`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`PHARMACYCLICS LLC,
`Patent Owner.
`
`__________________
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`__________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`
`I.
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`
`II.
`
`The Patented Invention .................................................................................... 4
`
`III. The Clinical Efficacy Limitations Must Be Given Patentable Weight ........... 5
`
`A.
`
`Legal Standard ....................................................................................... 6
`
`B.
`
`C.
`
`The Efficacy Limitations Here “Demand Efficacy” as Shown
`by the Claims and the Intrinsic Record ................................................. 8
`
`The Clinical Efficacy Limitations Are Not an Inherent or
`Intended Result .................................................................................... 12
`
`D. Once Given Patentable Weight, There Is Little Dispute as to
`Construction ........................................................................................ 15
`
`IV. Claims 6-8, 29-31, 44-46, and 51-53 Are Not Unpatentable at Least
`Because of their Claimed Clinical Efficacies ................................................ 16
`
`V.
`
`Claims 4, 13, and 15 (and claims depending therefrom), Directed to
`Treatment of Specific Patient Populations, Are Not Anticipated by
`the ’085 Publication ....................................................................................... 20
`
`VI. Claims 4, 13, and 15 (and claims depending therefrom), Directed to
`Treatment of Specific Patient Populations, Are Not Obvious....................... 22
`
`A. Ground 2: The ’085 Publication in View of a POSA’s
`Knowledge ........................................................................................... 22
`
`1.
`
`2.
`
`3.
`
`The ’085 Publication would not have motivated a POSA
`to treat steroid-resistant/refractory cGVHD with ibrutinib ...... 22
`
`Petitioner ignores the requirement for a reasonable
`expectation of success ............................................................... 24
`
`A POSA would not have reasonably expected success
`based on the limited disclosure of the ’085 Publication ........... 25
`
`B.
`
`Ground 3: The ’085 Publication in View of Shimabukuro-
`Vornhagen and Herman ...................................................................... 28
`
`i
`
`

`

`
`
`1.
`
`2.
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`None of the asserted references contain any in vitro,
`preclinical, or clinical data for ibrutinib in cGVHD ................. 30
`
`Shimabukuro-Vornhagen would not have given rise to a
`reasonable expectation of success ............................................. 31
`
`a.
`
`b.
`
`c.
`
`d.
`
`The role of B cells in cGVHD pathogenesis was
`complex and poorly understood ..................................... 31
`
`Rituximab and ibrutinib are fundamentally
`different drugs ................................................................. 33
`
`Drugs targeting both B and T cells presented safety
`concerns in cGVHD patients .......................................... 36
`
`Steroid-resistant/refractory cGVHD patients were
`notoriously difficult to treat and rituximab studies
`were met with skepticism ............................................... 38
`
`3.
`
`Herman’s disclosures regarding cytokines would not
`have given rise to a reasonable expectation of success ............ 41
`
`C.
`
`Ground 4: The ’085 Publication, Shimabukuro-Vornhagen, and
`Uckun .................................................................................................. 44
`
`1.
`
`Like the ’085 Publication and Shimabukuro-Vornhagen,
`Uckun does not contain any in vitro, preclinical, or
`clinical data for ibrutinib in cGVHD ........................................ 45
`
`2. Mouse models cannot establish a reasonable expectation
`of success for treating steroid-resistant/refractory
`cGVHD patients ........................................................................ 45
`
`3.
`
`4.
`
`Petitioner improperly conflates aGVHD with cGVHD
`and prophylaxis with treatment ................................................. 46
`
`LFM-A13 had not been shown to prevent or treat
`aGVHD ..................................................................................... 48
`
`VII. Claims 24, 28, 35, 39, 43, 50, and 55 Are Neither Anticipated nor
`Obvious at Least Because of Their 420 mg Daily Dose ............................... 50
`
`ii
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`VIII. Claim 1 Is Not Unpatentable, Thus All Challenged Claims Are Not
`Unpatentable .................................................................................................. 52
`
`A. Ground 1 Fails as to Claim 1 Because the ’085 Publication
`Does Not Enable Treatment of cGVHD with Ibrutinib ...................... 53
`
`B.
`
`Grounds 2-4 Fail as to Claim 1 Because No Reference, Alone
`or in Combination, Provides a Motivation to Treat cGVHD
`with Ibrutinib with a Reasonable Expectation of Success .................. 56
`
`IX. The Objective Indicia Compel a Finding of Nonobviousness ...................... 57
`
`A.
