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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`ACERTA PHARMA B.V.,
`Patent Owner.
`_________________________________________________
`
`
`Case IPR 2023-00478
`Patent No. 10,272,083
`
`_________________________________________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
`
`INTRODUCTION ..................................................................................................... 1
`BACKGROUND ....................................................................................................... 5
`I.
`The ’083 Patent ................................................................................................ 5
`II.
`The Challenged Claims ................................................................................... 8
`III. The Grounds References ................................................................................. 9
`Barf-PCT (EX1006) ............................................................................ 10
`
`Barf (EX1005) ..................................................................................... 11
`Cheson (EX1008) ................................................................................ 12
`
`IV. The Relevant Prosecution History ................................................................. 13
`ARGUMENT ........................................................................................................... 17
`V.
`The Board Should Exercise Its Discretion Pursuant to §ֻ 325(d) to
`Deny Institution ............................................................................................. 19
`The Same or Substantially the Same Art Previously Was
`
`Presented to the Office ........................................................................ 19
`The Same or Substantially the Same Arguments Previously
`Were Presented to the Office .............................................................. 24
`Petitioner Has Not Demonstrated that the Office Erred in a
`Manner Material to the Patentability of the Challenged Claims ......... 28
`1.
`The Examiner Did Not Materially Err by Citing Example
`1, Rather Than Example 6 in Barf-PCT ................................... 29
`The Examiner Correctly Considered Barf-PCT’s Dosing
`Range and the Presumption of Obviousness ............................ 31
`The Examiner Evaluated Clinical Dosing References
`Regarding Other BTK Inhibitors and Correctly Applied
`the Law of Routine Experimentation ........................................ 33
`The Examiner Properly Allowed the Claims Based on
`Unexpected Results ................................................................... 39
`Barf Is Not Prior Art ............................................................................ 42
`
`
`
`
`
`
`
`
`
`2.
`
`3.
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`4.
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`VI. Petitioner Has Not Established a Reasonable Likelihood of Prevailing
`on Any Ground .............................................................................................. 45
`Sandoz Proposes and Relies on an Erroneous Construction of
`
`Claim 8 ................................................................................................ 46
`No Motivation to Combine the Grounds References .......................... 49
`1.
`No presumption of obviousness of the claimed dose ............... 49
`2.
`No motivation to select claimed daily dose of 200 mg ............ 51
`3.
`No motivation to practice claimed dosing schedule of
`twice daily ................................................................................. 55
`No Reasonable Expectation of Success in Treating MCL with
`100 mg Twice-Daily Dose of Acalabrutinib ....................................... 57
`Twice Daily Dosing of Acalabrutinib Proved Unexpectedly
`Superior ............................................................................................... 58
`VII. The Board Should Exercise Its Discretion Pursuant to § 314(a) to
`Deny Institution ............................................................................................. 58
`CONCLUSION ........................................................................................................ 62
`
`
`
`
`
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`
`ii
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`
`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
`
`TABLE OF AUTHORITIES
`
`
`Cases
`Advanced Bionics, LLC v. MED-EL Electromedizinishe Gerӓte GmbH,
` IPR2019-01469, Paper 6 (P.T.A.B. Feb. 13, 2020) ..................................... passim
`
