UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`
`EVERGREEN THERAGNOSTICS, INC.,
`
`Petitioner,
`
`v.
`
`ADVANCED ACCELERATOR APPLICATIONS S.A.,
`
`Patent Owner.
`
`______________________
`
`Case PGR2021-00003
`
`U.S. Patent No. 10,596,276
`______________________
`
`
`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
`
`
`
`
`

`

`
`
`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. Maus Was Overcome in Prosecution and Evergreen Presents
`Substantially the Same Arguments .........................................................21
`1. Substantially the Same Art, and Substantially the Same
`Arguments Were Presented to the PTO ..............................................23
`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 ...................................................................................23
`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 .........................................24
`2. Evergreen Fails to Sufficiently Point Out Material Error by the
`PTO ......................................................................................................26
`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 .......................................................27
`b) Becton factor (e): whether Petitioner has pointed out
`sufficiently how the Examiner erred in its evaluation of the
`asserted prior art ...........................................................................29
`c) Becton factor (f): the extent to which additional evidence
`and facts presented in the petition warrant reconsideration
`of the prior art or arguments .........................................................31
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`
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`B. Evergreen Fails to Show Maus Anticipates the Claimed
`Invention ....................................................................................................36
`1. Maus Does Not Explicitly Disclose the Required Stability
`Characteristics .....................................................................................37
`2. Maus Does Not Inherently Disclose the Required Stability
`Characteristics .....................................................................................38
`
`C. Evergreen Fails to Show That the Protocol Is Prior Art ......................42
`1. Strosberg and Protocol Are Two Separate Documents .......................44
`2. Evergreen Has Failed to Carry Its Burden of Proving the
`Protocol Is Prior Art ............................................................................47
`
`D. Evergreen Fails to Show That the Protocol Anticipates Any
`Claim ..........................................................................................................61
`1. The Protocol Does Not Explicitly Disclose the Required
`Stability Characteristics .......................................................................62
`2. The Protocol Does Not Inherently Disclose the Required
`Stability Characteristics .......................................................................68
`
`E. Obviousness ...............................................................................................73
`1. Evergreen’s Petition Offers Only Pro Forma Statements
`Concerning Motivation to Combine ....................................................73
`2. Evergreen’s Expert Declarant Is Not a Person of Ordinary Skill,
`Which Is a Team Including both Radiochemists and Individuals
`Skilled in Administering Radiopharmaceuticals .................................75
`
`F. Evergreen’s Contingent Enablement Argument Is Legally
`Incorrect, Internally Inconsistent, and Foreclosed by Its
`Admissions ................................................................................................79
`
`ii
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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, 79
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) .............................. 21, 23, 30, 31
`Albaad Massuot Yitzhak, Ltd. v. Edgewell Pers. Care Brands, LLC,
`IPR2017-00693, Paper 11 (PTAB July 17, 2017) ............................ 40, 42, 69, 71
`Apple, Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 14 (PTAB Aug. 12, 2015) ................................. 50, 51, 52
`In re Bayer,
`568 F.2d 1357 (C.C.P.A. 1978) .......................................................................... 55
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ................................... 21, 22, 31
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 74
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F.3d 629 (Fed. Cir. 2011) ...................................................................... 39, 68
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) .......................................................................... 43
`Bruckelmyer v. Ground Heaters, Inc.,
`445 F.3d 1374 (Fed. Cir. 2006) .......................................................................... 44
`C.R. Bard, Inc. v. Medline Indus., Inc.,
`IPR2015-00511, Paper 9 (PTAB July 15, 2015) .......................................... 40, 70
`C.R. Bard, Inc. v. U.S. Surgical Corp.,
`388 F.3d 858 (Fed. Cir. 2004) ............................................................................ 64
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ...................................................................... 33, 35
`
`
`
`iii
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`
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`

`

`Coalition for Affordable Drugs V, LLC, et. al. v. Biogen MA, Inc.,
`IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017) ............................................. 78
`Cordis Corp. v. Bos. Sci. Corp.,
`561 F.3d 1319 (Fed. Cir. 2009) .......................................................................... 59
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 54
`Crown Operations Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .................................................................... 41, 71
`Endo Pharm. Inc. v. Depomed, Inc.,