`
`B.
`
`There Is a Strong Nexus Between the Challenged Claims and
`the Objective Indicia of Nonobviousness ........................................... 57
`
`Substantial Industry Acclaim, Including from Petitioner’s
`Expert, Demonstrates Nonobviousness ............................................... 58
`
`C.
`
`The Claimed Methods Satisfied a Long-felt, Unmet Need ................. 61
`
`D.
`
`Failures of Others Negate Any Expectation of Success ..................... 63
`
`E.
`
`Ibrutinib Is Unexpectedly Effective in Treating cGVHD ................... 65
`
`X.
`
`Constitutional Challenge under Arthrex ........................................................ 66
`
`iii
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`
`
`Federal Cases
`
`Allergan Sales LLC v. Sandoz, Inc.,
`935 F.3d 1370 (Fed. Cir. 2019) ...................................................................passim
`
`Allergan, Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .................................................................. 7, 8, 12
`
`Arthrex, Inc. v. Smith & Nephew Inc.,
`941 F.3d 1320 (Fed. Cir. 2019) .......................................................................... 66
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .............................................................. 12, 13, 14
`
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .......................................................................... 21
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 63
`
`Eli Lilly & Co. v. Teva Parenteral Meds., Inc.,
`845 F.3d 1357 (Fed. Cir. 2017) .................................................................... 51, 52
`
`Endo Pharm. Inc. v. Depomed, Inc.,
`IPR2014-00654, Paper 69 (PTAB Sept. 21, 2015) ............................................. 59
`
`Ferring B.V. v. Watson Labs, Inc.,
`764 F.3d 1401 (Fed. Cir. 2014) .......................................................................... 63
`
`Ferrum Ferro Capital, LLC v. Allergan Sales, LLC,
`IPR2015-00858, Paper 10 (PTAB Sept. 31, 2015) ............................................... 7
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 52
`
`Gambro Lundia AB v. Baxter Healthcare Corp.,
`110 F.3d 1573 (Fed. Cir. 1997) .......................................................................... 59
`
`iv
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`Grunenthal GmbH v. Alkem Labs. Ltd.,
`919 F.3d 1333 (Fed. Cir. 2019) .......................................................................... 20
`
`Impax Labs., Inc. v. Aventis Pharm., Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .............................................................. 53, 55, 56
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge, Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 24
`
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 43
`
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) ............................................................................ 6
`
`LA Biomedical Research Inst. v. Eli Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) .............................................................. 7, 8, 9, 12
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................ 9
`
`Minton v. Nat’l Ass’n of Sec. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) ........................................................................ 8, 9
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 57
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .................................................................... 12, 14
`
`Mylan Labs, Ltd. v. Aventis Pharma S.A.,
`IPR2016-00712, Paper 112 (PTAB Oct. 22, 2019) ........................................ 7, 25
`
`Novartis Pharms. Corp. v. West-Ward Pharm. Int’l Ltd.,
`923 F.3d 1051 (Fed. Cir. 2019) ........................................................ 19, 28, 36, 41
`
`Nuvo Pharm. (Ireland) Designated Activity Co. v. Dr. Reddy’s Labs.
