingent Enablement Argument Is Legally
`Incorrect, Internally Inconsistent, and Foreclosed by Its
`Admissions ................................................................................................74
`
`F. Evergreen’s Improper Dependency Argument Is Incorrect ................76
`
`ii
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`
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`TABLE OF AUTHORITIES
`
`
`Pages(s)
`
`
`Cases
`
`Adaptics Ltd. v. Perfect Co.,
`IPR2018-01596, Paper 20 (PTAB Mar. 6, 2019) ........................... 5, 6, 67, 68, 74
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) .............................. 53, 54, 61, 66
`Albaad Massuot Yitzhak, Ltd. v. Edgewell Pers. Care Brands, LLC,
`IPR2017-00693, Paper 11 (July 17, 2017) ............................................. 47, 50, 51
`Andersen Corp. v. Fiber Composites, LLC,
`474 F.3d 1361 (Fed. Cir. 2007) .......................................................................... 42
`Apple, Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 14 (PTAB Aug. 12, 2015) ....................................... 29, 30
`In re Bayer,
`568 F.2d 1357 (C.C.P.A. 1978) .......................................................................... 33
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ............................. 53, 54, 62, 66
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 69
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F.3d 629 (Fed. Cir. 2011) ............................................................................ 46
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) .......................................................................... 21
`Bruckelmyer v. Ground Heaters, Inc.,
`445 F.3d 1374 (Fed. Cir. 2006) .......................................................................... 22
`C.R. Bard, Inc. v. Medline Indus., Inc.,
`IPR2015-00511, Paper 9 (July 15, 2015) ........................................................... 48
`C.R. Bard, Inc. v. U.S. Surgical Corp.,
`388 F.3d 858 (Fed. Cir. 2004) ............................................................................ 42
`
`
`
`iii
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`
`
`
`
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ...................................................................... 63, 65
`Coalition for Affordable Drugs V, LLC, et. al. v. Biogen MA, Inc.,
`IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017) ............................................. 73
`Cordis Corp. v. Bos. Sci. Corp.,
`561 F.3d 1319 (Fed. Cir. 2009) .......................................................................... 37
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 32
`Crown Operations Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .......................................................................... 49
`Edmund Optics, Inc. v. Semrock Inc.,
`IPR2014-00583, Paper 9 (PTAB Sept. 19, 2014) ............................................... 67
`Eli Lilly & Co. v. Barr Labs., Inc.,
`251 F.3d 955 (Fed. Cir. 2001) ............................................................................ 46
`Endo Pharm. Inc. v. Depomed, Inc.,
`IPR2014-00653, Paper 12 (Sept. 29, 2014) ........................................................ 52
`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00002, Paper 2 (PTAB Oct. 2, 2020) .................................... 18, 19, 51
`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00003, Paper 2 (PTAB Oct. 2, 2020) .................................. 7, 8, 18, 19
`Galderma Laboratories, L.P. v. Teva Pharmaceuticals USA, Inc.,
`799 F. App’x 838 (Fed. Cir. 2020) ......................................................... 46, 48, 50
`Gillette Co. v. Energizer Holdings, Inc.,
`405 F. 3d 1367 (Fed. Cir. 2005) ......................................................................... 76
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ........................................................................ 2, 21
`Homeland Housewares, LLC v. Whirlpool Corp.,
`865 F.3d 1372 (Fed. Cir. 2017) .......................................................................... 38
`
`
`
`iv
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`Hulu, LLC v. Sound View Innovations,
`LLC, IPR2018-02003, Paper 29 (PTAB Dec. 20, 2019) .................................... 21
`HZNP Medicines LLC v. Actavis Labs. UT, Inc.,
`940 F.3d 680, 692 (Fed. Cir. 2019) .................................................................... 76
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 70
`Kyocera Wireless Corp. v. Int’l Trade Comm’n,
`545 F.3d 1340 (Fed. Cir. 2008) .......................................................................... 21
`Ex parte Levy,
`17 USPQ2d 1461 (Bd. Pat. App. & Inter. 1990) ................................................ 50
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 28
`Louisiana-Pacific Corp., v. Huber Engineered Woods LLC,
`IPR2020-00596, Paper 12 (PTAB Aug. 20, 2020) ............................................. 27