`Alarm.com, Inc., v. Vivint, Inc.,
` IPR2022-00728, Paper 6 (P.T.A.B. Nov. 1, 2022) ....................................... 21, 22
`
`Alkermes Pharma Ir. Ltd. v. Otsuka Pharm. Co.,
` IPR2017-00287, Paper 13 (P.T.A.B. May 4, 2017) .............................................57
`
`Allergan, Inc. v. Sandoz Inc.,
` 796 F.3d 1293 (Fed. Cir. 2015) ............................................................................58
`
`Apotex Inc. v. Auspex Pharms., Inc.,
` IPR2021-01507, Paper 9 (P.T.A.B. Mar. 9, 2022) ...............................................41
`
`Apotex Inc. v. Celgene Corp.,
` IPR2018-00685, Paper 8 (P.T.A.B. Sept. 27, 2018) ............................................42
`
`Apple, Inc. v. Fintiv,
` IPR2020-00019, Paper 11 (P.T.A.B. Mar. 20, 2020) ...........................................58
`
`Bicon, Inc. v. Straumann Co.,
` 441 F.3d 945 (Fed. Cir. 2006) ..............................................................................47
`
`Cambrios Film Solutions Corp. V. C3Nano Inc.,
` IPR2019-00709, Paper 15 (P.T.A.B. Aug. 26, 2019) ..........................................37
`
`Daiichi Sankyo Co. v. Matrix Laboratories., Ltd.,
` 619 F.3d 1346 (Fed. Cir. 2010) ..................................................................... 35, 42
`
`Edwards Lifesciences Corp. v. Boston Scientific Scimed Inc.,
` IPR2017-00444, Paper 8 (P.T.A.B. May 22, 2017) .............................................28
`
`Eli Lilly & Co. v. Teva Pharms. Int'l GmbH,
` 8 F.4th 1331 (Fed. Cir. 2021) ...............................................................................48
`
`
`iii
`
`

`

`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
`
`
`Genetics Institute, LLC v. Novartis Vaccines &Diagnostics, Inc.,
` 655 F.3d 1291 (Fed. Cir. 2011) ............................................................................50
`
`Global Tel*Link Corp. v. Securus Technologies, Inc.,
` IPR2014-00824, Paper 36 (P.T.A.B. Dec. 2, 2015) .............................................45
`
`Horizon Pharma Ir. Ltd. v. Actavis Laboratories, UT, Inc.,
` 2017 WL 2703785, (D.N.J. May 12, 2017) .........................................................37
`
`In re Applied Materials,
` 692 F.3d 1289 (Fed. Cir. 2012) ............................................................................58
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig.,
` 676 F.3d 1063 (Fed. Cir. 2012) ............................................................................37
`
`In re Peterson,
` 315 F.3d 1325 (Fed. Cir. 2003) ............................................................... 32, 49, 50
`
`Ivantis, Inc. et al v. Sight Sciences, Inc.
` IPR2022-01530, Paper 14 (P.T.A.B. Mar. 27, 2023) .................................... 21, 22
`
`Johnson & Johnson Surgical Vision, Inc., v. Alcon Inc.
` IPR2021-01069, Paper 16 (P.T.A.B. Dec. 10, 2021) ...........................................21
`
`Leo Pharm. Prods., Ltd. v. Rea,
` 726 F.3d 1346 (Fed. Cir. 2013) ............................................................................37
`
`Merck & Co. v. Biocraft Laboratories, Inc.,
` 874 F.2d 804 (Fed. Cir. 1989) ..............................................................................37
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
` 395 F.3d 1364 (Fed. Cir. 2005) ............................................................................47
`
`Microsoft Corp., v. Koninklijke Philips N.V.,
` IPR2018-00279, Paper 11 (P.T.A.B. June 8, 2018) .............................................34
`
`Miltenyi Biomedicine GmbH v. Trs. of the Univ. of Pa.,
` IPR2022-00853, Paper 11 (P.T.A.B. Oct. 11, 2022)............................................57
`
`
`iv
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`

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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
`
`
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corp.,
` IPR2019-00554, Paper 40 (P.T.A.B. Jul. 23, 2020) .............................................49
`
`Nokia of America Corp. v. Godo Kaisha IP Bridge 1,
` IPR2022-00755, Paper 9 (P.T.A.B. Nov. 2, 2022) ..............................................61
`
`Panduit Corp. v. Corning Optical Communications LLC,
` IPR2021-01562, Paper 20 (P.T.A.B. April 6, 2022) ............................................23
`
`Regents of the Univ. of California v. Eli Lilly & Co.,
` 119 F.3d 1559 (Fed. Cir. 1997) ............................................................................21
`
`Samsung Elecs. Co., v. Cal. Inst. of Tech.,
` IPR2023-00133, Paper 10 (P.T.A.B. May 4, 2023) .............................................58
`
`Twi Pharms., Inc. v. Merck Serono SA,