`Inc.,
`923 F.3d 1368 (Fed. Cir. 2019) ............................................................................ 9
`
`OSI Pharm., LLC v. Apotex Inc.,
`939 F.3d 1375 (Fed. Cir. 2019) ..................................................19, 28, 43, 56, 57
`
`v
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ............................................................................ 35
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 13
`
`PPG Indus., Inc. v. Guardian Indus. Corp.,
`75 F.3d 1558 (Fed. Cir. 1996) ............................................................................ 20
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) .......................................................................... 55
`
`Sanofi v. Lupin Atlantis Holdings S.A.,
`No. 15-415, 2016 WL 5842327 (D. Del. Oct. 10, 2016) .................................... 16
`
`US Endodonics, LLC v. Gold Standard Instruments, LLC,
`IPR2015-00632, Paper 29 (PTAB Aug. 5, 2015) ........................................... 9, 10
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .............................................................. 57, 58, 61
`
`Federal Statutes
`
`21 U.S.C. § 356 ........................................................................................................ 63
`
`
`
`
`
`
`vi
`
`

`

`
`
`GLOSSARY
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`’604 patent
`
`U.S. Patent No. 9,795,604
`
`aGVHD
`
`Acute graft versus host disease
`
`ANDA
`
`Abbreviated New Drug Application
`
`BTK
`
`Bruton’s tyrosine kinase
`
`cGVHD
`
`Chronic graft versus host disease
`
`CLL
`
`FDA
`
`HCT
`
`IFNγ
`
`Chronic lymphocytic leukemia
`
`Food and Drug Administration
`
`Hematopoietic cell transplantation
`
`Interferon gamma
`
`IL-1, IL-4, IL-6,
`IL-10
`
`Interleukin 1, Interleukin 4, Interleukin 6,
`Interleukin 10
`
`IL-6R
`
`IPR
`
`Interleukin 6 receptor
`
`Inter partes review
`
`Italicized text
`
`Emphasis added unless otherwise indicated
`
`ITK
`
`JAK2
`
`kDa
`
`MMF
`
`MTX
`
`Interleukin-2-inducible T cell kinase
`
`Janus kinase 2
`
`Kilodalton
`
`Mycophenolate mofetil
`
`Methotrexate
`
`vii
`
`

`

`
`
`NIH
`
`Office
`
`National Institutes of Health
`
`United States Patent and Trademark Office
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`Patent Owner
`
`Pharmacyclics LLC
`
`Petitioner
`
`Sandoz Inc.
`
`PLK
`
`POSA
`
`TNFα
`
`Polo-like kinase
`
`Person of ordinary skill in the art
`
`Tumor necrosis factor alpha
`
`
`
`viii
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`I.
`
`Introduction
`
`The ’604 patent teaches that ibrutinib, a small molecule kinase inhibitor,
`
`successfully treats chronic graft versus host disease (“cGVHD”). The patent
`
`describes and claims treatment of the most difficult-to-treat patients (those with
`
`steroid-resistant/refractory disease), the achievement of specific clinical efficacies,
`
`and an effective daily dosing regimen.
`
`cGVHD is a devastating complication of allogeneic stem cell transplant,
`
`resulting in severe harm to the body’s tissues and organs, with a 50% risk of
`
`mortality within the first five years after diagnosis. EX2006, 1-2. At the time of
`
`invention, there was no FDA-approved treatment for cGVHD and no satisfactory
`
`long-term treatment, particularly for the many patients resistant to steroids. EX2004,
`
`9-10; EX2005, 33.
`
`The challenges of treating cGVHD were universally recognized. Indeed,
`
`Petitioner’s expert, Dr. Ferrara, characterized treating cGVHD as akin to “three-
`
`dimensional chess”—“one of the most challenging scenarios, not only in transplant
`
`medicine, but in all of medicine.” EX2045, 2; EX2056, 91:16-92:20.
`
`Numerous interventions had been tested for cGVHD, including about 40
`
`drugs in steroid-resistant/refractory patients and many more in animal models.
`
`EX2059, 204; EX2056, 222:13-223:13. But, as Dr. Ferrara conceded, “[d]espite
`
`dozens of trials, nothing has ever worked.” EX2045, 2. He testified that while “so
`
`1
`
`

`

`
`many” therapies had appeared promising in animals, those had not “borne fruit” in
`
`the clinic. EX2056, 150:24-151:4. He explained that “GVHD is where new drugs
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`go to die.” Id., 38:19-39:24; EX2046, 1.
`
`The grounds that Petitioner cobbles together do not suggest that ibrutinib
`
`would have been any different. The ’085 Publication, Petitioner’s lead reference, is
`
`directed to delayed-release ibrutinib formulations that could theoretically bypass
`
`absorption in the stomach. It merely speculates, in a laundry list of over 150 widely
`
`varying diseases, that ibrutinib could be used to treat GVHD—failing to disclose
`
`any relevant data for any disease. The other references either fail to disclose
`
`ibrutinib at all (Shimabukuro-Vornhagen) or fail to disclose its use in treating
`
`cGVHD (Herman, Uckun). Thus, despite the background of failures and, as Dr.
`
`Ferrara characterized it, the “Stone Age” state of the art (EX2056, 21:20-22:19),
`
`Petitioner identified no in vitro, preclinical, or clinical investigation of ibrutinib or
`
`structurally similar compounds, in treating cGVHD.
`
`Given these deficiencies, and for at least the following reasons, the Board
`
`should find that the challenged claims have not been shown to be unpatentable.