`IPR2014-00653, Paper 12 (PTAB Sept. 29, 2014)....................................... 37, 73
`
`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00001, Paper 2 (PTAB Oct. 2, 2020) ................................................ 18
`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00002, Paper 2 (PTAB Oct. 2, 2020) ................................................ 18
`Galderma Labs., L.P. v. Teva Pharm. USA, Inc.,
`799 F. App’x 838 (Fed. Cir. 2020) ................................ 39, 40, 41, 42, 68, 70, 71
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ........................................................................ 3, 43
`Homeland Housewares, LLC v. Whirlpool Corp.,
`865 F.3d 1372 (Fed. Cir. 2017) .......................................................................... 60
`Hulu, LLC v. Sound View Innovations,
`LLC, IPR2018-01039, Paper 29 (PTAB Dec. 20, 2019) .................................... 42
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 74
`Kyocera Wireless Corp. v. Int’l Trade Comm’n,
`545 F.3d 1340 (Fed. Cir. 2008) .......................................................................... 43
`Ex parte Levy,
`17 USPQ2d 1461 (Bd. Pat. App. & Inter. 1990) .......................................... 42, 71
`
`
`
`iv
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`

`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 50
`Louisiana-Pacific Corp., v. Huber Engineered Woods LLC,
`IPR2020-00596, Paper 12 (PTAB Aug. 20, 2020) ............................................. 49
`Metalcraft of Mayville, Inc. v. The Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017) .......................................................................... 74
`Microsoft Corp. v. Enfish, LLC,
`662 F. App’x 981 (Fed. Cir. 2016) ..................................................................... 74
`Microsoft v. Biscotti,
`IPR2014-01457, Paper 21 (PTAB June 2, 2015) ............................................... 59
`In re Nat. Alternatives, LLC,
`659 F. App’x 608 (Fed. Cir. 2016) ............................................................... 33, 35
`In re NuVasive,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 74
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) .......................................................................... 78
`Rexnord Indus., LLC v. Kappos,
`705 F.3d 1347 (Fed. Cir. 2013) ........................................................ 37, 39, 61, 68
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ........................................................................ 41, 71
`RPX Corp. et. al., v. Parity Networks, LLC,
`IPR2018-00097, Paper 7 (PTAB Apr. 24, 2018) ............................................... 78
`Samsung Elecs. Co., Ltd., v. Bell Northern Research, LLC,
`IPR2020-00613, Paper 10 (PTAB Aug. 24, 2020) ....................................... 50, 51
`Samsung Elecs. Co. v. Infobridge Pte. Ltd.,
`929 F.3d 1363 (Fed. Cir. 2019) .......................................................................... 44
`In re Schreiber,
`128 F.3d 1473 (Fed. Cir. 1997) .................................................................... 39, 68
`
`
`
`v
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`

`

`Smith & Nephew, Inc. v. Conformis, Inc.,
`IPR2017-00487, Paper 7 (PTAB July 7, 2017) ............................................ 40, 70
`Symantec Corp. v. Trustees of Columbia Univ.,
`IPR2015-00370, Paper 13 (PTAB June 17, 2015) ............................................. 52
`TQ Delta, LLC v. Cisco Sys., Inc.,
`942 F.3d 1352 (Fed. Cir. 2019) .......................................................................... 75
`ZTE Corp. v. ContentGuard Holdings, Inc.,
`IPR2013-00137, Paper 58 (PTAB July 1, 2014) .......................................... 42, 71
`Statutes
`35 U.S.C. §324 ......................................................................................................... 20
`35 U.S.C. §325(d) ................................................................................................ 2, 21
`Other Authorities
`Manual of Patent Examining Procedure, Ninth Ed., Rev. 10.2018,
`Last Rev. June 2020 §2112 (IV) ............................................................. 41, 42, 71
`Regulations
`35 C.F.R. §42.65 ................................................................................................ 53, 67
`
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`vi
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`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`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;
`App’x 2 - What to Expect;
`App’x 3 - New Manuscripts;
`App’x 4 - Supplementary Appendix
`
`2006
`
`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”)
`
`
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`
`PGR2021-00003
`U.S. Patent No. 10,596,276
`
`PRELIMINARY STATEMENT
`Evergreen’s Petition recycles a reference, Maus, overcome during prosecution
`
`after the Examiner found that it lacked several claim elements. Evergreen makes no
`
`new arguments about this old reference, and fails to identify a single legitimate error
`
`in the Examiner’s consideration of it. Evergreen fails to address at all prosecution
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`record evidence and persuasive arguments of teaching away. Although Evergreen
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`solicited a declaration from co-author Mr. Maus, he lacks essential expertise, and
`
`does little more than parrot the language Evergreen’s attorneys employ in the
`
`Petition. Nor do the various ancillary references Evergreen cites add to the analysis
`
`since they either were considered by the Examiner, or are cumulative. Evergreen
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`also relies on a Protocol document held out as prior art, but lacking any evidence
`
`showing public accessibility prior to the filing date of the ’276 Patent. Neither
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`Evergreen nor its putative expert makes any new arguments that justify institution.
