`
`Date Filed: November 20, 2020
`
`Filed On Behalf Of:
`Novartis Pharmaceuticals Corporation
`
`By:
`Nicholas N. Kallas
`nkallas@Venable.com
`(212) 218-2243
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`BIOCON PHARMA LIMITED,
`Petitioner,
`
`v.
`
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
`
`
`Case IPR2020-01263
`Patent 8,101,659
`
`
`
`NOVARTIS’S PATENT OWNER
` PRELIMINARY RESPONSE
`
`
`
`

`

`
`
`
`
`
`
`TABLE OF CONTENTS
`TABLE OF AUTHORITIES ................................................................................... iii
`TABLE OF ABBREVIATIONS .............................................................................. vi
`I.
`INTRODUCTION ........................................................................................... 1
`II.
`BACKGROUND ............................................................................................. 4
`The Prior Art ......................................................................................... 4
`1.
`EP ’072: Biocon improperly compares the heart failure
`model of EP ’072 Example 1(b) with the hypertension
`models in the Webb Declaration and ignores the failed
`hypertension model results of EP ’072 Example 2. .................... 4
`Gomez-Monterrey ..................................................................... 14
`2.
`The Claimed Invention ........................................................................ 15
`1.
`The ’659 Patent specification discloses the antihypertensive
`activity of sacubitril and valsartan and cites EP ’072. .............. 15
`The ’659 Patent’s parent application was allowed based on
`the Webb Declaration. .............................................................. 16
`The ’659 Patent was allowed based on the Webb Declaration. 19
`3.
`Claim Construction And The Person Of Ordinary Skill In The Art ... 21
`III. BIOCON’S PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM IS
`UNPATENTABLE ........................................................................................ 22
`The Board Should Deny Institution Under 35 U.S.C. § 325(d); Biocon
`Fails To Show The Examiner Erred In A Manner Material To
`Patentability In Finding Unexpected Results ...................................... 22
`1.
`The Examiner considered substantially the same art and/or
`arguments during prosecution (Becton factors (a), (b), (d)). .... 23
`Biocon has not established the Office erred in a manner
`material to patentability in finding unexpected results
`(Becton factors (c), (e), (f)). ...................................................... 27
`i
`
`2.
`
`2.
`
`
`
`
`
`

`

`
`
`a.
`
`
`
`b.
`
`Biocon does not challenge that the Webb Declaration
`reported synergistic antihypertensive results. ................ 28
`Biocon’s argument, that EP ’072 Example 1(b) reports
`a synergistic antihypertensive effect, lacks support and
`is factually incorrect. ...................................................... 28
`EP ’072 Example 2’s failed hypertension results
`further confirm the unexpectedness of the Webb
`Declaration data. ............................................................. 32
`Biocon’s remaining arguments similarly lack merit. ..... 35
`d.
`In Both Grounds 1 And 2, Biocon Fails To Show A Motivation To
`Combine .............................................................................................. 38
`1.
`Biocon’s motivation analysis based on Gomez-Monterrey is
`deficient. .................................................................................... 39
`a.
`Gomez-Monterrey explores NEP’s active site. .............. 40
`b.
`Gomez-Monterrey concludes that non-thiol inhibitors
`may be preferred to explore the structure of NEP (not
`for treatment) using distinct compounds (not SQ
`28603 or sacubitril). ........................................................ 41
`Gomez-Monterrey expressly contradicts Biocon’s
`assertion that thiol inhibitors would not be ideal for
`optimal recognition of the zinc ligand. ........................... 43
`The prior art, including Gomez-Monterrey, reports
`thiol inhibitors that are more potent than carboxylate
`inhibitors. ........................................................................ 44
`Biocon selects Ksander and the ’996 Patent without
`credible explanation. ....................................................... 45
`Biocon’s remaining Ground 2 motivation arguments are
`legally insufficient..................................................................... 47
`IV. CONCLUSION .............................................................................................. 50
`CERTIFICATE OF COMPLIANCE ....................................................................... 51
`
`c.
`
`c.
`
`d.
`
`e.
`
`2.
`
`ii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Cases
`3Shape A/S v. Align Tech., Inc.,
`IPR2020-00173, Paper 14 (PTAB June 12, 2020) ...................................... 39, 40
`Actavis LLC v. Abraxis Bioscience, LLC,
`IPR2017-01103, Paper 7 (PTAB Oct. 10, 2017) ................................................35
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`IPR 2019-01469, Paper 6 (PTAB Feb. 13, 2020) .................................. 23, 26, 27
`Amneal Pharm., LLC v. Supernus Pharm., Inc.,
`IPR2013-00368, Paper 8 (PTAB Dec. 17, 2013) ...............................................37
`Apotex Inc. v. Celgene Corp.,
`IPR2018-00685, Paper 8 (PTAB Sep. 27, 2018) ................................................35
`Argentum Pharm. LLC v. Novartis AG,
`IPR2016-01479, Paper 61 (PTAB Oct. 5, 2020) ......................................... 30, 31
`Ayla Pharma LLC v. Novartis AG,
`IPR2020-00295, Paper 12 (PTAB Aug. 6, 2020) ...............................................47
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ..........................................................................49
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ............................ 23, 27, 31, 37
`Boragen, Inc. v. Syngenta Participations AG,
`IPR2020-00124, Paper 18 (PTAB Aug. 10, 2020) .............................................36
`Cosmax Co. v. AmorePacific Corp.,
`IPR2018-01516, Paper 8 (PTAB Feb. 20, 2019) ......................................... 31, 37
`CSL Behring GmbH v. Bioverativ Therapeutics Inc.,
`IPR2018-01313, Paper 10 (PTAB Jan. 9, 2019) ................................... 31, 34, 37
`Dorco Co. v. Gillette Co.,
`IPR 2017-00500, Paper 7 (PTAB June 21, 2017) ..............................................25
`
`iii
`
`

