Case: 21-2270 Document: 59 Page: 1 Filed: 11/15/2022
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`NOTE: This disposition is nonprecedential.
`
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`PHARMACYCLICS LLC, JANSSEN BIOTECH, INC.,
`Plaintiffs-Appellees
`
`v.
`
`ALVOGEN, INC., NATCO PHARMA LIMITED,
`Defendants-Appellants
`______________________
`
`2021-2270
`______________________
`
`Appeal from the United States District Court for the
`District of Delaware in No. 1:19-cv-00434-CFC-CJB, Chief
`Judge Colm F. Connolly.
`______________________
`
`Decided: November 15, 2022
`______________________
`
`CHRISTOPHER NEIL SIPES, Covington & Burling LLP,
`Washington, DC, argued for all plaintiffs-appellees. Plain-
`tiff-appellee Pharmacyclics LLC also represented by ERICA
`NICOLE ANDERSEN, BRIANNE BHARKHDA.
`
` IRENA ROYZMAN, Kramer Levin Naftalis & Frankel
`LLP, New York, NY, for plaintiff-appellee Janssen Biotech,
`Inc. Also represented by CHRISTINE WILLGOOS; HANNAH
`YUNKYUNG LEE, DANIEL DAVID WILLIAMS, Redwood Shores,
`CA.
`
`

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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`
` SIEGMUND Y. GUTMAN, Proskauer Rose LLP, Los Ange-
`les, CA, argued for defendants-appellants. Also repre-
`sented by DAVID M. HANNA; JOHN E. ROBERTS, Boston, MA.
`______________________
`
`Before CHEN, BRYSON, and HUGHES, Circuit Judges.
`BRYSON, Circuit Judge.
`Appellees Pharmacyclics LLC and Janssen Biotech,
`Inc., (collectively, “Pharmacyclics”) own several patents re-
`lated to the compound ibrutinib, which is the active ingre-
`dient in Pharmacyclics’ branded drug Imbruvica. Ibrutinib
`is one of a genus of compounds, known as “BTK inhibitors,”
`that block the protein Bruton’s tyrosine kinase (“BTK”).
`Imbruvica is used to treat a cancer of the immune system
`known as mantle cell lymphoma (“MCL”), including the
`“relapsed” or “refractory” type of MCL (“R/R MCL”).1
`In November 2018, appellants Alvogen, Inc., and Natco
`Pharma Limited (collectively, “Alvogen”) filed an abbrevi-
`ated new drug application (“ANDA”) to market a generic
`version of Imbruvica. Pursuant to procedures set forth in
`the Hatch-Waxman Act, Pharmacyclics then brought this
`lawsuit charging Alvogen with infringement of a number
`of Pharmacyclics’ patents relating to ibrutinib. The district
`court held a bench trial and determined that all of the as-
`serted claims were infringed and not invalid. We affirm.
`I
`A
`Pharmacyclics originally asserted dozens of claims
`across 17 patents, but by the time of trial, it had reduced
`the number of asserted claims to five: claim 10 of U.S.
`
`1 R/R MCL is MCL that occurs in patients who have
`already received at least one prior therapy for MCL.
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`Patent No. 8,008,309 (“the ’309 patent”), claim 2 of U.S. Pa-
`tent No. 8,754,090 (“the ’090 patent”), claim 5 of U.S. Pa-
`tent No. 9,725,455 (“the ’455 patent”), and claims 30 and
`37 of U.S. Patent No. 9,655,857 (“the ’857 patent”).
`Claim 10 of the ’309 patent recites the ibrutinib com-
`pound:
`10. The compound of claim 1 [which claims a genus
`of BTK inhibitor compounds] having the formula 1-
`((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyra-
`zolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-
`1-one.
`’309 patent, claim 10.
`Claim 2 of the ’090 patent, which depends from claim 1
`of that patent, recites a method of treating MCL using ib-
`rutinib at an oral dose of about 560 mg:
`1. A method for treating mantle cell lymphoma in
`an individual who has already received at least one
`prior therapy for mantle cell lymphoma comprising
`administering to the individual once per day be-
`tween about 420 mg to about 840 mg of an oral dose
`of an inhibitor of Bruton’s tyrosine kinase (Btk)
`having the structure:
`
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`2. The method of claim 1, wherein the once per
`day oral dose is about 560 mg.
