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 PGR2021-00002
`
`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 ...................................................................................................................... 5
`
`A. Radionuclide Cancer Therapy Prior to July 2018 .................................. 5
`1. Therapeutic Rationale ............................................................................ 5
`2. Problem of Stability ............................................................................... 8
`3. Advanced Accelerator Applications S.A. ............................................14
`4. The Invention .......................................................................................14
`5. Prosecution ..........................................................................................15
`
`
`
`B. Evergreen’s Petition .................................................................................17
`
`
`ARGUMENT ..........................................................................................................18
`
`A. Maus Was Overcome in Prosecution and Evergreen Presents
`Substantially the Same Arguments .........................................................19
`1. Substantially the Same Art, and Substantially the Same
`Arguments Were Presented to the PTO ..............................................22
`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 ...................................................................................22
`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 .........................................23
`2. Evergreen Fails to Sufficiently Point Out Material Error by the
`PTO ......................................................................................................25
`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 .......................................................25
`b) Becton factor (e): whether Petitioner has pointed out
`sufficiently how the Examiner erred in its evaluation of the
`asserted prior art ...........................................................................28
`c) Becton factor (f): the extent to which additional evidence
`and facts presented in the petition warrant reconsideration
`of the prior art or arguments .........................................................30
`
`
`
`i
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`

`

`
`
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`
`
`
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`
`
`
`
`B. Evergreen Fails to Show Maus Anticipates the Claimed
`Invention ....................................................................................................35
`1. Maus Does Not Explicitly Disclose the Required Stability
`Characteristics .....................................................................................35
`2. Maus Does Not Inherently Disclose the Required Stability
`Characteristics .....................................................................................36
`
`C. Obviousness ...............................................................................................40
`1. Evergreen’s Petition Improperly Multiplies Its Obviousness
`Grounds ...............................................................................................41
`2. Evergreen’s Petition Offers Only Pro Forma Statements
`Concerning Motivation to Combine ....................................................42
`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 .................................45
`
`D. Evergreen’s Contingent Enablement Argument Is Legally
`Incorrect, Internally Inconsistent, and Foreclosed by Its
`Admissions ................................................................................................48
`
`ii
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`
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`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`
`Adaptics Ltd. v. Perfect Co.,
`IPR2018-01596, Paper 20 (PTAB Mar. 6, 2019) ........................... 3, 4, 41, 42, 48
`
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) .............................. 19, 20, 21, 29
`
`Albaad Massuot Yitzhak, Ltd. v. Edgewell Pers. Care Brands, LLC,
`IPR2017-00693, Paper 11 (PTAB July 17, 2017) ........................................ 38, 40
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ............................. 20, 21, 30, 34
`
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 44
`
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F.3d 629 (Fed. Cir. 2011) ............................................................................ 37
`
`C.R. Bard, Inc. v. Medline Indus., Inc.,
`IPR2015-00511, Paper 9 (PTAB July 15, 2015) ................................................ 38
`
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ...................................................................... 32, 34
`
`Coalition for Affordable Drugs V, LLC, et. al. v. Biogen MA, Inc.,
`IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017) ............................................. 47
`
`Crown Operations Int'l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .......................................................................... 39
`
`Edmund Optics, Inc. v. Semrock Inc.,
`IPR2014-00583, Paper 9 (PTAB Sept. 19, 2014) ............................................... 42
`
`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00001 ................................................................................................. 17
`
`
`
`iii
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`
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`