`Metalcraft of Mayville, Inc. v. The Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017) .......................................................................... 69
`Microsoft Corp. v. Enfish, LLC,
`662 F. App’x 981 (Fed. Cir. 2016) ..................................................................... 70
`Microsoft v. Biscotti,
`Case IPR2014-01457, Paper 21 (PTAB June 2, 2015)....................................... 37
`In re Nat. Alternatives, LLC,
`659 F. App’x 608 (Fed. Cir. 2016) ............................................................... 63, 65
`In re NuVasive,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 69
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) .......................................................................... 74
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .......................................................................... 46
`
`
`
`v
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`
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`Rexnord Indus., LLC v. Kappos,
`705 F.3d 1347 (Fed. Cir. 2013) .................................................................... 39, 47
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 50
`RPX Corp. et. al., v. Parity Networks, LLC,
`IPR2018-00097, Paper 7 (PTAB Apr. 24, 2018) ............................................... 73
`Samsung Elecs. Co. v. Infobridge Pte. Ltd.,
`929 F.3d 1363 (Fed. Cir. 2019) .......................................................................... 22
`Samsung Electronics Co., Ltd., v. Bell Northern Research, LLC,
`IPR2020-00613, Paper 10 (PTAB Aug. 24, 2020) ............................................. 28
`SAS Institute Inc. v. Iancu,
`138 S. Ct. 1348 (2018) ........................................................................................ 68
`In re Schreiber,
`128 F.3d 1473 (Fed. Cir. 1997) .......................................................................... 46
`Smith & Nephew, Inc. v. Conformis, Inc.,
`IPR2017-00487, Paper 7 (July 7, 2017) ............................................................. 48
`Symantec Corp. v. Trustees of Columbia Univ.,
`IPR2015-00370, Paper 13 (PTAB June 17, 2015) ............................................. 30
`TQ Delta, LLC v. Cisco Sys., Inc.,
`942 F.3d 1352 (Fed. Cir. 2019) .......................................................................... 70
`ZTE Corp. v. ContentGuard Holdings, Inc.,
`IPR2013-00137, Paper 58 (PTAB July 1, 2014) ................................................ 50
`Statutes
`35 U.S.C. §324 ......................................................................................................... 20
`35 U.S.C. § 325(d) ............................................................................................... 4, 52
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`vi
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`Other Authorities
`Guidance on the Impact of SAS on AIA Trial Proceedings (April 26,
`2018). Available at: https://www.uspto.gov/patents-application-
`process/patent-trial-and-appeal-board/trials/guidance-impact-sas-
`aia-trial ................................................................................................................ 68
`Manual of Patent Examining Procedure, Ninth Ed., Rev. 10.2018,
`Last Rev. June 2020 § 2112 (IV) .................................................................. 49, 50
`Regulations
`35 C.F.R. § 42.65 ..................................................................................................... 31
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`vii
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`
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`Exhibit
`2001
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`2002
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`2003
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`2004
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`2005
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`2006
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`2007
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`2008
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`PATENT OWNER’S EXHIBIT LIST
`
`Description
`Price et al., “Role of Supplementary Material in Biomedical Journal
`Articles: Surveys of Authors, Reviewers and Readers,” BMJ Open
`(2018) 2018;8:e021753. doi:10.1136/bmjopen-2018-021753 (“Price”)
`
`Pop and Salzberg, “Use and Mis-Use of Supplementary Material in
`Scientific Publications,” BMC Bioinformatics (2015) 16:237 (“Pop &
`Salzberg”)
`
`Chen et al., U.S. Patent Pub. No. 2007/0269375A1 (“Chen 375”)
`
`Liu et al., “Ascorbic Acid: Useful as a Buffer Agent and Radiolytic
`Stabilizer for Metalloradiopharmaceuticals,” Bioconjugate Chem.,
`(2003), 14, 1052-1056 (“Liu 2003”)
`
`Printouts from the New England Journal of Medicine Website
`(“NEJM Authors Center”)
`
`App’x 1 - Publication Process (at 2);
`App’x 2 - What to Expect (at 8);
`App’x 3 - New Manuscripts (at 11);
`App’x 4 - Supplementary Appendix (at 25)
`
`Supplementary Appendix to Strosberg J, El-Haddad G, Wolin E, et al.