`’090 patent, claims 1–2.
`Claim 5 of the ’455 patent, which depends from claim 1
`of that patent, recites a crystalline form of ibrutinib:
`1. A crystalline form A of [ibrutinib] that has an
`X-ray powder diffraction (XRPD) pattern compris-
`ing 2-Theta peaks at 5.7±0.1º, 18.9±0.1º, and
`21.3±0.1º.
`5. The crystalline form of claim 1, wherein the X-
`ray powder diffraction (XRPD) pattern further
`comprises 2-Theta peaks at 13.6±0.1º, 16.1±0.1º,
`and 21.6±0.1º.
`’455 patent, claims 1, 5.
`Claims 30 and 37 of the ’857 patent recite tablet formu-
`lations for ibrutinib:
`30. The high-load solid tablet formulation of claim
`1 [which recites a genus tablet formulation for ib-
`rutinib], consisting essentially of:
`a) about 70% w/w of ibrutinib,
`b) about 14% w/w of lactose monohydrate,
`c) about 5% w/w of microcrystalline cellu-
`lose,
`d) about 2% w/w of polyvinylpyrrolidone,
`e) about 7% w/w of croscarmellose sodium,
`f) about 1% w/w of sodium lauryl sulfate,
`g) about 0.5% w/w of colloidal silicon diox-
`ide, and
`h) about 0.5% w/w of magnesium stearate.
`37. The solid tablet formation of claim 27 [which
`recites a genus tablet formulation for ibrutinib in
`an amount of about 70 mg to about 840 mg] consist-
`ing essentially of
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`a) about 69% w/w to about 71% w/w of ib-
`rutinib,
`b) about 13% w/w to about 15% w/w of lac-
`tose monohydrate,
`c) about 2% w/w to about 5% w/w of micro-
`crystalline cellulose,
`d) about 1% w/w to about 3% w/w of polyvi-
`nylpyrrolidone,
`e) about 6% w/w to about 8% w/w of croscar-
`mellose sodium,
`f) about 1% w/w to about 4% w/w of sodium
`lauryl sulfate,
`g) about 0.4% w/w to about 0.6% w/w of col-
`loidal silicon dioxide, and
`h) about 0.4% w/w to about 0.6% w/w of
`magnesium stearate.
`’857 patent, claims 30, 37.
`
`B
`At trial, Alvogen stipulated that it infringed the as-
`serted claims of the ’309, ’090, and ’455 patents, and the
`district court found that Alvogen infringed the asserted
`claims of the ’857 patent. Pharmacyclics LLC v. Alvogen
`Pine Brook LLC, 556 F. Supp. 3d 377, 385–86 (D. Del.
`2021). Alvogen alleged that each of the asserted claims is
`invalid, based on various theories. The district court re-
`jected each of those theories and held that none of the
`claims had been proved invalid by clear and convincing ev-
`idence. See id. at 424.
`
`1
`Alvogen argued that claim 10 of the ’309 patent (the
`compound claim) was anticipated by an article referred to
`as “Pan.” The parties did not dispute that the Pan article
`describes ibrutinib, but Pharmacyclics argued that the in-
`vention of claim 10 of the ’309 patent pre-dated the publi-
`cation of Pan. Id. at 390.
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`The Pan article was published on December 12, 2006,
`and the application for the ’309 patent was filed on Decem-
`ber 28, 2006. Id. However, Pharmacyclics argued that the
`date of invention of claim 10 was the date that one of two
`provisional patent applications was filed: either September
`22, 2006, or October 6, 2006.2 Id. Alvogen argued that the
`provisional applications did not establish priority because
`they did not satisfy the written description and enablement
`requirements of 35 U.S.C. § 112 with respect to the ibru-
`tinib compound. Id. at 390–91. Therefore, Alvogen argued,
`the Pan article anticipated claim 10 of the ’309 patent. Id.