`

`Evergreen Theragnostics, Inc. v. Advanced Accelerator Applications
`SA,
`PGR2021-00003 ............................................................................................. 6, 17
`
`Galderma Labs., L.P. v. Teva Pharm. USA, Inc.,
`799 F. App’x 838 (Fed. Cir. 2020) ......................................................... 37, 38, 40
`
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 44
`
`Ex parte Levy,
`17 USPQ2d 1461 (Bd. Pat. App. & Inter. 1990) ................................................ 40
`
`Metalcraft of Mayville, Inc. v. The Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017) .......................................................................... 43
`
`Microsoft Corp. v. Enfish, LLC,
`662 F. App’x 981 (Fed. Cir. 2016) ..................................................................... 44
`
`In re Nat. Alternatives, LLC,
`659 F. App’x 608 (Fed. Cir. 2016) ............................................................... 32, 34
`
`In re NuVasive,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 43
`
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) .......................................................................... 48
`
`Rexnord Indus., LLC v. Kappos,
`705 F.3d 1347 (Fed. Cir. 2013) .......................................................................... 37
`
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 40
`
`RPX Corp. et. al., v. Parity Networks, LLC,
`IPR2018-00097, Paper 7 (PTAB Apr. 24, 2018) ............................................... 48
`
`SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348 (2018) ........................................................................................ 42
`
`In re Schreiber,
`128 F.3d 1473 (Fed. Cir. 1997) .......................................................................... 37
`
`
`
`iv
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`

`

`Smith & Nephew, Inc. v. Conformis, Inc.,
`IPR2017-00487, Paper 7 (PTAB July 7, 2017) .................................................. 38
`
`TQ Delta, LLC v. CISCO Systems, Inc.,
`942 F.3d 1352 (Fed. Cir. 2019) .......................................................................... 44
`
`ZTE Corp. v. ContentGuard Holdings, Inc.,
`IPR2013-00137, Paper 58 (PTAB July 1, 2014) ................................................ 40
`
`Statutes
`
`35 U.S.C. § 324 ........................................................................................................ 19
`
`35 U.S.C. § 325(d) ............................................................................................... 2, 19
`
`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. ......................................................................................................... 41, 42
`
`Manual of Patent Examining Procedure, Ninth Ed., Rev. 10.2018,
`Last Rev. June 2020 § 2112 .......................................................................... 39, 40
`
`
`
`
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`v
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`Exhibit
`
`2001
`
`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”)
`
`2002
`
`Pop and Salzberg, “Use and Mis-Use of Supplementary Material in
`Scientific Publications,” BMC Bioinformatics (2015) 16:237 (“Pop &
`Salzberg”)
`
`2003
`
`Chen et al., U.S. Patent Pub. No. 2007/0269375A1 (“Chen 375”)
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`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
`
`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”)
`
`
`
`
`
`
`vi
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`

`

`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`
`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 ignores the prosecution record
`
`evidence of teaching away. Although Evergreen solicited a declaration from 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 cure these deficiencies since they either were already
`
`considered by the Examiner, or are cumulative. Neither Evergreen nor its putative
`
`expert make 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
`
`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.
`
`
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`1
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`

`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`
`Patent Owner Advanced Accelerator Applications SA (AAA) discovered a
`
`large-scale manufacturing process that results in radiochemical solutions with
`
`enhanced stability. AAA researchers found that addition of particular radiochemical
`
`stabilizers in particular amounts that went against the accepted teachings of the time
`
`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 its challenge on a scientific paper, Maus (Ex. 1009), alleging
`
`that it anticipates the claims or renders them obvious—either alone or over a legion
`
`of combinations with other ancillary references. All challenges presented should be
`
`denied for their threshold deficiencies:
`
`First, Evergreen fails to show why its challenges based on Maus raise any
`
`new issues that the Board should entertain. See 35 U.S.C. § 325(d). Maus was cited
`
`by the Patent Office Examiner, was discussed in detail, and was overcome for failing
`
`to disclose several claimed elements. Evergreen identifies no error in that analysis
`
`and fails to even acknowledge let alone address the teaching away discussed in the
`
`
`
`2
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`