`
`In the past, radioactive cancer medicines had to be manufactured close to the
`
`patient’s bedside because these drugs degrade quickly due to the destructive energy
`
`of the radioactivity itself. The instability of these medicines meant they could not
`
`be shipped far from where they were made. The dangers of handling radioactive
`
`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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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`expertise were effectively denied these treatments.
`
`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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`stabilizers in particular amounts that went against the accepted teachings of the time
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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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`pharmaceuticals, including the challenged U.S. Patent No. 10,596,276 (’276 Patent).
`
`Evergreen rests its challenge on two references, Maus (Ex. 1009), a scientific
`
`paper, and a Protocol document (Ex. 1012). Evergreen alleges anticipation over
`
`each, and obviousness over many permutations of these two references with other
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`ancillary references. All challenges presented should be denied for their threshold
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`deficiencies:
`
`First, Evergreen fails to show why Maus raises a new issue that the Board
`
`should entertain. See 35 U.S.C. §325(d). Maus was cited by the Patent Office
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`Examiner for obviousness, was discussed in detail, and was overcome for failing to
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`disclose several claimed elements. Evergreen identifies no error in the Examiner’s
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`analysis and ignores prosecution record evidence of teaching away. Although
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`Evergreen submits a declaration from Mr. Maus in an attempt to resurrect the article,
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`he does nothing to fill the voids in the reference laid bare during prosecution.
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`Second, Evergreen fails to carry its burden to show that the Protocol, the other
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`reference, was publicly accessible before the priority date, which is the “touchstone”
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`of determining whether it is prior art. In re Hall, 781 F.2d 897, 899 (Fed. Cir. 1986).
`
`This defect alone disposes of all challenges based upon the Protocol. Evergreen’s
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`declarant librarian, Dr. Hsieh-Yee, examined the Protocol’s availability in 2020. But
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`she did not offer evidence that the Protocol was publicly accessible prior to the
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`patent’s effective filing date in 2018, either from personal knowledge or from
`
`documentary sources. She attempts to backfill this gap by insisting that the Protocol
`
`is “one document” together with an exhibit Evergreen filed separately, Strosberg
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`(Ex. 1011). But this opinion lacks contemporaneous support and ignores record facts
`
`showing that the Protocol and Strosberg are two different documents.
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`These documents display indicia of different origins, different treatment by
`
`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
`
`peer-reviewed, is not typeset by the NEJM, and is a lengthy compilation of 676 pages
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`3
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`of various documents from apparently different sources. The Protocol today is listed
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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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
`
`accessibility. The Protocol’s contents were not (and are not now) searchable in any
`
`database or index by a person of ordinary skill. The Protocol has numerous
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`“confidential” stamps throughout and Evergreen fails to provide any evidence
`
`showing that the Protocol was not accordingly redacted, as the NEJM editors allow.
`
`Evergreen ignores all of these documentary record facts, resting its case on the
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`unsupported and conclusory librarian opinion, which should be given no weight.
`
`Third, Evergreen argues that both Maus and the Protocol disclose every
`
`element of the claimed formulation, including the high radiochemical purity AAA’s
`
`invention requires. Evergreen concedes that the Protocol does not disclose how to
`
`make the clinical trial formulation it describes. Nor does it disclose measuring
`
`stability of the medicine over the timeframe the claims require. But Evergreen
`
`argues that whatever the Protocol fails to disclose explicitly, it discloses inherently.
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`Similarly, Evergreen tacitly concedes that Maus does not explicitly discuss
`
`measuring the purity of any disclosed solution after storage at 25ºC for 72 hours.
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`Proof of inherency requires evidence beyond mere possibilities or
`
`probabilities. Instead of offering documentary evidence or data, Evergreen asks the
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`Board to accept its word that the clinical trial formulation disclosed in the Protocol
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`and an unspecified solution disclosed in Maus would have maintained the claimed
`
`radiochemical purity as the “natural result flowing from” its composition. This
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`allegation is conclusory, lacks any factual showing, and thus fails to meet the high
`
`bar for proving inherent anticipation.
`
`Fourth, Evergreen’s allegations of obviousness are legally insufficient for at
`
`least three reasons.
`
`1. Each obviousness contention is based on either the Maus article, which the
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`Patent Office already addressed—or the Protocol document—which Evergreen has
`
`failed to demonstrate is prior art.
