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 PGR2021-00001
`
`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
`
`
`
`
`

`

`
`
`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
`
`i
`
`
`
`
`
`
`
`
`
`

`

`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
`
`
`
`
`
`
`
`
`
`
`
`

`

`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
`
`
`
`

`

`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
`
`
`
`

`

`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
`
`
`
`

`

`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
`
`
`
`vi
`
`
`
`

`

`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
`
`
`
`
`vii
`
`
`
`

`

`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`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”)
`
`
`
`
`
`viii
`
`
`
`

`

`
`
`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
`
`art, yet presents no evidence showing the Protocol’s public accessibility before the
`
`priority date. Evergreen hedges its bet on the Protocol by recycling a reference,
`
`Maus, addressed at length during prosecution. But Evergreen argues nothing new
`
`about Maus, and identifies no errors in the Examiner’s consideration of it. Although
`
`Evergreen solicited a declaration from one of that document’s authors, he lacks
`
`essential expertise and does little more than parrot the language Evergreen’s
`
`attorneys employ. Nothing here supports 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
`
`training for physicians and nurses, none of which was widely available. As a result,
`
`cancer patients who were not located close enough to the necessary facilities and
`
`expertise were effectively denied these treatments.
`
`Patent Owner Advanced Accelerator Applications SA (AAA) discovered a
`
`manufacturing process that results in radiochemical solutions with enhanced
`
`stability. AAA researchers found that addition of particular radiochemical
`
`
`
`1
`
`
`
`

`

`
`stabilizers in particular amounts that went against the accepted teachings of the time
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`produced stable concentrated radionuclide complex solutions. One advantage that
`
`such solutions possessed—especially those centrally manufactured on large scales—
`
`was their capacity to be shipped to distant places to treat cancer patients in a ready-
`
`for-use form. The Patent Office recognized this innovation and awarded AAA two
`
`patents directed to the manufacturing process and the resultant radioactive
`
`pharmaceutical solutions, including the challenged U.S. Patent No. 10,596,278 (’278
`
`Patent).
`
`Evergreen rests nearly every challenge to the ’278 Patent on two references,
`
`a Protocol document (Ex. 1012) and a scientific paper, Maus (Ex. 1009), alleging
`
`anticipation over the Protocol, and obviousness over many permutations of the
`
`Protocol, Maus, and other references. All challenges presented should be denied for
`
`their threshold deficiencies:
`
`First, Evergreen fails to carry its burden to show that the Protocol was
`
`publicly accessible before the priority date, which is the “touchstone” 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 declarant
`
`librarian, Dr. Hsieh-Yee, examined the Protocol’s availability in 2020. But she did
`
`not offer evidence that the Protocol was publicly accessible prior to the patent’s
`
`effective filing date in 2018, either from personal knowledge or from documentary
`
`
`
`2
`
`
`
`

`

`
`sources. She attempts to backfill this gap by insisting that the Protocol and Strosberg
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`(filed separately by Evergreen as Ex. 1011) together make “one document”—hoping
`
`to transfer facts particular for Strosberg over to the Protocol. But this opinion lacks
`
`contemporaneous support and ignores record facts showing that the Protocol and
`
`Strosberg are two different documents.
`
`The two documents display indicia of different origins, different treatment by
`
`the New England Journal of Medicine (NEJM) and its readership, and different
`
`timing of preparation. Strosberg is an article from the NEJM that was subject to the
`
`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
`
`of various documents from apparently different sources. The Protocol today is listed
`
`as a Supplementary Material related to Strosberg on the NEJM website, but that
`
`listing does not meld it with Strosberg—today or in 2018.
`
`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. Evergreen has not addressed
`
`numerous “confidential” stamps throughout the Protocol especially since the NEJM
`
`allows for authors to redact confidential materials. Evergreen ignores all of these
`
`facts, resting its case on the unsupported and conclusory librarian opinion, which
`
`should be given no weight.
`
`
`
`3
`
`
`
`