`The provisional applications disclosed ibrutinib and
`noted that the synthesis of ibrutinib “was accomplished us-
`ing a procedure analogous to that described for” another
`compound, referred to as “[C]ompound 4.” See J.A. 18001–
`02. The procedure described for Compound 4 begins with
`another compound, “[I]ntermediate 2.” J.A. 16611, 18001.
`Alvogen argued that because the provisional applications
`did not disclose how to synthesize Intermediate 2, Com-
`pound 4 (and, by extension, ibrutinib) had not been ena-
`bled. Pharmacyclics, 556 F. Supp. 3d at 393.
`The district court found that “the disclosure of the
`structure of Intermediate 2 in the Compound 4 Scheme
`would have enabled a skilled artisan to synthesize Inter-
`mediate 2.” Id. at 394. The court based that finding on two
`considerations. First, the court observed that “[t]he provi-
`sional applications have a bracketed citation to the World
`Intellectual Property Organization patent WO 2001019829
`[“WO ’829”] immediately after they mention Intermediate
`2.” Id. at 393. The court found that “[a]n artisan of ordi-
`nary skill would have understood that the inventors cited
`[WO ’829] to explain how to synthesize Intermediate 2.” Id.
`
`
`2 Those applications are U.S. Provisional Patent Ap-
`plication Nos. 60/826,720 and 60/828,590.
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`Second, and in the alternative, the district court found
`that “an artisan of ordinary skill could also have synthe-
`sized Intermediate 2 without the teachings of [WO ’829]
`based on the structure of Intermediate 2 disclosed in the
`diagram of the Compound 4 Scheme.” Id. In so finding,
`the court relied on testimony from Pharmacyclics’ expert,
`Dr. Paul Reider, who testified that “his undergraduate stu-
`dents—whose abilities would fall below that of [an artisan
`of ordinary skill]—would have been able to synthesize In-
`termediate 2 . . . by working backwards from its structure
`to known starting compounds.” Id. at 393–94.
`Based on those findings, the district court concluded
`that the provisional applications contained adequate writ-
`ten description support for and sufficiently enabled claim
`10 of the ’309 patent. Id. at 398. Accordingly, the court
`concluded that claim 10 of the ’309 patent was entitled to
`an invention date of September 22, 2006, and was not an-
`ticipated by the Pan article. Id.
`2
`Alvogen argued that claim 2 of the ’090 patent (the
`method-of-treatment claim) was not adequately described
`or enabled, was obvious in view of four prior art references,
`and was invalid for obviousness-type double patenting. Id.
`at 398.
`As for written description, the district court found that
`“ibrutinib is the only BTK inhibitor identified by name in
`the Summary of the Invention and is the only BTK [inhib-
`itor] identified for the treatment of R/R MCL.” Id. at 401.
`For those reasons, the court found that a skilled artisan
`would have recognized ibrutinib as “the inventor’s pre-
`ferred BTK inhibitor for treating R/R MCL.” Id. The court
`then referred to “Example 13” in the written description,
`which discloses a protocol for a Phase II clinical trial in-
`volving the use of BTK inhibitors at a dose of 560 mg per
`day to treat R/R MCL. Id. (citing ’090 patent, col. 141, line
`58, through col. 142, line 27). The court found that
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`“[a]lthough Example 13 does not explicitly identify a spe-
`cific BTK inhibitor to use,” a skilled artisan “would under-
`stand to use the inventor’s preferred BTK inhibitor (i.e.,
`ibrutinib) in the Phase II protocol described in Example
`13.” Id. The court therefore concluded that Alvogen had
`not shown that claim 2 of the ’090 patent was not ade-
`quately described. Id. at 407.
`Alvogen’s arguments on enablement largely mirrored
`its arguments on written description. The district court
`concluded that claim 2 had been enabled because “an arti-
`san of ordinary skill would be able to follow the protocol of
`Example 13 using ibrutinib and thus practice the method
`described in claim 2.” Id. at 406.