`
`First, the Board incorrectly ignored the claimed efficacy limitations during
`
`institution on grounds they “do not affect the manner in which ibrutinib is
`
`administered.” Decision, 8. Because treatment is the core of the invention, Federal
`
`Circuit precedent requires that these efficacy limitations be given patentable weight.
`
`2
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`Once properly considered as substantive limitations, the Board must dismiss
`
`Petitioner’s challenges to the twelve claims reciting specific and measurable efficacy
`
`limitations (claims 6-8, 29-31, 44-46, and 51-53), as Petitioner’s only argument
`
`depends on improperly removing those limitations from the analysis.
`
`Second, the Board should find that the fifteen claims directed to steroid-
`
`resistant/refractory patients (claims 4, 13, 15, 28-31, 43-46, and 50-53) are not
`
`unpatentable. The Board correctly determined at institution that these claims were
`
`not anticipated by the ’085 Publication. Decision, 20-21. The Board should likewise
`
`find that the full record does not support Petitioner’s obviousness challenges to these
`
`claims, as the trial evidence establishes the unpredictability and difficulty in treating
`
`these immunocompromised patients. As Patent Owner’s expert Dr. Koreth
`
`(EX2055, ¶¶1-13, 68-70, 254-256) explains, Petitioner’s theories are untethered to
`
`the basic realities of drug development and wholly unsupported in the historical
`
`context of cGVHD: in this field, a POSA would not have been motivated to pursue,
`
`and would not have reasonably expected success, based on preliminary studies
`
`involving an entirely different type of drug, having an entirely different mechanism
`
`of action, and exhibiting what Petitioner’s expert admitted was a different “kind” of
`
`effect on B cells (EX2056, 132:5-23).
`
`Third, the Board should reject all of Petitioner’s challenges because, as the
`
`full record establishes, the ’085 Publication central to all four Grounds does not
`
`3
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`enable treatment of cGVHD. The ’085 Publication is a formulation reference and
`
`provides no enabling teaching with respect to any of the 150 diseases it mentions,
`
`much less treatment for a condition as complex and daunting as cGVHD.
`
`Finally, the objective indicia compel a finding of nonobviousness.
`
`Imbruvica® (ibrutinib) was the first drug approved for treating cGVHD and was
`
`widely recognized by both medical leaders and Petitioner’s expert as an “important
`
`advance” over prior options. EX2044, 2. Indeed, Dr. Ferrara admits that use of
`
`Imbruvica® (ibrutinib) for cGVHD, which embodies the claimed methods, achieves
`
`“remarkable” results, with “very high and extremely encouraging” response rates.
`
`EX2045, 2; EX2044, 2.
`
`II. The Patented Invention
`
`The ’604 patent discloses and claims methods of treating cGVHD by
`
`administering a therapeutically effective amount of ibrutinib. EX1001; EX2055,
`
`¶¶52-67. The specification explains that cGVHD is a leading cause of non-relapse
`
`mortality following allogeneic stem cell transplant. EX1001, 1:29-46; EX2055, ¶53.
`
`There was a dearth of suitable treatments, particularly for steroid-resistant patients,
`
`before development of the claimed methods. EX1001, 67:52-57; EX2055, ¶52.
`
`The specification discloses both pre-clinical and clinical data demonstrating
`
`ibrutinib’s efficacy in treating cGVHD. EX1001, 63:60-74:23; EX2055, ¶54.
`
`Example 2, a mouse model, and Example 3, an in vitro study of cells from a cGVHD
`
`4
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`patient, describe ibrutinib’s inhibitory effect on B and T cell activation in cGVHD.
`
`EX1001, 63:60-66:42. The studies “confirmed a dramatic therapeutic response to
`
`ibrutinib which allowed for complete resolution of cGVHD.” Id., 64:26-30;
`
`EX2055, ¶55.
`
`Examples 6 and 7 provide clinical data supporting ibrutinib’s efficacy in
`
`cGVHD. EX2055, ¶56. Example 6 describes treatment of a post-HCT patient with
`
`refractory CLL and cGVHD. EX1001, 73:23-28; Figure 8. Despite extensive
`
`rituximab treatment as well as steroid therapy, the patient’s cGVHD persisted.
`
`EX1001, 72:23-73:12. After enrollment in a clinical trial to treat his CLL with
`
`ibrutinib, the patient achieved a complete response for cGVHD. Id., 73:16-28;
`
`EX2055, ¶¶56-57. Similar results are shown in Example 7, where treatment with
`
`ibrutinib rendered a patient’s CLL undetectable and resolved the patient’s cGVHD,
`
`with responses sustained even after ibrutinib discontinuation. EX1001, 73:63-74:22;
`
`EX2055, ¶58.