`

`Second, Evergreen argues that the Protocol discloses every element of the
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`
`
`claimed formulation, including the high radiochemical purity AAA’s centralized
`
`commercial manufacturing 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. Proof of inherency requires evidence beyond mere possibilities
`
`or probabilities. Instead of offering documentary evidence or data, Evergreen asks
`
`the Board to accept its word that the clinical trial formulation disclosed in the
`
`Protocol would have maintained the claimed radiochemical purity as the “natural
`
`result flowing from” its composition. This allegation is conclusory, lacks any factual
`
`showing, and thus fails to meet the high bar for proving inherent anticipation.
`
`Third, Evergreen fails to show why its other reference, Maus, raises a new
`
`issue that the Board should entertain. See 35 U.S.C. § 325(d). Maus was cited by
`
`the Patent Office Examiner for obviousness, was discussed in detail, and was
`
`overcome for failing to disclose several claimed elements. Evergreen identifies no
`
`error in the Examiner’s analysis and does not address the teaching away discussed
`
`in the record. Although Evergreen solicited a declaration from Mr. Maus in an
`
`attempt to resurrect the article, he does nothing to fill the voids in the reference laid
`
`bare during prosecution.
`
`
`
`4
`
`
`
`

`

`Fourth, Evergreen’s allegations of obviousness are legally insufficient for at
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`
`
`least three separate reasons.
`
`1. Each obviousness contention is based on the Protocol document—
`
`which Evergreen has failed to demonstrate is prior art—and the majority of
`
`the combinations rely on the Maus article, which the Patent Office already
`
`addressed.
`
`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 concerning motivation to
`
`make the alleged combinations are deficient as a matter of law.
`
`3.
`
` Although Evergreen offers testimony from Mr. Maus, a
`
`radiochemist, the perspective he offers is insufficient. Nearly every piece of
`
`prior
`
`art on which Evergreen
`
`relies
`
`addresses
`
`administering
`
`radiopharmaceuticals to patients and monitoring their biological effects. Mr.
`
`Maus lacks this clinical training, and so his testimony that a person of ordinary
`
`
`
`5
`
`
`
`

`

`
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`skill in the art (POSA) would have found the claims obvious over any one of
`
`the proposed combinations is insufficient.
`
`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
`
`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
`
`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
`
`claims of the ’278 patent so as to provide the recited stability.” Petition 74; Maus
`
`Dec. (Ex. 1006) ¶425. 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 just that. Evergreen concedes as much, condemning this challenge to
`
`failure.
`
`For these and other reasons below, the Board should not institute any ground.
`
`
`
`6
`
`
`
`

`

`
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`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
`Therapeutic Rationale
`1.
` 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
`
`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 (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).
`
`
`
`7
`
`
`
`

`

`Somatostatin, a natural peptide hormone, was known to specifically bind to
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`
`
`receptors that are expressed on the surfaces of certain types of cancer cells far more
`
`than normal cells. Banerjee (Ex. 1016) 18–20. OctreoTATE and OctreoTIDE, are
`
`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; 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 and Isotopes, 66(4):497-505, Apr. 2008
`
`(Chen 2008) (Ex. 2008) 12; Chen 365 (Ex. 2007) ¶¶11–13. This self-destructive
`
`
` 2 Chen 2008 was filed as Exhibit 1029 in Evergreen’s co-pending petition against
`AAA. See Petition 3, Ex. 1029.
`
`
`
`8
`
`
`
`

`

`
`activity is called autoradiolysis. It is “one of the most challenging aspects in the
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`development of a therapeutic radiopharmaceutical.” See, e.g., Chen 2008 (Ex.
`
`2008) 1.
`
`For that reason, most of these 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 time for
`
`the radioactivity to harm the medicine itself prior to administration. Das (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.
`
`Problem of Stability
`2.
`The viability of large-scale manufacturing depended on 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. 2007) ¶¶11–15. This process
`
`both reduces the amount of effective medicine and increases the amount of
`
`radioactivity that can travel in an untargeted fashion throughout the patient’s body.
`
`Id. ¶12. It is important for a physician to know how much effective medicine is
`
`being administered to a patient. Thus, measuring radiochemical purity (RCP)—the
`
`percentage of radioactivity in a sample present in the radiolabeled peptide as
`
`
`
`9
`
`
`
`