`On the issue of obviousness, Alvogen proposed a com-
`bination of four prior art references: U.S. Patent Publica-
`tion No. 2008/0076921 (“the ’921 publication”); U.S. Patent
`No. 8,952,015 (“the ’015 patent”); an article referred to as
`“Pollyea”; and a December 2009 press release. Id. at 401–
`02. Alvogen also sought to rely on another reference, “Ad-
`vani,” but the district court determined that Advani could
`not be considered part of Alvogen’s obviousness combina-
`tion and would instead be treated as background art. Id.
`at 402–03 n.7.
`The ’015 patent discloses ibrutinib by its chemical
`name, and it also discloses dozens of other compounds ei-
`ther by name or by structure.3 ’015 patent, col. 4, ll. 1–26;
`id. at col. 36, line 30 through col. 51, line 37. The written
`description of the ’015 patent discloses a general dose range
`of “0.02–5000 mg per day” or “about 1–1500 mg per day” to
`
`
`3 As the district court observed, the ’921 publication
`and the ’015 patent “share essentially the same written de-
`scription and differ only in their claims.” Pharmacyclics,
`556 F. Supp. 3d at 401. Allusions to the ’015 patent in this
`opinion therefore apply to both references.
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`treat a variety of conditions. Id. at col. 84, ll. 31–34. It
`adds that a “therapeutically effective amount[] may be de-
`termined by routine experimentation, including but not
`limited to a dose escalation clinical trial.” Id. at col. 21, ll.
`49–52. The ’015 patent, however, does not specifically dis-
`close using ibrutinib to treat R/R MCL. Pharmacyclics, 556
`F. Supp. 3d at 401.
`The Pollyea article reported the interim results of a
`Phase I dose escalation study of ibrutinib. The article dis-
`closed dosing based on the patient’s weight rather than us-
`ing a fixed dose of about 560 mg per day. J.A. 16671. It
`further disclosed that none of the seven patients involved
`in the trial had exhibited complete or partial responses to
`treatment. See J.A. 16672. The December 2009 press re-
`lease disclosed subsequent interim results for the Pollyea
`study and reported that two patients who suffered from
`had R/R MCL exhibited a partial response to the treat-
`ment. See J.A. 15041, 16451.
`The district court found that a skilled artisan would not
`have been motivated to combine Alvogen’s references to
`treat R/R MCL with a once-daily dose of about 560 mg of
`ibrutinib, for three reasons. First, the district court found
`that a skilled artisan would not have interpreted the re-
`sults of the study disclosed in Pollyea “as showing that ib-
`rutinib could be used as a treatment for R/R MCL,” given
`the “unpredictable nature of oncology” and that only two
`R/R MCL patients in the study had exhibited any response
`to the treatment. Pharmacyclics, 556 F. Supp. 3d at 403.
`Second, the court found that none of the references, alone
`or in combination, would have motivated a skilled artisan
`to use a once-daily dose of about 560 mg. Id. That was
`because
`“[t]he only references
`that mention R/R
`MCL . . . disclose a weight-based dosing regimen,” and the
`evidence did not suggest that conventional methods of de-
`termining an effective dose “would lead to a dose of about
`560 mg.” Id. Third, the court found that “safety concerns
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`about ibrutinib would have discouraged an artisan of ordi-
`nary skill from treating R/R MCL with ibrutinib.” Id.
`For similar reasons, the district court found that a
`skilled artisan would not have had a reasonable expecta-
`tion of success in treating R/R MCL with a daily dose of
`about 560 mg of ibrutinib. Id. at 404. The court also found
`that six secondary considerations favored nonobviousness:
`a long-felt but unmet need, the failure of others, skepti-
`cism, unexpected results, praise, and commercial success.
`Id. at 404–06. The court therefore concluded that claim 2
`of the ’090 patent would not have been obvious because of
`the lack of a motivation to combine the references, the lack
`of a reasonable expectation of success, and the secondary
`considerations of nonobviousness. Id. at 407.