`
`III. The Clinical Efficacy Limitations Must Be Given Patentable
`Weight
`
`The Petition incorrectly disregarded multiple efficacy limitations, leading the
`
`Board to err in its Institution Decision. Pet., 15-17, 39-40; Decision, 7-9. Under
`
`Federal Circuit precedent, these limitations are central to the claimed methods and
`
`must be given patentable weight.
`
`5
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`1
`
`55
`
`Claim Term
`“A method of treating chronic graft versus host disease (GVHD) comprising
`administering to a patient having chronic GVHD a therapeutically effective
`amount of [ibrutinib] thereby treating the chronic GVHD in the patient.”
`“A method of treating chronic graft versus host disease (GVHD) comprising
`administering to a patient having chronic GVHD about 420 mg/day of
`[ibrutinib].”
`“The method of claim [1, 4, 13, 15] wherein, following administration of the
`compound, the patient achieves partial response (PR), wherein the PR is an
`objective response in one involved organ in the patient with no evidence of
`progression elsewhere and no requirements for additional systemic
`therapy.”
`“The method of claim [1, 4, 13, 15] wherein, following administration of the
`compound, the patient achieves complete response (CR), wherein the CR is
`a complete restoration of symptoms attributable to GVHD.”
`
`6, 29,
`44, 51
`
`7, 30,
`45, 52
`
`
`
`
`
`8, 31,
`46, 53
`
`“The method of claim [1, 4, 13, 15] wherein, following administration of the
`compound, the severity of the GVHD is reduced.”
`
`A. Legal Standard
`
`Clinical efficacy clauses in method of treatment claims must be given
`
`patentable weight when, as here, “they are material to patentability and express the
`
`inventive aspect of the claimed invention.” Allergan Sales LLC v. Sandoz, Inc., 935
`
`F.3d 1370, 1373-76 (Fed. Cir. 2019). This is true for both “method of treating”
`
`preambles, as well as “wherein” and “whereby” clauses that require achievement of
`
`particular clinical efficacies. Id. at 1376; Jansen v. Rexall Sundown, Inc., 342 F.3d
`
`1329, 1333 (Fed. Cir. 2003).
`
`Numerous precedential decisions in pharmaceutical cases with claims
`
`substantially similar to those here require that efficacy limitations be given
`
`6
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`patentable weight. For example, in Allergan Sales, the Federal Circuit held that
`
`limitations reciting an “effective” method that “reduces the incidence of” disease
`
`must be given patentable weight because the intrinsic record demonstrated “they are
`
`material to patentability and express the inventive aspect of the claimed invention.”
`
`935 F.3d at 1373-76. Similarly, in LA Biomedical, the Federal Circuit held that a
`
`claim limitation specifying “arresting or regressing” disease must be given
`
`patentable weight because it did not “merely duplicate” the claimed method but
`
`instead “demands efficacy.” LA Biomedical Research Inst. v. Eli Lilly & Co., 849
`
`F.3d 1049, 1061-62 (Fed. Cir. 2017); see also Allergan, Inc. v. Sandoz, Inc., 726
`
`F.3d 1286, 1294 n.1 (Fed. Cir. 2013) (construing limitation requiring no “loss of
`
`efficacy” to have patentable weight).
`
`The Board has likewise correctly given analogous efficacy limitations
`
`patentable weight. See, e.g., Mylan Labs, Ltd. v. Aventis Pharma S.A., IPR2016-
`
`00712, Paper 112, at 12-14 (PTAB Oct. 22, 2019) (petitioner required to show
`
`reasonable expectation of success in achieving the method’s purpose in the recited
`
`patient population); Ferrum Ferro Capital, LLC v. Allergan Sales, LLC, IPR2015-
`
`00858, Paper 10, at 5-8 (PTAB Sept. 31, 2015) (giving patentable weight to clause
`
`specifying “without loss of efficacy”).