`“Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine
`tumors,” New England J. Med. (2017);376:125-35. DOI:
`10.1056/NEJMoa1607427 (“Strosberg Supplementary Appendix”)
`
`Chen, et al., U.S. Published Patent Application No. US 2012/0065365
`(“Chen 365”)
`
`J. Chen et al., “Synthesis, stabilization and formulation of [177Lu]Lu-
`AMBA, a systemic radiotherapeutic agent for Gastrin Releasing
`Peptide receptor positive tumors,” Applied Radiation & Isotopes,
`(2008) 66(4):497–505 (“Chen 2008”)
`
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`viii
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`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`PRELIMINARY STATEMENT
`Evergreen’s Petition anchors itself to a Protocol document it holds out as prior
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`art, yet presents no evidence showing the Protocol’s public accessibility before the
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`priority date. Evergreen hedges its bet on the Protocol by recycling a reference,
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`Maus, addressed at length during prosecution. But Evergreen argues nothing new
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`about Maus, and identifies no errors in the Examiner’s consideration of it. Although
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`Evergreen solicited a declaration from one of that document’s authors, he lacks
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`essential expertise and does little more than parrot the language Evergreen’s
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`attorneys employ. Nothing here supports institution.
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`In the past, radioactive cancer medicines had to be manufactured close to the
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`patient’s bedside because these drugs degrade quickly due to the destructive energy
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`of the radioactivity itself. The instability of these medicines meant they could not
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`be shipped far from where they were made. The dangers of handling radioactive
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`isotopes while synthesizing the medicines required specialized equipment and
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`training for physicians and nurses, none of which was widely available. As a result,
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`cancer patients who were not located close enough to the necessary facilities and
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`expertise were effectively denied these treatments.
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`Patent Owner Advanced Accelerator Applications SA (AAA) discovered a
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`manufacturing process that results in radiochemical solutions with enhanced
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`stability. AAA researchers found that addition of particular radiochemical
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`1
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`stabilizers in particular amounts that went against the accepted teachings of the time
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`produced stable concentrated radionuclide complex solutions. One advantage that
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`such solutions possessed—especially those centrally manufactured on large scales—
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`was their capacity to be shipped to distant places to treat cancer patients in a ready-
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`for-use form. The Patent Office recognized this innovation and awarded AAA two
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`patents directed to the manufacturing process and the resultant radioactive
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`pharmaceutical solutions, including the challenged U.S. Patent No. 10,596,278 (’278
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`Patent).
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`Evergreen rests nearly every challenge to the ’278 Patent on two references,
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`a Protocol document (Ex. 1012) and a scientific paper, Maus (Ex. 1009), alleging
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`anticipation over the Protocol, and obviousness over many permutations of the
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`Protocol, Maus, and other references. All challenges presented should be denied for
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`their threshold deficiencies:
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`First, Evergreen fails to carry its burden to show that the Protocol was
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`publicly accessible before the priority date, which is the “touchstone” of determining
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`whether it is prior art. In re Hall, 781 F.2d 897, 899 (Fed. Cir. 1986). This defect
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`alone disposes of all challenges based upon the Protocol. Evergreen’s declarant
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`librarian, Dr. Hsieh-Yee, examined the Protocol’s availability in 2020. But she did
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`not offer evidence that the Protocol was publicly accessible prior to the patent’s
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`effective filing date in 2018, either from personal knowledge or from documentary
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`2
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`sources. She attempts to backfill this gap by insisting that the Protocol and Strosberg
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`(filed separately by Evergreen as Ex. 1011) together make “one document”—hoping
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`to transfer facts particular for Strosberg over to the Protocol. But this opinion lacks
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`contemporaneous support and ignores record facts showing that the Protocol and
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`Strosberg are two different documents.
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`The two documents display indicia of different origins, different treatment by
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`the New England Journal of Medicine (NEJM) and its readership, and different
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`timing of preparation. Strosberg is an article from the NEJM that was subject to the
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`rigor of peer-review. Unlike it, the Protocol bears no date of publication, was not
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`peer-reviewed, is not typeset by the NEJM, and is a lengthy compilation of 676 pages
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`of various documents from apparently different sources. The Protocol today is listed
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`as a Supplementary Material related to Strosberg on the NEJM website, but that
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`listing does not meld it with Strosberg—today or in 2018.