`On the issue of obviousness-type double patenting, Al-
`vogen argued that it was entitled to a presumption of obvi-
`ousness because claim 20 of the ’015 patent recites the
`administration of a “therapeutically effective amount” of
`ibrutinib, which the specification of that patent identified
`as falling within the range of 1 mg to 1500 mg. Id. at 407.
`The dosage recited in claim 2 of the ’090 patent, about 560
`mg, would fall within that range. Id.
`The district court rejected Alvogen’s presumption-of-
`obviousness argument for four reasons. First, the court
`noted that there were other differences, besides the dosage
`amount, between claim 20 of the ’015 patent and claim 2 of
`the ’090 patent. Id. at 408 (citing Tris Pharma, Inc. v. Ac-
`tavis Labs. FL, Inc., 503 F. Supp. 3d 183, 203 (D. Del.
`2020)). Second, the court pointed out that the breadth of
`the ranges in the written description of the ’015 patent
`weighed against applying the presumption of obviousness.
`Id. Third, the court restated its earlier finding that “rou-
`tine experimentation would not have resulted in a dose
`amount of 560 mg.” Id. at 409. And fourth, the court found
`that the evidence presented by Pharmacyclics at trial
`“would have rebutted any presumption of obviousness.” Id.
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`3
`Alvogen argued that claim 5 of the ’455 patent (the
`crystalline form claim) was inherently anticipated by the
`clinical study disclosed in the Pollyea article and another
`reference, “Fowler,” which disclosed updated results for the
`same study. Id. at 413. Alvogen also argued that the claim
`was obvious in view of a combination of four references. Id.
`at 412.
`The written description of the ’455 patent indicates
`that ibrutinib exists in multiple crystalline forms and in an
`amorphous form. ’455 patent, col. 10, ll. 17–50. Claim 5 of
`the ’455 patent recites one of those forms, “Form A,” which
`is “the most stable form of ibrutinib currently known.”
`Pharmacyclics, 556 F. Supp. 3d at 410.
`On the issue of inherent anticipation, the study dis-
`closed in the Pollyea and Fowler references used a BTK in-
`hibitor known as PCI-32765. J.A. 16466, 16671. The
`district court found that PCI-32765 refers to ibrutinib gen-
`erally, and not to any specific form of ibrutinib. Pharma-
`cyclics, 556 F. Supp. 3d at 410. But the evidence presented
`at trial showed that every lot of PCI-32765 used in the
`study was Form A of ibrutinib. See Appellants’ Br. 34–35.
`The district court concluded that Alvogen had not
`proved that the study disclosed in Pollyea and Fowler
`“could only be conducted with crystalline Form A of ibru-
`tinib.” Pharmacyclics, 556 F. Supp. 3d at 414. The court
`added that “a skilled artisan, reviewing Pollyea or Fowler,
`would not have necessarily recognized that Pollyea’s or
`Fowler’s authors used crystalline Form A for their reported
`clinical study.” Id. (citing Endo Pharms. Sols., Inc. v. Cus-
`topharm Inc., 894 F.3d 1374, 1382 (Fed. Cir. 2018))
`(cleaned up). Accordingly, the court determined that claim
`5 of the ’455 patent was not inherently anticipated by the
`study disclosed in Pollyea and Fowler. See id.
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`On the issue of obviousness, Alvogen argued that claim
`5 of the ’455 patent would have been obvious in view of the
`following four references: an article referred to as “Ho-
`nigberg”; U.S. Patent No. 7,514,444 (“the ’444 patent”); and
`two general references addressing polymorphism, “Miller”
`and “Bauer.”4 Id. at 410–11.
`The Honigberg reference discloses the chemical struc-
`ture of ibrutinib and notes that ibrutinib had “shown prom-
`ising clinical activity” as a “potent, selective and
`irreversible [BTK] inhibitor.” J.A. 16472. Similarly, the
`’444 patent discloses the chemical name and structure of
`ibrutinib, along with other compounds, as well as a method
`for synthesizing ibrutinib. ’444 patent, col. 4, ll. 4–6; id. at
`col. 97, ll. 1–35. The patent further states that the dis-
`closed compounds “may be in various forms,” including
`crystalline forms, but does not assert that any crystalline
`forms of ibrutinib actually exist. Id. at col. 60, ll. 38–49.