`
`Respectfully, the Institution Decision improperly disregarded these efficacy
`
`limitations, citing a single, sixteen-year-old case about computerized securities
`
`7
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`trading systems. Decision, 8 (citing Minton v. Nat’l Ass’n of Sec. Dealers, Inc., 336
`
`F.3d 1373, 1381 (Fed. Cir. 2003)). In Minton, the claim phrase at issue, “whereby
`
`the security is traded efficiently,” did nothing to further define or limit the claimed
`
`methods of trading securities—it was merely “laudatory,” and “nothing in the
`
`specification or prosecution history suggest[ed]” it was central to defining the
`
`claimed methods. 336 F.3d at 1381. The Federal Circuit recently explained that
`
`Minton does not apply in the pharmaceutical context when, as here, the clinical
`
`efficacy limitations reflect the essence of the invention and define the claimed
`
`methods. See Allergan Sales, 935 F.3d at 1379 (J. Prost, concurring).
`
`Similarly, the Board erred in stating that the claimed efficacy limitations can
`
`be disregarded because they “do not affect the manner in which ibrutinib is
`
`administered to treat cGVHD.” Decision, 8. In none of LA Biomedical, Allergan v.
`
`Sandoz, or Allergan Sales did the recited results affect how the drug was being
`
`administered, yet in every instance these efficacy limitations were given patentable
`
`weight. See 849 F.3d at 1061-62; 726 F.3d at 1294 n.1; 935 F.3d at 1373-76. The
`
`same result should apply here.
`
`B.
`
`The Efficacy Limitations Here “Demand Efficacy” as
`Shown by the Claims and the Intrinsic Record
`
`As in LA Biomedical, the clinical efficacy limitations here “demand[]
`
`efficacy.” 849 F.3d at 1061. The language of the claims makes this clear: they do
`
`8
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`not merely recite a method of administering ibrutinib to patients with cGVHD, but
`
`instead recite narrower methods of administering drug in “a therapeutically effective
`
`amount” sufficient to “treat” the cGVHD. EX2055, ¶86. See, e.g., Nuvo Pharm.
`
`(Ireland) Designated Activity Co. v. Dr. Reddy’s Labs. Inc., 923 F.3d 1368, 1378
`
`(Fed. Cir. 2019) (“[I]t is nonsensical to read the claims to require effective amounts
`
`[] without specifying the result effectively achieved.”); Merck & Co. v. Teva Pharm.
`
`USA, Inc., 395 F.3d 1364, 1372 (Fed. Cir. 2005) (“A claim construction that gives
`
`meaning to all the terms of the claim is preferred over one that does not.”).
`
`Moreover, the claimed methods accomplish specifically recited and
`
`measurable clinical efficacies of “partial response,” “complete response,” and
`
`“reduced severity.” EX2055, ¶¶83-85; EX2056, 199:16-200:20. These specific,
`
`quantifiable measures are defined in the specification by established NIH consensus
`
`criteria for treating cGVHD (EX1001, 71:42-67; see also EX2048) and serve to
`
`define and limit the claimed method. See Allergan Sales, 935 F.3d at 1379 (J. Prost,
`
`concurring) (“On their face, these clauses state specific requirements rather than a
`
`general purpose or aspirational result for the claimed method.”); LA Biomedical, 849
`
`F.3d at 1061 (the efficacy clause “does not merely duplicate” other aspects of the
`
`claim); US Endodonics, LLC v. Gold Standard Instruments, LLC, IPR2015-00632,
`
`Paper 29, at 12 (PTAB Aug. 5, 2015) (“[U]nlike the merely laudatory term to which
`
`9
`
`

`

`
`the court declined to give weight in Minton, the ‘wherein’ clause in this case sets
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`forth a specific, quantitative test.”).
`
`The specification and prosecution history confirm the importance of the
`
`clinical efficacy limitations. EX2055, ¶¶77-82. The specification explains the
`
`seriousness of cGVHD (EX1001, 1:29-46; 28:48-29:51); that existing treatments are
`
`ineffective (id., 28:57-59); and that ibrutinib effectively treats the disease (id., e.g.,
`
`40:55-64; 42:29-33). EX2055, ¶79; see also id., ¶¶52-59. The specification
`
`distinguishes “treatment” from “prophylaxis” (EX1001, 38:38-45) and provides
`
`specific, NIH consensus criteria for measuring the claimed patient responses,
`
`disclosing treatment of a previously intractable condition. Id., 71:42-67; see also
`
`EX2023, 4-5; EX2055, ¶79. The specification touts the efficacy of the claimed
`
`methods over the prior art, including the specific efficacy limitations of the
`
`dependent claims. For example, Example 6 features a clinical case study where a
`
`patient experienced rapidly progressive disease when treated with prior art therapies,
`
`but when treated with ibrutinib his cGVHD completely resolved. EX1001, 72:2-
`
`73:28; EX2055, ¶¶56-57.