` IPR2023-00050, Paper 8 at 16 (P.T.A.B. Mar. 28, 2023) ....................................50
`
`Ziegmann v. Stephens,
` IPR2015-01860, Paper 13 (P.T.A.B. Sept. 6, 2017) ............................................24
`
`Statutes and Other Authority
`35 U.S.C. § 100(h) ...................................................................................................45
`35 U.S.C. § 102(a)-(c) ..........................................................................................2, 45
`35 U.S.C. § 314(a) ........................................................................................ 4, 18, 62
`35 U.S.C. § 325(d) ........................................................................................... passim
`MPEP § 7.17.02 .......................................................................................................45
`
`
`
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`v
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`PATENT OWNER’S EXHIBIT LIST
`
`
`Description
`
`Exhibit
`
`2001
`
`2002
`
`2003
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`Defendants’ Invalidity Contentions (Excerpt)
`
`Reserved
`
`Reserved
`Merck-Covalution Agreement
`
`Claim Construction Stipulation, Acerta Pharma, et al. v.
`Alembic Pharmaceuticals Ltd, et al., No. 22-154-GBW-SRF,
`Dkt. No. 1083 (D. Del. Mar. 13, 2023)
`108th Congress, House Report H.R. 2391
`
`S7520, Senate Report, June 25, 2004
`
`Acerta Company Report
`
`Acerta History Report
`
`
`
`
`
`
`vi
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`INTRODUCTION
`
`The Board should exercise its discretion to deny institution of Sandoz Inc.’s
`
`
`
`
`
`(“Sandoz”) Petition for inter partes review of U.S. Patent No. 10,272,083 (“the ’083
`
`patent”). During prosecution, Patent Owner Acerta Pharma B.V. (“Acerta”)
`
`overcame two rejections raising the same arguments Sandoz rehashes in its two
`
`Grounds, based on the same or cumulative art. Acerta overcame the Examiner’s
`
`rejections for good reason: the ’083 patent discloses novel methods of treating
`
`mantle cell lymphoma (“MCL”) using acalabrutinib (a compound about which the
`
`prior art disclosed next to nothing) using a different, substantially lower dose (100
`
`mg) and different dosing schedule (twice daily) than the 560 mg, once-daily dose
`
`taught by the breakthrough treatment ibrutinib (a more potent compound and at the
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`time the only marketed compound in acalabrutinib’s class). On this record, there is
`
`no reasonable basis to conclude that the claims are not patentable.
`
`1.
`
`Sandoz’s IPR is a prototypical candidate for discretionary denial under
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`35 U.S.C. § 325(d). Sandoz admits that Acerta overcame rejections based on its
`
`primary reference in Ground 2, WO 2013/010868 (“Barf-PCT”), and admits that its
`
`primary reference in Ground 1, U.S. Patent No. 9,758,524 (“Barf”) is a related U.S.
`
`patent with a specification identical to Barf-PCT. While Barf includes specific
`
`1
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`

`

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`claims to methods of using the compound now known as acalabrutinib1 to treat
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`MCL, those claims add nothing beyond the disclosure in Barf-PCT—relied upon by
`
`the Examiner in the rejections overcome by Acerta—that acalabrutinib is useful in
`
`treating lymphomas which include MCL. In addition, Barf does not qualify as prior
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`art under 35 U.S.C. § 102(a)(2) because it arose out of the subject matter of a joint
`
`research agreement under § 102(b)(2)(C) and § 102(c). The only other reference in
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`both Grounds 1 and 2 that Sandoz relies on is a series of publications that Sandoz
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`labels “Cheson,” a single sentence of which disclosed that an early-stage compound
`
`(CC-292) was being evaluated for twice-daily dosing. But other references the
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`Examiner relied upon in the rejections overcome by Acerta likewise mentioned the
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`possibility of twice-daily dosing, rendering Cheson cumulative, at best. In short,
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`Sandoz’s IPR presents the same arguments made by the Examiner and overcome by
`
`Acerta during prosecution, relying on references that are the same or substantially
`
`the same as those previously considered.