`The Miller and Bauer references are general references
`on polymorphism. Neither mentions ibrutinib or teaches
`how to make a crystalline form of ibrutinib. See generally
`J.A. 17837–93 (Miller); J.A. 17401–09 (Bauer). Miller
`“gives a general introduction to crystal forms, crystal sta-
`bility, crystallization, and polymorph screening.” Pharma-
`cyclics, 556 F. Supp. 3d at 411. Bauer teaches that
`“crystalline solids are usually highly stable” but that the
`polymorphs of a particular drug that will form under cer-
`tain conditions “cannot be predicted.” Id. (citing J.A.
`17402).
`The district court found that a skilled artisan “would
`have been motivated to develop a crystalline form of
`
`
`“Polymorphism” refers to a compound having more
`4
`than one crystalline form. Pharmacyclics, 556 F. Supp. 3d
`at 409. The crystalline forms of such a compound are re-
`ferred to as “polymorphs.” Id.
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`ibrutinib” based on the four references identified by Al-
`vogen, but that none of those references “would have moti-
`vated an artisan to develop a crystalline form of ibrutinib
`with the claimed 2-Theta peaks,” i.e., Form A. Id. at 412.
`That was because none of the references disclosed such a
`crystalline form or “suggested that [Form A] would be more
`desirable than any other crystalline form.” Id.
`The district court similarly found that a skilled artisan
`“could not reasonably have expected to make a crystalline
`form of ibrutinib with the six claimed 2-Theta peaks.” Id.
`The court based that finding on the fact that “discovering
`new crystalline forms is challenging and unpredictable,”
`and that the prior art did not teach which of “numerous
`variables in the crystallization process” would have been
`“key to crystallizing ibrutinib.” Id. The court also found
`that two secondary considerations weighed in favor of non-
`obviousness: unexpected benefits and copying. Id. at 412–
`13.
`In view of its findings regarding the motivation to com-
`bine, the reasonable expectation of success, and the second-
`ary considerations, the court concluded that claim 5 of the
`’455 patent would not have been obvious. Id. at 414.
`4
`Alvogen argued that claims 30 and 37 of the ’857 patent
`(the tablet formulation claims) were invalid for lack of ad-
`equate written description and obviousness. Id.
`The district court observed that the written description
`of the ’857 patent “recites verbatim the formulations
`claimed in claims 30 and 37.” Id. at 415 (citing ’857 patent,
`col. 43, line 47 through col. 44, line 6). Second, the court
`noted that the specification discloses an ibrutinib tablet
`formulation, BK21A, which satisfies the limitations of
`claims 30 and 37. Id. at 416 (citing ’857 patent at Table
`1F). Third, the court noted that the specification describes
`experiments conducted using the BK21A formulation at
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`doses of 140 mg and 560 mg. Id. (citing ’857 patent at Ta-
`bles 7, 8). In view of those disclosures, the court found that
`a skilled artisan could have scaled the formulations dis-
`closed in the ’857 patent “to make a tablet with the full
`range of claimed ibrutinib amounts.” Id. Accordingly, the
`court concluded that claims 30 and 37 were not invalid for
`lack of adequate written description. Id. at 424.
`On the issue of obviousness, the district court con-
`cluded that claims 30 and 37 would not have been obvious
`in view of Alvogen’s proposed combination of references.
`Id. at 423–24. That ruling is not at issue in this appeal.
`II
`Alvogen challenges several of the district court’s deter-
`minations. First, Alvogen argues that the court erred in
`rejecting Alvogen’s written description and obviousness
`challenges to claim 2 of the ’090 patent. Second, Alvogen
`argues that the court erred in concluding that claim 5 of
`the ’455 patent was neither inherently anticipated nor ob-
`vious. Third, Alvogen argues that the court erred in reject-
`ing Alvogen’s written description challenges to claims 30
`and 37 of the ’857 patent. Fourth, Alvogen argues that the
`court erred in concluding that claim 10 of the ’309 patent
`was not anticipated by the Pan reference. We reject each
`of Alvogen’s arguments.