`
`2. Evergreen proposes to combine these two documents with a legion of other
`
`references, in a vast multiplicity of combinations that is reason enough to deny
`
`institution. Adaptics Ltd. v. Perfect Co., IPR2018-01596, Paper 20 at 24 (PTAB
`
`Mar. 6, 2019) (denying institution for lacking particularity where the petition was
`
`based on two primary anticipatory references and “voluminous and excessive”
`
`secondary obviousness combinations).
`
` Evergreen’s pro
`
`forma statements
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`concerning motivation to make these alleged combinations are deficient as a matter
`
`of law.
`
`3. Although Evergreen offers testimony from Mr. Maus, a radiochemist, the
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`perspective he offers is legally insufficient because it is missing the full perspective
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`of a person of ordinary skill in the art. Nearly every piece of prior art on which
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`Evergreen relies addresses administering radiopharmaceuticals to patients and
`
`monitoring their biological effects. Mr. Maus lacks this training, and so his
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`testimony that a person of ordinary skill (POSA) would have found the claims
`
`obvious over any one of the proposed combinations is unsupported.
`
`As a final hedge, Evergreen offers a half-hearted, contingent allegation of
`
`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
`
`choice” whether to institute all the proposed challenges. Adaptics, IPR2018-01596,
`
`Paper 20 at 16–18 (denying institution and identifying as “the worst offender”
`
`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
`
`must be possessed” by a solution “meeting the structural limitations recited in the
`
`claim 24 (by virtue of its dependence on claims 1, 20, and 22) [of the ’276 Patent]
`
`so as to provide the recited stability recited in claim 24.” Pet. 85; Maus Decl. (Ex.
`
`1005) ¶573. But the “factors” and “variables” Evergreen insists must be possessed
`
`are absent from the claim language. The proper enablement inquiry asks whether
`
`the patent discloses information sufficient to make and use the claimed invention
`
`without undue experimentation. The patent sets out detailed examples of how to do
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`just that. Evergreen concedes as much, condemning this challenge to failure.
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`For these and other reasons below, the Board should not institute any ground.
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`FACTS
`The facts are from the Petition (Pet.) and filed Exhibits (Ex.), including
`
`references on the Patent’s face and those cited by Mr. Maus and Dr. Hsieh-Yee.
`
`A. Radionuclide Cancer Therapy Prior to July 2018
`1. Therapeutic Rationale
` The goal of cancer treatment is to destroy or neutralize cancer cells while
`
`leaving healthy cells intact. One approach to achieving this goal is to deliver a potent
`
`treatment specifically to the cancer cells while avoiding the normal cells. The outer
`
`surface of cancer cells differs from normal cells. See Banerjee (Ex. 1016) 3. That
`
`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
`
`the cancer cells and sparing the healthy ones. Id. A radioactive atom (called a
`
`radioisotope or a radionuclide) is one such agent that can be linked to the targeting
`
`molecule. Id. The resulting radioactive medicine can then be infused into a cancer
`
`patient’s bloodstream, where it will specifically bind to cancer cells. The
`
`radioactivity will cause the proximate cancer cells to die while minimally harming
`
`healthy tissue. Id.; Chen 365 (U.S. Patent Pub. No. 2012/0065365) (Ex. 1019) ¶9.
`
`Somatostatin, a natural peptide hormone, was known to specifically bind to
`
`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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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`synthetic peptides similar to somatostatin that selectively bind to those somatostatin
`
`receptors (SSRs). Id. Cancer physicians teamed with radiochemists to devise ways
`
`to chemically link these synthetic peptides to certain radionuclides. Id.; see also
`
`Kwekkeboom (Ex. 1010) 2–3. 177Lu is one such radionuclide. A chelator
`
`compound, such as DOTA, binds 177Lu. That chelator-bound-radionuclide is in turn
`
`tethered to a synthetic peptide. See Banerjee (Ex. 1016) 7–9. 177Lu-DOTA-TATE
`
`is one such radiolabeled peptide useful as a cancer treatment. Id.
`
`There was a practical problem in linking the radioactive atom so close to the
`
`peptide. The radioactivity given off by the radionuclide not only killed cancer cells
`
`in the patient, it also degraded the synthetic peptide once linked to the radionuclide.
`
`In other words, the radioactivity degraded the medicine itself. Id. at 9; see also, e.g.,
`
`Liu 2001 (Ex. 1023) 1; Chen 2008 (Ex. 1029) 1; Chen 365 (Ex. 1019) ¶¶11–13. This
`
`self-destructive activity is called autoradiolysis. It is “one of the most challenging
`
`aspects in the development of a therapeutic radiopharmaceutical.” See, e.g., Chen
`
`2008 (Ex. 1029).