`
`Sandoz’s two rote and conclusory paragraphs related to the Examiner’s
`
`purported errors do not begin to approach Sandoz’s burden of demonstrating that the
`
`Examiner erred in a way material to patentability. Sandoz implicitly admits as much
`
`
`1 Acalabrutinib was not yet named in the prior art, but was instead only referred to
`
`as a numbered figure or by its chemical formula.
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`2
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`by preemptively requesting a reply to Acerta’s POPR. Far from “not consider[ing]”
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`U.S. Patent No. 10,272,083
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`that acalabrutinib was exemplified in Barf-PCT, the Examiner and Acerta repeatedly
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`discussed that fact during prosecution. And, in contrast to Sandoz’s unfounded
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`allegation that the Examiner “failed to consider Barf-PCT’s dosing range,” Acerta
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`directly quoted Barf-PCT’s dosing range in overcoming the Examiner’s rejections.
`
`In allowing the claims, the Examiner correctly determined that the prior art
`
`did not teach or suggest the use of a twice-daily, 100 mg dose of acalabrutinib to
`
`treat MCL. Barf-PCT’s only disclosure related to the dosing of its compounds is the
`
`huge range of between 0.0001-25 mg/kg. In overcoming the Examiner’s rejections,
`
`Acerta persuasively argued that disclosure did not teach or suggest the use of a
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`specific, 100 mg, twice-daily dose of acalabrutinib to treat MCL with a reasonable
`
`expectation of success. Similarly, Acerta correctly argued that the prior art
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`disclosure of the FDA-approved, 560 mg once-daily use of ibrutinib to treat MCL
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`taught away from a lower dose, twice-daily regimen for acalabrutinib.
`
`2.
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`Relatedly, institution is not warranted because Sandoz has not
`
`demonstrated a reasonable likelihood of success on the merits. The prior art
`
`disclosed the FDA-approved use of a once-daily, 560 mg dose of the first-in-class
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`compound ibrutinib to treat MCL. Barf and Barf-PCT disclose acalabrutinib among
`
`dozens of other exemplified compounds, and reveal only general data about those
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`compounds’ potency against a handful of enzymes, including BTK. Those limited,
`
`3
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`

`

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`prior-art data show that the dozens of disclosed compounds were less potent than
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`U.S. Patent No. 10,272,083
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`ibrutinib, and therefore the POSA would have had no motivation to pursue the
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`counterintuitive approach of a using a lower dose than ibrutinib’s 560 mg daily dose
`
`to treat MCL, much less have a reasonable expectation of success. Cheson, on the
`
`whole, emphasizes the prominence of the breakthrough treatment ibrutinib
`
`administered once per day at a high dose, even while discussing other compounds in
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`development. The disclosure that another compound more potent than Barf-PCT’s
`
`disclosed compounds was being evaluated for twice-daily dosing would not have
`
`provided a reasonable expectation of success even when combined with Barf or
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`Barf-PCT: Cheson does not teach or suggest that a daily dose lower than 560 mg
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`(let alone a dose as low as 100 mg twice-daily) would be safe and effective to treat
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`MCL, even if dosed more than once-daily.
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`3.
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`Discretionary denial is also appropriate under 35 U.S.C. § 314(a) for
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`efficiency reasons. Instituting trial here would only result in redundant litigation of
`
`issues between these proceedings and related, ongoing proceedings in the U.S.