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`Critically, Evergreen fails to offer proof of the Protocol’s first public
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`accessibility. The Protocol’s contents were not (and are not now) searchable in any
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`database or index by a person of ordinary skill. Evergreen has not addressed
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`numerous “confidential” stamps throughout the Protocol especially since the NEJM
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`allows for authors to redact confidential materials. Evergreen ignores all of these
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`facts, resting its case on the unsupported and conclusory librarian opinion, which
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`should be given no weight.
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`3
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`Second, Evergreen argues that the Protocol discloses every element of the
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`
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`claimed formulation, including the high radiochemical purity AAA’s centralized
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`commercial manufacturing invention requires. Evergreen concedes that the Protocol
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`does not disclose how to make the clinical trial formulation it describes. Nor does
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`it disclose measuring stability of the medicine over the timeframe the claims require.
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`But Evergreen argues that whatever the Protocol fails to disclose explicitly, it
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`discloses inherently. Proof of inherency requires evidence beyond mere possibilities
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`or probabilities. Instead of offering documentary evidence or data, Evergreen asks
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`the Board to accept its word that the clinical trial formulation disclosed in the
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`Protocol would have maintained the claimed radiochemical purity as the “natural
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`result flowing from” its composition. This allegation is conclusory, lacks any factual
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`showing, and thus fails to meet the high bar for proving inherent anticipation.
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`Third, Evergreen fails to show why its other reference, Maus, raises a new
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`issue that the Board should entertain. See 35 U.S.C. § 325(d). Maus was cited by
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`the Patent Office Examiner for obviousness, was discussed in detail, and was
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`overcome for failing to disclose several claimed elements. Evergreen identifies no
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`error in the Examiner’s analysis and does not address the teaching away discussed
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`in the record. Although Evergreen solicited a declaration from Mr. Maus in an
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`attempt to resurrect the article, he does nothing to fill the voids in the reference laid
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`bare during prosecution.
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`4
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`Fourth, Evergreen’s allegations of obviousness are legally insufficient for at
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`
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`least three separate reasons.
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`1. Each obviousness contention is based on the Protocol document—
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`which Evergreen has failed to demonstrate is prior art—and the majority of
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`the combinations rely on the Maus article, which the Patent Office already
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`addressed.
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`2. Evergreen proposes to combine these two documents with a legion
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`of other references, in a vast multiplicity of combinations that is reason
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`enough to deny institution. Adaptics Ltd. v. Perfect Co., IPR2018-01596,
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`Paper 20 at 24 (PTAB Mar. 6, 2019) (denying institution for lacking
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`particularity where the petition was based on two primary anticipatory
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`references and “voluminous and excessive” secondary obviousness
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`combinations). Evergreen’s pro forma statements concerning motivation to
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`make the alleged combinations are deficient as a matter of law.
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`3.
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` Although Evergreen offers testimony from Mr. Maus, a
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`radiochemist, the perspective he offers is insufficient. Nearly every piece of
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`prior
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`art on which Evergreen
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`relies
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`addresses
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`administering
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`radiopharmaceuticals to patients and monitoring their biological effects. Mr.
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`Maus lacks this clinical training, and so his testimony that a person of ordinary
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`skill in the art (POSA) would have found the claims obvious over any one of
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`the proposed combinations is insufficient.
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`As a final hedge, Evergreen offers a half-hearted, contingent allegation of
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`non-enablement. There is no provision for contingent arguments in a PGR, and this
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`challenge should be denied as improper because the Board must make “a binary
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`choice” whether to institute all the proposed challenges. Adaptics, IPR2018-01596,
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`Paper 20 at 16–18 (denying institution and identifying as “the worst offender”
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`petitioner’s contingent argument of obviousness). Citing no authority, Evergreen
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`summarily states that the AAA patent does not disclose “factor(s) or variable(s) that
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`must be possessed” by a solution “meeting the structural limitations recited in the
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`claims of the ’278 patent so as to provide the recited stability.” Petition 74; Maus
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`Dec. (Ex. 1006) ¶425. But the “factors” and “variables” Evergreen insists must be
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`possessed are absent from the claim language. The proper enablement inquiry asks
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`whether the patent discloses information sufficient to make and use the claimed
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`invention without undue experimentation. The patent sets out detailed examples of
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`how to do just that. Evergreen concedes as much, condemning this challenge to
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`failure.