`

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`prosecution 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
`
`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`laid bare during prosecution.
`
`Evergreen tries to evade one such gap by arguing that the Maus article
`
`inherently discloses the high radiochemical stability that AAA’s centralized
`
`manufacturing invention requires. With no documentary evidence or data,
`
`Evergreen merely insists that an unspecified formulation this document discloses
`
`would have maintained the claimed radiochemical purity as the “natural result
`
`flowing from” its composition. The allegation is conclusory, lacks any factual
`
`showing, and thus fails to meet the high bar set for inherent anticipation, which
`
`requires proof beyond mere possibilities or probabilities.
`
`Second, Evergreen’s allegations of obviousness are legally insufficient for at
`
`least three separate reasons.
`
`1. Each obviousness contention is based on the Maus article, which the Patent
`
`Office already addressed and dismissed in the context of obviousness. Evergreen
`
`raises no new arguments or evidence, nor identifies any legitimate errors in the
`
`Examiner’s analysis that could justify institution.
`
`2. Evergreen proposes to combine the Maus article with a host of other
`
`references, in a vast multiplicity of combinations that is reason enough to deny
`
`institution. See Pet. at Challenges 2-13; see also Adaptics Ltd. v. Perfect Co.,
`
`
`
`3
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`

`

`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`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, to
`
`support all of the obviousness challenges, the perspective he offers is incomplete by
`
`comparison with nearly every piece of prior art on which Evergreen relies because
`
`he lacks experience administering radiopharmaceuticals to patients and monitoring
`
`their biological effects. Mr. Maus’s testimony thus offers insufficient evidence that
`
`a person of ordinary skill in the art (POSA) would have found the claims obvious
`
`over any one of the proposed combinations.
`
`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 Ltd., IPR2018-
`
`01596, Paper 20 at 16–18 (PTAB Mar. 6, 2019) (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
`
`
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`4
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`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`limitations recited in the claims of the ’278 patent so as to provide the recited
`
`stability.” Pet. 79; Maus Dec. (Ex. 1007) ¶394. But the “factors” and “variables”
`
`Evergreen insists must be possessed are absent from the claim language.
`
`Furthermore, it is irrelevant whether the patent discusses every possible way to make
`
`the claimed invention, every possible potential pitfall, or such factors and variables
`
`that are unclaimed. 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.
`
`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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`5
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`

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`PGR2021-00002
`U.S. Patent No. 10,596,278
`
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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.; U.S. Patent Pub. No. 2012/0065365 (Chen 365) (Ex. 2007) ¶9.1
`
`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
`
`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.
`
`
` 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.
`
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`6
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`PGR2021-00002
`U.S. Patent No. 10,596,278
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`
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`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
`
`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.
`
`2008).
`
`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, 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
`
`
` 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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`7
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`often were very sick) had to travel long distances for such treatment, limiting
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`PGR2021-00002
`U.S. Patent No. 10,596,278
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`availability and use of this medicine.
`
`2. Problem of Stability
`
`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
`
`compared to degraded species — gives physicians a window into the potency and
`
`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 dose 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),
`
`
`
`8
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`

`

`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`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.,
`
`Chen 365 (Ex. 2007) ¶251; Liu 2001 (Ex. 1023) 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., id. ¶¶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
`
`confronted with great unpredictability in determining which stabilizers should be
`
`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
`
`
`
`9
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`