`
`District Court for the District of Delaware. Sandoz here challenges the validity of a
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`small but overlapping subset of the claims asserted, and the art identified, in the
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`district court proceedings, which also involve five additional patents. Thus, all of
`
`the claims that Sandoz challenges here already face validity challenges based on the
`
`same art in the district court proceeding. What is more, the district court proceeding
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`4
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`

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`involves four additional generic manufacturer defendants whose invalidity
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`contentions demonstrate that they will pursue the same arguments raised here,
`
`regardless of the outcome of this proceeding. Finally, an unchallenged Orange
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`Book-listed patent does not expire until 2026, so institution will not accelerate
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`generic entry. Consistent with that timeline, the district court trial is scheduled for
`
`March 3, 2025. Simply put, Sandoz’s challenge here to seven claims of the ’083
`
`patent is a non-dispositive and duplicative offshoot of much larger proceedings in
`
`the district court. Discretionary denial here is the more efficient outcome.
`
`In light of the substantial reasons for discretionary denial and Sandoz’s failure
`
`to show a likelihood of success on the merits, the Board should deny institution.
`
`I.
`
`The ’083 Patent
`
`BACKGROUND
`
`Ibrutinib, marketed under the trade name Imbruvica®, was the first-in-class,
`
`small-molecule inhibitor of Bruton’s tyrosine kinase (“BTK”). EX1001, 56:18-22,
`
`69:20-25, 72:3-6. BTK is a protein in the B-cell receptor signaling pathway that
`
`contributes to malignant B-cell survival and proliferation. Id., 1:14-33, 69:18-20.
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`Ibrutinib forms a covalent bond with an amino acid residue on BTK and thereby
`
`blocks its activity. Id., 56:56-57, 74:36-37; EX1002 ¶¶ 82-83; EX1019, 4.
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`As of the priority date, ibrutinib was the first and only BTK inhibitor to be
`
`FDA-approved to treat B-cell malignancies, with an approved dosing regimen of 560
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`mg once-daily for MCL and 420 mg once-daily for chronic lymphocytic leukemia
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`(“CLL”). EX1004, 998-99. Ibrutinib was “highly potent in inhibiting BTK,”
`
`EX1001, 56:53-54, and demonstrated “substantial antitumor activity” in patients
`
`with various relapsed or refractory cancers. Id., 56:22-50. In addition to BTK,
`
`ibrutinib was known to bind to and inhibit kinases other than BTK, rather than
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`selectively inhibiting BTK. Id., 56:51-64. Despite its off-target activity, numerous
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`medical journals reported that ibrutinib was safe at high doses: in clinical trials of
`
`ibrutinib as a single agent against B-cell malignancies, no maximum tolerated dose
`
`was found, and ibrutinib was considered “well tolerated at dose levels through 840
`
`mg.” Id., 56:22-36.
`
`Departing from the path paved by ibrutinib, the inventors of the ’083 patent
`
`conceived of a method of treating MCL, CLL, and small lymphocytic lymphoma
`
`(“SLL”) using a less potent compound at a much lower total daily dose. EX1001,
`
`57:5-18, 57:19-23, 66:34-68:67, 99:2-32 (claim 1), 100:39-65 (claim 8). The
`
`inventors of the ’083 patent also departed from ibrutinib’s dosing regimen by dosing
`
`acalabrutinib more frequently, twice per day. Id., 65:20-21, 66:34-68:67, Figs. 3, 9–
`
`12.
`
`There were no data in the prior art suggesting that the 100 mg, twice-daily
`
`administration of acalabrutinib would be safe or effective in treating humans
`
`suffering from MCL or the other types of cancers discussed in the ’083 patent. For
`
`6
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`

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`instance, Sandoz’s expert, Dr. John P. Fruehauf, does not suggest that the prior art
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`U.S. Patent No. 10,272,083
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`provided data on acalabrutinib’s pharmacologic properties, including its terminal
`
`elimination half-life, in any model, let alone in actual human patients. Rather, the
`
`only data available on acalabrutinib—which Sandoz highlights in its brief and expert
`
`declaration—was on potency in preliminary biochemical assays that were not
`
`conducted in cells or in an animal model, let alone in human patients. Pet., 19, 25,
`
`32-33; EX1002 ¶¶ 83, 95, 122-23. However, those data showed that acalabrutinib
`
`was less potent in those biochemical assays than ibrutinib. This data would have
`
`taught away from attempting to use a lower dose of acalabrutinib (as compared to
`
`the approved dosing regimen for ibrutinib) to treat MCL.