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`For these and other reasons below, the Board should not institute any ground.
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`6
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`FACTS
`The facts are from the Petition (Pet.) and filed Exhibits (Ex.), including
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`references on the Patent’s face and those cited by Mr. Maus and Dr. Hsieh-Yee.
`
`A. Radionuclide Cancer Therapy Prior to July 2018
`Therapeutic Rationale
`1.
` The goal of cancer treatment is to destroy or neutralize cancer cells while
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`leaving healthy cells intact. One approach to achieving this goal is to deliver a potent
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`treatment specifically to the cancer cells while avoiding the normal cells. The outer
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`surface of cancer cells differs from normal cells. See Banerjee (Ex. 1016) 3. That
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`difference can be exploited to devise a targeting molecule that will only bind to
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`cancer cells and not to normal cells, thereby delivering the treatment particularly to
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`the cancer cells and sparing the healthy ones. Id. A radioactive atom (called a
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`radioisotope or a radionuclide) is one such agent that can be linked to the targeting
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`molecule. Id. The resulting radioactive medicine can then be infused into a cancer
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`patient’s bloodstream, where it will specifically bind to cancer cells. The
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`radioactivity will cause the proximate cancer cells to die while minimally harming
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`healthy tissue. Id.; Chen 365 (Ex. 2007) ¶9.1
`
`
` 1 Chen 365 was filed as Exhibit 1019 in Evergreen’s co-pending petition against
`AAA. See Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA, PGR2021-00003 (Petition 3), Ex. 1019 (PTAB Oct. 2, 2020).
`
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`7
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`Somatostatin, a natural peptide hormone, was known to specifically bind to
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`PGR2021-00001
`U.S. Patent No. 10,596,278
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`
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`receptors that are expressed on the surfaces of certain types of cancer cells far more
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`than normal cells. Banerjee (Ex. 1016) 18–20. OctreoTATE and OctreoTIDE, are
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`synthetic peptides similar to somatostatin that selectively bind to those somatostatin
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`receptors (SSRs). Id. Cancer physicians teamed with radiochemists to devise ways
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`to chemically link these synthetic peptides to certain radionuclides. Id.; see also
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`Kwekkeboom (Ex. 1010) 2–3. 177Lu is one such radionuclide. A chelator
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`compound, such as DOTA, binds 177Lu. That chelator-bound-radionuclide is in turn
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`tethered to a synthetic peptide. See Banerjee (Ex. 1016) 7–9. 177Lu-DOTA-TATE
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`is one such radiolabeled peptide useful as a cancer treatment. Id.
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`There was a practical problem in linking the radioactive atom so close to the
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`peptide. The radioactivity given off by the radionuclide not only killed cancer cells
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`in the patient, it also degraded the synthetic peptide once linked to the radionuclide.
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`In other words, the radioactivity degraded the medicine itself. Id. at 9; see also, e.g.,
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`Liu 2001 (Ex. 1023) 1; J. Chen et al., Synthesis, stabilization and formulation of
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`[177Lu]Lu-AMBA, a systemic radiotherapeutic agent for Gastrin Releasing Peptide
`
`receptor positive tumors, Applied Radiation and Isotopes, 66(4):497-505, Apr. 2008
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`(Chen 2008) (Ex. 2008) 12; Chen 365 (Ex. 2007) ¶¶11–13. This self-destructive
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` 2 Chen 2008 was filed as Exhibit 1029 in Evergreen’s co-pending petition against
`AAA. See Petition 3, Ex. 1029.
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`activity is called autoradiolysis. It is “one of the most challenging aspects in the
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`development of a therapeutic radiopharmaceutical.” See, e.g., Chen 2008 (Ex.
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`2008) 1.
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`For that reason, most of these medicines historically were produced near the
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`patient’s bedside, such as in a specially equipped hospital pharmacy. See, e.g., Das
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`(Ex. 1021) 1; see generally, Kwekkeboom (Ex. 1010) 3; Filice (Ex. 1028) 3. The
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`medicine was made on-site and then quickly administered so there was less time for
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`the radioactivity to harm the medicine itself prior to administration. Das (Ex. 1021)
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`2. Since few hospitals had this required personnel and equipment, patients (who
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`often were very sick) had to travel long distances for such treatment, limiting
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`availability and use of this medicine.