`
`Moreover, during prosecution, the applicant specifically relied on the claimed
`
`efficacy limitations to obtain the ’604 patent. EX2055, ¶¶81-82. See Allergan Sales,
`
`935 F.3d at 1373-76 (relying on prosecution history when giving efficacy limitations
`
`patentable weight). The examiner rejected the original claims, which encompassed
`
`10
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`both prevention and treatment of cGVHD, asserting the specification was enabling
`
`only for methods that treat cGVHD. EX1021, 7. The applicant overcame that
`
`rejection by amending the claims to delete prevention and focus only on treatment—
`
`in other words, focusing the claims specifically on clinical efficacy for patients
`
`already experiencing cGVHD.1 EX1009, 2-3, 6; EX2030, 3. Subsequently, the
`
`applicant added additional terms further limiting the claimed methods, specifying
`
`particular required clinical outcomes: partial response, complete response, and
`
`reduction in severity. EX2058, 3-6. The Examiner deemed these claims allowable
`
`because the prior art did not “teach or suggest the claimed methods.” EX2029, 7.
`
`Together, the claim language, specification, and prosecution history
`
`demonstrate that the preamble and “wherein” limitations “were expressly relied on
`
`to define the claimed methods and distinguish them from the prior art.” Allergan
`
`Sales, 935 F.3d at 1376.
`
`
`1 The Board erred by failing to recognize that the claims are limited to treating
`
`cGVHD. This error affected its obviousness analysis. See Decision, 41; infra §
`
`VI.C.3.
`
`11
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`
`C. The Clinical Efficacy Limitations Are Not an Inherent or
`Intended Result
`
`Petitioner incorrectly relies on an unsupported theory of “inherency” in an
`
`attempt to discount the clinical efficacy limitations. E.g., Pet., 15, 34-35, 37, 40, 50.
`
`Petitioner relies on Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d
`
`1368, 1375 (Fed. Cir. 2001) and In re Montgomery, 677 F.3d 1375, 1381 (Fed. Cir.
`
`2012) to argue that the clinical efficacy limitations are merely the “intended” or
`
`“inherent” result of the claimed methods and can therefore be disregarded in the
`
`validity analysis.
`
`Courts consider inherency in evaluating whether claim terms should be given
`
`patentable weight—repeatedly finding that non-inherent efficacy limitations should
`
`be given patentable weight. See, e.g., LA Biomedical, 849 F.3d at 1061 (efficacy
`
`clause deserving of patentable weight because it differed from cases “in which
`
`efficacy is inherent in carrying out the claim steps”); Allergan, 726 F.3d at 1294 n.1
`
`(“The evidence of record does not establish that the … efficacy limitation is an
`
`inherent property or a necessary result of the [claimed administration].”); Allergan
`
`Sales, 935 F.3d at 1378 (J. Prost, concurring) (“Sandoz has put forth no evidence
`
`how either clause ‘merely states the result of the limitations in the claim.’”).
`
`Here, Petitioner’s assertions of inherency are entirely conclusory and should
`
`be rejected. Petitioner simply asserts, citing no evidence, that “administering a
`
`12
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`therapeutically effective amount of ibrutinib to a patient with chronic GVHD
`
`inherently and necessarily treats the disease” (Pet., 34) and that “the patient
`
`outcomes recited in [the] dependent claims are an inherent and necessary effect of
`
`administering a therapeutically effective amount of ibrutinib to a patient with
`
`chronic GVHD” (Pet., 40). These unsupported assertions cannot carry Petitioner’s
`
`burden, particularly since the ’085 Publication’s formulations are prophetic and had
`
`not been made or tested, much less shown to necessarily treat any disease. See
`
`generally EX1002; EX2055, ¶¶91-92.
`
`Moreover, the record establishes that the claimed clinical efficacy limitations
`
`are not inherent to administering ibrutinib, with some patients showing no response,
`
`some patients achieving a PR, and some patients achieving a CR. See § IX.C., infra;
`
`EX2023, 3-4, Fig. 1; EX2056, 25:23-27:19 (“Imbruvica does not produce either a
`
`partial or a complete resolution of all GVHD symptoms in every patient.”); EX2055,
`
`¶¶87-88, 142. The mere fact that a particular response may result is insufficient to
`
`est