`
`Nonetheless, clinical data reported for the first time in the ’083 patent shows
`
`that patients receiving acalabrutinib 100 mg, twice-daily substantially outperformed
`
`patients receiving acalabrutinib once-daily (as well as patients previously reported
`
`to have received ibrutinib) in a number of different ways. EX1001, 66:34-53 (Table
`
`5), Figs. 9–12, 7:62-8:6, 68:14-56. The amount of BTK occupied, and the length of
`
`that occupancy, was greater and longer in the acalabrutinib twice-daily group, as
`
`compared to ibrutinib and acalabrutinib once-daily groups. Id., 67:53-63 (reporting
`
`“94%-99%” BTK occupancy for 200 mg total dose of acalabrutinib versus “80%-
`
`90%” BTK occupancy for 420 mg and 840 mg doses of ibrutinib); EX1004, 1078-
`
`79 (discussing Byrd’s report of higher sustained BTK occupancy for 100 mg twice-
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`7
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`daily than for various once-daily doses of acalabrutinib at drug trough of 24 hours
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`U.S. Patent No. 10,272,083
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`post-dose). The clinical data ultimately proved that acalabrutinib dosed twice per
`
`day at the lower dose was as effective as ibrutinib at a much higher once-daily dose,
`
`with fewer side effects. EX1004, 1078, 1382. As a result, when the FDA approved
`
`acalabrutinib to treat MCL under the trade name Calquence®, the approved dosing
`
`regimen was 100 mg, twice-daily (“BID”). Id., 994-95.
`
`II. The Challenged Claims
`
`The ’083 patent claims methods of treating CLL, SLL, and MCL through a
`
`specified oral dosing regimen of a BTK inhibitor of Formula (II), namely
`
`acalabrutinib. EX1001, Claims 1, 8.
`
`Claim 8, the sole independent claim that Sandoz challenges, recites “[a]
`
`method of treating a mantle cell lymphoma (MCL) in a human subject suffering
`
`therefrom comprising the step of orally administering, to the human subject, a dose
`
`of 100 mg twice daily of [acalabrutinib] . . . or a pharmaceutically-acceptable salt,
`
`hydrate, or solvate thereof.” EX1001, 100:39-65.
`
`The remaining dependent claims that Sandoz seeks to cancel further recite
`
`using a pharmaceutically acceptable salt of acalabrutinib (claim 9); yielding an
`
`increase in “monocytes and NK cells in peripheral blood” of the human subject after
`
`treatment for a period of “about 14 days, about 28 days, [or] about 56 days” (claim
`
`10);
`
`treating certain subtypes of MCL (claim 11); co-administering “a
`
`8
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`

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`therapeutically effective dose” of an anti-CD20 antibody (claim 12); administering
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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`the free form of acalabrutinib (claim 19); or administering a salt of acalabrutinib
`
`(claim 20). Id., 100:66-101:36, 102:34-39.
`
`For purposes of this preliminary response only, Patent Owner does not
`
`challenge Sandoz’s proposed priority date of January 21, 2015, which is the filing
`
`date of International Application PCT/IB2015/000645, from which the ’083 patent
`
`issued. See Pet. 12, citing EX1001, 1(22). Patent Owner reserves the right to assert
`
`any other priority date for the ’083 patent in any subsequent proceeding.2
`
`III. The Grounds References
`
`Sandoz alleges two grounds of unpatentability, each based on obviousness
`
`over Barf (EX1005) or Barf-PCT (EX1006), in view of Cheson (EX1008). Pet., 5.
`
`Sandoz concedes that its reasoning in Grounds 1 and 2 are “substantially the same.”
`
`Id., 49.