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`Problem of Stability
`2.
`The viability of large-scale manufacturing depended on stability of the
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`radiolabeled peptide. Degradation of the peptide by autoradiolysis renders it unable
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`to bind specifically to cancer cells. E.g., Chen 365 (Ex. 2007) ¶¶11–15. This process
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`both reduces the amount of effective medicine and increases the amount of
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`radioactivity that can travel in an untargeted fashion throughout the patient’s body.
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`Id. ¶12. It is important for a physician to know how much effective medicine is
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`being administered to a patient. Thus, measuring radiochemical purity (RCP)—the
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`percentage of radioactivity in a sample present in the radiolabeled peptide as
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`compared to degraded species—gives physicians a window into the potency and
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`safety of the medicine. See Kwekkeboom (Ex. 1010) 3; Filice (Ex. 1028) 3 (“quality
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`controls”). RCP needs to be very high so that the radioactivity administered is
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`delivered selectively to the cancer by the targeting molecule and does not simply
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`randomly spread as degraded species throughout the body. See, e.g., Chen 365 (Ex.
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`2007) ¶12.
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`One strategy to achieve high RCP over longer time periods is to add stabilizers
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`to help reduce radiochemical degradation. See, e.g., Liu 2001 (Ex. 1023) 1. The
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`prior art disclosed numerous options for stabilizers, including ethanol (EtOH),
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`ascorbic acid (AA), sodium ascorbate (NaAsc), gentisic acid (GA), and methionine
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`(Met), among others. Id. at 1–2; Chen 2008 (Ex. 2008) 2. These, in turn, could be
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`added singly or in combination, at various points in the manufacturing process, and
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`at various concentrations. Chen 365 (Ex. 2007) ¶¶20, 22.
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`Complicating matters, in some instances stabilizers were known to impede
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`chelation of the radionuclide and thus were both a help and a hindrance. See, e.g.,
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`id. ¶251; Liu 2001 (Ex. 1023) 3–4. The medicine’s efficacy also depends on other
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`variables, including the particular radionuclide atom used and the type of radiation
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`emitted. See, e.g., Chen 365 (Ex. 2007) ¶¶54–57; Chen 2008 (Ex. 2008) 7–8.
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`Different radiolabeled peptides enjoy different levels of protection from different
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`stabilizers. Chen 2008 (Ex. 2008) 7–8. In sum, a person of ordinary skill was
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`confronted with great unpredictability in determining which stabilizers should be
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`added, at what step in manufacture, and in what amounts in order to yield a viable
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`medicine.
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`The art showed that most successful stabilization of 177Lu-DOTA-TATE (and
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`-TOC) required high concentrations of stabilizers such as AA or GA, and the use of
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`ethanol. For example:
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`Maus (Ex. 1009) compared several radiolabeling procedures for 177Lu-
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`DOTA-TATE. All included more than 100 mg/mL NaAsc and 25 mg/mL GA
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`during chelation; some stripped the stabilizers out; some included re-addition of a
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`stabilizer; and each was diluted to various volumes. RCP exceeded 95% at 72 hours
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`only if: (1) ascorbate and GA were present during both chelation and storage, and at
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`high concentrations (13.4 mg/mL and 3 mg/mL, respectively), or (2) stabilizers were
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`removed after chelation but then AA was reintroduced at a high (17.6 mg/mL)
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`concentration along with 25% EtOH. Id. at 4, Table 1. Accordingly, the authors
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`concluded “re-addition of AA post tC18 SPE purification is required to maintain
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`RCP of 177Lu-DOTA-TATE.” Id. at 2. But “[r]e-addition of GA (100 mmol/L)
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`[15.4 mg/mL] ... had only minor stabilizing properties” such that RCP still decreased
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`below <95% within 24h post-radiolabeling. Id. at 6.
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`Chen 365 (Ex. 2007) echoes the need for high concentrations of stabilizers to
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`achieve RCP at acceptably high percentages, disclosing that “many stabilizers have
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`been identified that alone or in combination, inhibit radiolytic damage to
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`radiolabeled compounds….” Id. ¶22. Table 1 of Chen 365 shows many stabilizers
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`that were tested (id. ¶161); Table 2 shows GA used