`
`For that reason, most of these types of medicines historically were produced
`
`near the patient’s bedside, such as in a specially equipped hospital pharmacy. See,
`
`e.g., Das (Ex. 1021) 1; see generally, Kwekkeboom (Ex. 1010) 3; Filice (Ex. 1028)
`
`3. The medicine was made on-site and then quickly administered so there was less
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`time for the radioactivity to harm the medicine itself prior to administration. Das
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`PGR2021-00003
`U.S. Patent No. 10,596,276
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`(Ex. 1021) 2. Since few hospitals had this required personnel and equipment,
`
`patients (who often were very sick) had to travel long distances for such treatment,
`
`limiting availability and use of this medicine.
`
`2. Problem of Stability
`The viability of large-scale manufacturing depended upon stability of the
`
`radiolabeled peptide. Degradation of the peptide by autoradiolysis renders it unable
`
`to bind specifically to cancer cells. E.g., Chen 365 (Ex. 1019) ¶¶11–15. This process
`
`both reduces the amount of effective medicine and increases the amount of
`
`radioactivity that can distribute in an untargeted fashion throughout the patient’s
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`body. Id. ¶12. It is important for a physician to know how much effective medicine
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`is being administered to a patient. Thus, measuring radiochemical purity (RCP)—
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`the 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 is not simply
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`randomly distributed as degraded species throughout the body. See, e.g., Chen 365
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`(Ex. 1019) ¶12.
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`9
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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. 1029) 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. 1019) ¶¶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) 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. 1019) ¶¶54–57; Chen 2008 (Ex. 1029) 7–8.
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`Different radiolabeled peptides enjoy different levels of protection from different
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`stabilizers. Chen 2008 (Ex. 1029) 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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`10
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`Maus (Ex. 1009) compared several radiolabeling procedures for 177Lu-
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`DOTA-TATE, all of which included more than 100 mg/mL NaAsc and 25 mg/mL
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`GA during chelation, some of which then stripped the stabilizers out, some of which
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`included re-addition of a stabilizer, and each of which was diluted to various
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`volumes. RCP exceeded 95% at 72 hours only if: (1) ascorbate and GA were present
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`during both chelation and storage, and at high concentrations (13.4 mg/mL and 3
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`mg/mL, respectively), or (2) stabilizers were removed after chelation but then AA
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`was reintroduced at a high (17.6 mg/mL) concentration along with 25% EtOH. Id.
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`at 4, Table 1. Accordingly, the authors concluded “re-addition of AA post tC18 SPE
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`purification is required to maintain RCP of 177Lu-DOTA-TATE.” Id. at 2. But
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`“[r]e-addition of GA (100 mmol/L) [15.4 mg/mL] … had only minor stabilizing
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`properties” such that RCP still decreased below <95% within 24h post-radiolabeling.
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`Id. at 6.
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`Chen 365 (Ex. 1019) echoed 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 at a concentration of 10 mg/mL
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`and AA at 50 mg/mL (id. ¶163). In each case the stabilizers were added after the
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`chelation reaction completed.
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`11
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`Chen 375 (U.S. Patent Pub. No. US2007/0269375) (Ex. 2003) (considered
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`during prosecution) reports “none of the eight reagents tested” (AA, GA, human
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`serum albumin, HSA, TCEP, PDCA, HPA, ME or EtOH) “provided adequate
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`radiostability (RCP>90%) for 48 hours.” Id. ¶265. The concentration of each was
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`6.6 mg/mL. See id., Table 5. Chen says “[t]his result was unexpected as gentisic
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`acid, ascorbic acid, HAS, and 3,4-pyridinedicarboxylic acid have all been reported
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`by others to provide satisfactory protection against radiolysis for other radio
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`pharmaceuticals.” Id. ¶265 (emphasis added); see also id., Table 5, Example 3.
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`Chen 2008 (Ex. 1029) reports a “2-vial formulation for the preparation of
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`[177Lu]Lu-AMBA” (a different molecule than DOTA-TATE or -TOC) “that is
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`suitable for clinical trials in patients….” Id. at 8–9. Chen reports that by using
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`seleno-methionine “as a stabilizer during [] radiolabeling, combined with an
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`ascorbic acid solution used to dilute and further stabilize the reaction solution[,]” a
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`“high yield” and “excellent recovery (>98%) are obtained and maintained for at least
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`2 days, when stored at RT.” Id. at 9. Chen states “[o]f all the tested compounds, Se-
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`Met proved the most effective in protecting [177Lu]Lu-AMBA from radiolytic
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`destruction (Table 4).” Id. at 8. In contrast, Chen states: “AA and GA had
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`signi