`
`
`2 Petitioner’s assertion that “[a]lthough the ʼ083 patent claims priority to three
`
`provisional applications filed
`
`in 2014, none describes treating MCL by
`
`administering 100 mg of acalabrutinib twice daily,” Pet., 12, is irrelevant since
`
`Petitioner acknowledges that its “grounds references predate the earliest provisional
`
`filing of January 21, 2014.” Id., 13 n. 2.
`
`
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`9
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
`
` Barf-PCT (EX1006)
`Barf-PCT is a 2013 international patent publication that discloses a genus of
`
`BTK inhibitor compounds and exemplifies 133 compounds in that genus, one of
`
`which—Example 6—is the compound now known as acalabrutinib. EX1006, 1(43),
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`10:19-16:27, 35:16-36:2. Barf-PCT discloses that its compounds “can be used in
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`therapies to treat or prevent Bruton’s Tyrosine Kinase (Btk) mediated disorders,”
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`id., 21:19-20, which include, among others, “non-Hodgkin lymphoma (in particular
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`the subtypes diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma
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`(MCL)). Id., 22:15-17.
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`Barf-PCT provides tables containing data related to the exemplified
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`compounds’ potency against several enzymes, including BTK. Those data are the
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`results of biochemical assays used to determine the concentration of the test
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`compound that is required for 50% inhibition of its maximum effect in vitro
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`(“EC50”). EX1006, 17:4-5. Of the 133 compounds, 79 (including acalabrutinib) are
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`described in those tables as having a BTK EC50 of less than 10 nM. Id., 94.
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`Dosing information in Barf-PCT is general to all the compounds in the
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`specification, and broadly discloses “a dosage for humans preferably contains
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`0.0001-25 mg per kg body weight,” id., 20:16, 20:24-25, which “may be presented
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`as one dose or as multiple subdoses administered at appropriate intervals throughout
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`10
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`the day, or, in case of female recipients, as doses to be administered at appropriate
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`daily intervals throughout the menstrual cycle.” Id., 20:25-27.
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`Barf (EX1005)
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`Sandoz contends that Barf is prior art solely under § 102(a)(2). Pet., 21. Barf
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`is U.S. patent No. 9,758,524, issued on September 12, 2017. EX1005, 1. Barf claims
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`priority to the same application chain as Barf-PCT, dating back to 2011. Id., 1(60).
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`Barf on its face is assigned to Merck Sharp & Dohme B.V., id., 1(73), and is licensed
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`to Acerta pursuant to a 2012 development agreement between Merck Sharp &
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`Dohme B.V. and Acerta’s predecessor-in-interest, Covalution Pharma B.V.
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`EX2004; EX2008; EX2009.
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`Barf has the same specification as Barf-PCT, including the same disclosed
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`genus, the same broad and general dosing information related to that genus, the same
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`disclosure that compounds in the genus are useful in treating BTK-mediated
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`disorders including MCL, the same example compounds, and the same tables
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`containing EC50 potency data. Id., 9:9-14:26, 145:1-24, 19:39-41,17:62-18:1, 27:36-
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`74:49. The only difference between Barf and Barf-PCT are their claims. Barf’s
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`claim 1 recites a method of treating MCL with the compound now known as
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`acalabrutinib. Claim 12, which depends from claim 1, further recites the method of
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`claim 1, wherein the “amount administered to the human subject is 0.0001-25 mg
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`per kg body weight.” Id., 150:3-32, 151:14-15.
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`Case No. IPR2023-00478
`U.S. Patent No. 10,272,083
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` Cheson (EX1008)
`“Cheson” is a compilation of four articles from different authors, who were
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`presenters at a conference chaired by Bruce D. Cheson. EX1008 at 1-15. Cheson
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`was published in September 2013 as a supplement in the journal Clinical Advances
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`in Hematology & Oncology. EX1008, 1.