`

`
`compared to degraded species—gives physicians a window into the potency and
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`safety of the medicine. See Kwekkeboom (Ex. 1010) 3; Filice (Ex. 1028) 3 (“quality
`
`controls”). RCP needs to be very high so that the radioactivity administered is
`
`delivered selectively to the cancer by the targeting molecule and does not simply
`
`randomly spread as degraded species throughout the body. See, e.g., Chen 365 (Ex.
`
`2007) ¶12.
`
`One strategy to achieve high RCP over longer time periods is to add stabilizers
`
`to help reduce radiochemical degradation. See, e.g., Liu 2001 (Ex. 1023) 1. The
`
`prior art disclosed numerous options for stabilizers, including ethanol (EtOH),
`
`ascorbic acid (AA), sodium ascorbate (NaAsc), gentisic acid (GA), and methionine
`
`(Met), among others. Id. at 1–2; Chen 2008 (Ex. 2008) 2. These, in turn, could be
`
`added singly or in combination, at various points in the manufacturing process, and
`
`at various concentrations. Chen 365 (Ex. 2007) ¶¶20, 22.
`
`Complicating matters, in some instances stabilizers were known to impede
`
`chelation of the radionuclide and thus were both a help and a hindrance. See, e.g.,
`
`id. ¶251; Liu 2001 (Ex. 1023) 3–4. The medicine’s efficacy also depends on other
`
`variables, including the particular radionuclide atom used and the type of radiation
`
`emitted. See, e.g., Chen 365 (Ex. 2007) ¶¶54–57; Chen 2008 (Ex. 2008) 7–8.
`
`Different radiolabeled peptides enjoy different levels of protection from different
`
`stabilizers. Chen 2008 (Ex. 2008) 7–8. In sum, a person of ordinary skill was
`
`
`
`10
`
`
`
`

`

`
`confronted with great unpredictability in determining which stabilizers should be
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`added, at what step in manufacture, and in what amounts in order to yield a viable
`
`medicine.
`
`The art showed that most successful stabilization of 177Lu-DOTA-TATE (and
`
`-TOC) required high concentrations of stabilizers such as AA or GA, and the use of
`
`ethanol. For example:
`
`Maus (Ex. 1009) compared several radiolabeling procedures for 177Lu-
`
`DOTA-TATE. All included more than 100 mg/mL NaAsc and 25 mg/mL GA
`
`during chelation; some stripped the stabilizers out; some included re-addition of a
`
`stabilizer; and each was diluted to various volumes. RCP exceeded 95% at 72 hours
`
`only if: (1) ascorbate and GA were present during both chelation and storage, and at
`
`high concentrations (13.4 mg/mL and 3 mg/mL, respectively), or (2) stabilizers were
`
`removed after chelation but then AA was reintroduced at a high (17.6 mg/mL)
`
`concentration along with 25% EtOH. Id. at 4, Table 1. Accordingly, the authors
`
`concluded “re-addition of AA post tC18 SPE purification is required to maintain
`
`RCP of 177Lu-DOTA-TATE.” Id. at 2. But “[r]e-addition of GA (100 mmol/L)
`
`[15.4 mg/mL] ... had only minor stabilizing properties” such that RCP still decreased
`
`below <95% within 24h post-radiolabeling. Id. at 6.
`
`Chen 365 (Ex. 2007) echoes the need for high concentrations of stabilizers to
`
`achieve RCP at acceptably high percentages, disclosing that “many stabilizers have
`
`
`
`11
`
`
`
`

`

`
`been identified that alone or in combination, inhibit radiolytic damage to
`
`PGR2021-00001
`U.S. Patent No. 10,596,278
`
`radiolabeled compounds….” Id. ¶22. Table 1 of Chen 365 shows many stabilizers
`
`that were tested (id. ¶161); Table 2 shows GA used