`On appeal from a bench trial, we review the district
`court’s legal conclusions de novo and the district court’s fac-
`tual findings for clear error. UCB, Inc. v. Watson Lab’ys
`Inc., 927 F.3d 1272, 1286 (Fed. Cir. 2019). The clear error
`standard requires courts to affirm the finding below unless
`we have a “definite and firm conviction that a mistake has
`been made.” Biogen Int’l GMBH v. Mylan Pharms. Inc., 18
`F.4th 1333, 1341 (Fed. Cir. 2021) (citation omitted). Antic-
`ipation and written description are issues of fact. Id.; UCB,
`927 F.3d at 1286. We review the legal conclusion of obvi-
`ousness de novo and any underlying factual findings for
`clear error. UCB, 927 F.3d at 1286.
`
`

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`Case: 21-2270 Document: 59 Page: 15 Filed: 11/15/2022
`
`PHARMACYCLICS LLC v. ALVOGEN, INC.
`
`15
`
`A
`Alvogen first argues that the district court erred in de-
`termining that claim 2 of the ’090 patent contained ade-
`quate written description support, was enabled, and would
`not have been obvious.
`
`1
`The specification of the ’090 patent discloses two clini-
`cal trial protocols relating to treating R/R MCL with a BTK
`inhibitor. One protocol, “Example 7,” discloses treating
`R/R MCL using a genus of BTK inhibitors dosed based on
`a patient’s weight. ’090 patent, col. 133, ll. 42–55. The
`other, “Example 13,” discloses treating R/R MCL using a
`broader genus of BTK inhibitors at a dose of 560 mg per
`day. Id. at col. 141, line 58 through col. 142, line 7. The
`summary of the invention section of the ’090 patent further
`discloses treating R/R MCL with ibrutinib. Id. at col. 4, ll.
`59–67. Alvogen argues that the district court “cherry-
`pick[ed]” those aspects of the specification in finding that
`there was written description support for claim 2. Appel-
`lants’ Br. 16.
`The written description requirement is satisfied if the
`specification conveys with reasonable clarity to those
`skilled in the art that the inventor was in possession of the
`claimed invention. Biogen, 18 F.4th at 1341–42. When a
`specification discloses its subject matter in terms of a broad
`genus, we have required that the specification “provide suf-
`ficient ‘blaze marks’ to guide a reader through the forest of
`disclosed possibilities” toward the claimed invention. No-
`vozymes A/S v. DuPont Nutrition Biosciences APS, 723
`F.3d 1336, 1346 (Fed. Cir. 2013) (quoting In re Ruschig, 379
`F.2d 990, 994–95 (C.C.P.A. 1967)).
`Alvogen argues that the specification of the ’090 patent
`did not contain sufficient blaze marks, because a skilled ar-
`tisan would not have understood ibrutinib to be the inven-
`tor’s preferred BTK inhibitor. As the district court
`
`

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`Case: 21-2270 Document: 59 Page: 16 Filed: 11/15/2022
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`16
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`observed, however, “ibrutinib is the only BTK inhibitor
`identified by name in the Summary of the Invention and is
`the only BTK [inhibitor] identified for the treatment of R/R
`MCL” in the ’090 patent. Pharmacyclics, 556 F. Supp. 3d
`at 401. In view of those disclosures, we hold that it was not
`clearly erroneous for the district court to find that the ’090
`patent demonstrated that ibrutinib was the inventor’s pre-
`ferred BTK inhibitor.
`Alvogen also argues that the protocol disclosed in Ex-
`ample 13, which describes treating R/R MCL with a genus
`of BTK inhibitors at a dose of 560 mg per day, does not de-
`scribe the full claimed scope of “about 560 mg.” That argu-
`ment is unpersuasive in view of the fact that the summary
`of the invention explicitly discloses one possible dosage of
`ibrutinib to be “about 560 mg/day.” ’090 patent, col. 5, ll.
`8–11.