`

`PGR2021-00002
`U.S. Patent No. 10,596,278
`
`
`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
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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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`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 radio
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`stability (RCP>90%) for 48 hours.” See id., Table 5, Example 3, ¶265. The
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`concentration of each was 6.6 mg/mL. Id. Chen says “[t]his result was unexpected
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`as gentisic acid, ascorbic acid, HAS, and 3,4-pyridinedicarboxylic acid have all been
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`reported by others to provide satisfactory protection against radiolysis for other radio
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`pharmaceuticals.” See Ex. 2003, Table 5, Example 3, ¶265.
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`Chen 2008 (Ex. 2008) 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…[,]”
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`a “high yield” and “excellent recovery (>98%) are obtained and maintained for at
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`least 2 days, when stored at RT.” Id. at 9. Chen states “[o]f all the tested compounds,
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`Se-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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`significant stabilizing effects, but at the concentrations tested [6.6 mg/mL], none of
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`the commonly used radioprotection agents evaluated (AA, GA, or HSA) supplied
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`enough protection to inhibit all radiolysis of [177Lu]Lu-AMBA.” Id. at 5.
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`Das 2014 (Ex. 1022) also echoes the call for high stabilizer concentrations,
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`showing that 177Lu-DOTA-TATE could be stable up to three days’ time from
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`radiolabeling, but only in the presence of 40 mg/mL GA. Id. at 5.
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`De Blois (Ex. 1017) stated “experiments showed that ethanol, in combination
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`with a mixture of gentisic- and ascorbic acid has a superior effect in stabilizing
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`radiolabelled peptides” including 177Lu-DOTA-TATE. Id. at 5. De Blois discloses
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`the concentration of AA and GA at the chelation stage is optimal at 0.5-0.6 mg/mL.
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`Id. at 2. But the data presented by De Blois show that formulations lacking EtOH
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`had RCP of less than 90% after storage for 72 hours. Id. at 6, Figures 6–7.
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`Likewise, Breeman 2016 (Ex. 1027) reported that “superior effects” were
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`obtained in stabilizing 177Lu-DOTA-TATE when EtOH was present with high
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`concentrations of both GA (7.7 mg/mL) and AA (8.8 mg/mL). Id. at 5.
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`Kwekkeboom (Ex. 1010) radiolabeled DOTA-TATE with 177Lu in a solution
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`containing very high stabilizer concentrations (67 mg/mL ascorbate and 15 mg/mL
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`GA), but after radiolabeling the resulting solution was highly diluted (to 0.4 mg/mL
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`ascorbate and 0.1 mg/mL GA). Id. at 3. No EtOH was present. The RCP was
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`accordingly only 88%. Id.
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`Liu 2001 (Ex. 1023) in the context of 90Y chelation by DOTA reported that
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`solution stability data obtained from small-scale, low-activity reactions (<20mCi)
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`“cannot be simply extrapolated” to large-scale, high activity reactions (>100mCi).
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`See id. at 4. The data also showed that scaling up the reaction to >100 mCi by
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`keeping the same ratio of stabilizer as the small-scale experiment did not achieve the
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`expected stability. See id.
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`Liu 20033 (Ex. 2004) (considered during prosecution) used GA or AA both
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`before and after radiolabeling. Liu said “[t]he post-labeling approach is particularly
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`useful when the use of a large amount of stabilizer interferes with radiolabeling.”
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`Id., Abstract. Liu used concentrations of 4 mg/mL and 20 mg/mL of GA or AA. The
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`data showed that the lower concentration was not sufficient to keep the RCP above
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`90%. See id., Figures 3 and 4.
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`These references collectively show that higher levels of stabilizer, substantial
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`amounts of ethanol, or both were generally necessary to achieve radiochemical
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`purity suitable for administration to patients. See, e.g., Breeman 2016 (Ex. 1027) 5;
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`de Blois (Ex. 1017) 3 & Fig. 2. To add to the complexity, the RCP is a moving
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`target, since as the radionuclide decays, it simultaneously reduces activity of the drug
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`and presents an ever-changing threat to the integrity of the molecule. Chen 2008
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`(Ex. 2008) 8 (“The degree of radiolytic damage observed is expected to be dependent
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`upon…the radioconcentration[.]”). Unlike most chemical compounds that remain
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`stable for months or years, these challenges are unique to radiopharmaceuticals—
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`and to each radiopharmaceutical combination of a particular peptide with a
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` 3 Liu et al., Ascorbic Acid: Useful as a Buffer Agent and Radiolytic Stabilizer for
`Metalloradiopharmaceuticals, Bioconjugate Chem, (2003), 14, 1052-1056 (Liu
`2003).
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`particular radionuclide. Id. Stability here is measured in hours to days and is ever-
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`changing.
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`3. Advanced Accelerator Applications S.A.
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`Since its founding in 2002, AAA has specialized in developing and
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`manufacturing radioactive pharmaceuticals, having grown from the five founders to
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`hundreds of employees worldwide. SEC Statement (Ex. 1018) 93–94, 136–37.
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`AAA possesses a production network, with manufacturing agreements in place with
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`other healthcare companies. Id. at 112. AAA’s business engages a diversified
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`customer based, including “public and private hospitals, universities, third-party
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`research laboratories, clinical centers and pharmaceutical companies.” Id. at 120.
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`In January 2018,