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`Cheson states its “Educational Objectives,” are to “compare current and
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`emerging treatment strategies for patients with B-cell malignancies,” and to
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`“[d]iscuss evidence produced by recent studies on investigational therapies or
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`regimens for treatment of some prevalent B-cell malignancies.” Id., 2. As a whole,
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`Cheson shows that ibrutinib was the most clinically advanced BTK inhibitor, with
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`data showing that a high once-daily dose was safe and effective. Cheson’s first
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`article, authored by Gribben, states that while “[s]everal BTK inhibitors are being
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`evaluated in clinical trials; the furthest in development is ibrutinib,” which is
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`“administered orally once daily.” Id., 4. The second article, authored by Cheson
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`himself, mentions various therapies of which ibrutinib is the only BTK inhibitor
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`discussed alongside its positive phase I clinical data. Id., 7. The third article,
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`authored by O’Brien, prominently discusses ibrutinib as a single agent and in
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`combination therapies, noting clinical data of a phase 1b/2 trial where patients
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`received “fixed doses of 420 mg or 840 mg daily,” which were “well tolerated” and
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`demonstrated the “substantial efficacy of ibrutinib in CLL patients.” Id., 9. The
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`12
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`final article, authored by Goy, discusses several therapies of which ibrutinib is again
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`the only BTK inhibitor discussed. Id., 13-14. Goy favorably reports on a phase 2
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`clinical trial with MCL patients who received ibrutinib “560 mg daily” and showed
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`an overall response rate of 68% with mild or moderate adverse events. Id.
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`IV. The Relevant Prosecution History
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`As discussed further below with respect to discretionary denial under 35
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`U.S.C. § 325(d), the arguments and references in Sandoz’s Grounds are either
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`identical to, or substantively the same as, those considered during prosecution.
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`In the first of two office actions, the Examiner rejected all the claims as
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`obvious over the combined disclosures of Smyth (US 2013/0338172), which the
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`Examiner referred to as “the 172,” and Barf-PCT, which the Examiner referred to as
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`“the 868” or “Johannes.” EX1004, 906-10. Smyth, the Examiner asserted, disclosed
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`methods of treating various lymphomas including MCL using formulations of BTK
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`inhibitor compounds, including ibrutinib, that were structurally similar to the
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`claimed compound of Formula II (acalabrutinib), and were delivered orally “at a
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`concentration from 300 to 1000 mg per day as much as 2 to 4 times a day.” Id., 908-
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`09. The Examiner further noted that Barf-PCT disclosed BTK inhibitor compounds
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`useful in treating lymphomas, including the “identical” compound of “claimed
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`formula II,” i.e., acalabrutinib.3 Id., 909. In the Examiner’s initial view, it would
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`have been obvious to combine “the specific compound of the 868 [acalabrutinib]
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`into the method of treatment of the 172 [“2 to 4 times a day”] in order to treat a
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`variety of cancer conditions with an oral multiple day formulation.” Id., 909.
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`To overcome the Examiner’s rejections, Acerta argued that the prior art taught
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`away from the claimed dose and dosing regimen, and submitted clinical data of
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`unexpected results of the claimed dosing regimen. Specifically, Acerta argued that
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`the Examiner had failed to consider the “entirety of the relevant art,” principally the
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`FDA-approved 2013 and 2014 labels of Imbruvica® (ibrutinib) for treatment of
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`MCL and CLL, which “reflect[ed] the understanding in the medical community that
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`relatively large, once daily dosing of IMBRUVICA® is required for treatment of
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`both mantle cell lymphoma (560 mg once daily) and chronic lymphocytic leukemia
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`(420 mg once daily).” EX1004, 998-99. In other words, the ibrutinib labels taught
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`3 The Examiner misidentified acalabrutinib as appearing in Example 1 rather than
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`Example 6 of Barf-PCT. EX1004, 909. But it is beyond doubt that he was
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`comparing “formula (II)” in the pending application to the identical compound in
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`Barf-PCT, which is acalabrutinib. In any event, Acerta removed any doubt in
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`responding to the Examiner’s rejection, where Acerta wrote “the compound of
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`Formula (II) is disclosed as Example 6 on page 30 o