`This case is unlike our recent decision in Biogen, in
`which we upheld a district court’s ruling that a method-of-
`treatment claim lacked adequate written description sup-
`port. Biogen, 18 F.4th at 1342–45. In that case, the
`claimed dosage of 480 mg was “listed only once in the entire
`specification,” and it appeared “at the end of one range
`among a series of ranges.” Id. at 1343. By contrast, the
`dosage of “about 560 mg/day” recited in claim 2 of the ’090
`patent is expressly recited by itself (rather than as part of
`a range) in the specification, and a 560 mg daily dose ap-
`pears again in the specification’s discussion of Example 13.
`Moreover, our standard of review is significant; in Biogen,
`we held that the district court did not clearly err when it
`found that the claim lacked written description support. 18
`F.4th at 1346. In this case, the court found the opposite:
`that claim 2 was adequately described by the specification.
`Viewing the written description of the ’090 patent in its
`entirety, we hold that the district court did not clearly err
`in finding that claim 2 of the ’090 was adequately sup-
`ported by the written description.
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`Case: 21-2270 Document: 59 Page: 17 Filed: 11/15/2022
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`17
`
`2
`Alvogen’s argument on the issue of enablement is sim-
`ilar to its argument on written description. Specifically,
`Alvogen argues that the specification does not teach a
`skilled artisan how to practice claim 2 without undue ex-
`perimentation.
`The crux of Alvogen’s argument is that Example 13 dis-
`closes a dose of exactly 560 mg per day, rather than the full
`claimed scope of “about” 560 mg per day. However, the
`summary of the invention explicitly discloses a dose of
`“about 560 mg/day.” ’090 patent, col. 5, ll. 8–11. With re-
`spect to enablement, the district court concluded that a
`skilled artisan “would be able to follow the protocol of Ex-
`ample 13 using ibrutinib and thus practice the method de-
`scribed in claim 2.” Pharmacyclics, 556 F. Supp. 3d at 406.
`We discern no error in that conclusion.
`3
`As to the obviousness of claim 2 of the ’090 patent, Al-
`vogen first challenges the district court’s finding that a
`skilled artisan would not have been motivated to treat R/R
`MCL with ibrutinib. Alvogen argues that “when claim 20
`of the ’015 patent discloses treating MCL with ibrutinib,”
`it necessarily discloses the treatment of R/R MCL. Appel-
`lant’s Br. 23. That argument runs headlong into the dis-
`trict court’s factual finding that “a disclosure of treating
`MCL with a drug” would not be interpreted by a skilled ar-
`tisan “as evidence that the drug would be effective at treat-
`ing R/R MCL.” Pharmacyclics, 556 F. Supp. 3d at 403 n.8.
`Alvogen also argues that the district court improperly
`discounted the disclosure in the December 2009 press re-
`lease that two R/R MCL patients had exhibited a partial
`response to ibrutinib. But given the small sample size, we
`are not persuaded that the district court clearly erred in
`finding that a skilled artisan “would not interpret th[o]se
`results as showing that ibrutinib could be used as a
`
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`Case: 21-2270 Document: 59 Page: 18 Filed: 11/15/2022
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`18
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`PHARMACYCLICS LLC v. ALVOGEN, INC.
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`treatment for R/R MCL,” particularly in view of the fact
`that “less than five percent of oncology drugs that enter a
`Phase I trial ultimately receive FDA approval.” Id. at 403.5
`Alvogen also argues that the district court failed to
`properly account for the admission in the ’015 patent that
`a “therapeutically effective amount” of ibrutinib could be
`determined using “routine experimentation.” See ’015 pa-
`tent, col. 21, ll. 49–52. The district court found, however,
`that a “typical 3+3 dose escalation study . . . would have
`reached the [maximum tolerated dose] as the dosage,”
`which for ibrutinib is “above 560 mg.” Pharmacyclics, 556
`F. Supp. 3d at 403. The district court further found that
`“[t]o reach the claimed dose of about 560 mg, an artisan
`would need to conduct a study using pharmacodynamic
`endpoints,” which Alvogen’s combination of references did
`not disclose. Id.