`

`
`
`Fujian Sanan Grp. Co. v. Epistar Corp.,
`IPR2018-00963, Paper 9 (PTAB Nov. 20, 2018) ...............................................49
`Gilead Sciences, Inc. v. Regents of the Univ. of Minnesota,
`IPR2017-01753, Paper 42 at 25 (PTAB Apr. 22, 2020) ............................. 34, 36
`Gilead Sciences, Inc. v. United States,
`IPR2019-01453, Paper 14 (PTAB Feb. 20, 2020) ..............................................37
`GlaxoSmithKline LLC v. Fibrogen, Inc.,
`IPR2016-01315, Paper 11 (PTAB Jan. 11, 2017) ....................................... 30, 31
`I-MAK, Inc. v. Gilead Pharmasset LLC,
`IPR2018-00122, Paper 10 (PTAB May 21, 2018) .............................................48
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ..........................................................................48
`In re Huellmantal,
`324 F.2d 998 (C.C.P.A. 1963) ............................................................................33
`In re Wesslau,
`353 F.2d 238 (CCPA 1965) ......................................................................... 34, 36
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2018-00827, Paper 9 (PTAB Oct. 16, 2018) ................................................39
`Koios Pharm. LLC v. medac Gesellschaft für klinische Spezialpräparate mbH,
`IPR2016-01370, Paper 13 (PTAB Feb. 8, 2017) ................................................37
`LG Electronics, Inc. v. Wi-Lan Inc.,
`IPR2018-00704, Paper 14 (PTAB Sep. 5, 2018) ................................................36
`Milwaukee Elec. Tool Corp. v. Irwin Indus. Tool Co.,
`IPR2015-01461, Paper 39 (PTAB Sept. 29, 2016).............................................36
`Mylan Pharm Inc. v. AstraZeneca AB,
`IPR2016-01325, Paper 11 (PTAB Dec. 14, 2016) .............................................37
`PersonalWeb Techs., LLC v. Apple, Inc.,
`848 F.3d 987 (Fed. Cir. 2017) ............................................................... 46, 47, 49
`Quanergy Sys., Inc. v. Velodyne LiDAR, Inc.,
`IPR2018-00256, Paper 14 (PTAB May 25, 2018) .............................................38
`
`iv
`
`

`

`
`
`Stihl Inc. v. ElectroJet Techs., Inc.,
`IPR2018-00022, Paper 13 (PTAB Apr. 11, 2018) .............................................48
`Statutes
`35 U.S.C. § 314(a) ...................................................................................................39
`35 U.S.C. § 325(d) ........................................................................................... passim
`Other Authorities
`Office Trial Practice Guide, 77 Fed. Reg. 48,756 ...................................................36
`
`
`
`
`
`
`
`v
`
`

`

`
`
`1K1C dog
`’390 Patent
`’570 Application
`
`’578 Patent
`’659 Patent
`’868 Application
`
`’996 Patent
`AHU377
`ANP
`ANF
`Ang II
`ARB
`
`Biocon
`Böhm
`
`TABLE OF ABBREVIATIONS
`1-kidney-1-clip hypertensive dog
`
`U.S. Patent No. 7,468,390 (Ex. 1014)
`
`U.S. Patent Application No. 12/147,570, now the ’659
`Patent
`
`U.S. Patent No. 5,399,578 (Ex. 1008)
`U.S. Patent No. 8,101,659 (Ex. 1001)
`U.S. Patent Application No. 10/341,868, now the ’390
`Patent
`
`U.S. Patent No. 5,217,996 (Ex. 1009)
`
`Sacubitril
`
`atrial natriuretic peptide
`
`atrial natriuretic factor
`
`angiotensin II
`
`angiotensin-receptor blocker (also called AT 1-antagonist or
`Ang II antagonist)
`Biocon Pharma Limited
`Böhm et al., “DESENSITIZATION OF ADENYLATE
`CYCLASE AND INCREASE OF Giα IN CARDIAC
`HYPERTROPHY DUE TO ACQUIRED
`HYPERTENSION,” Hypertension, Vol. 20, No. 1, July
`1992, 103–12 (Ex. 2002)
`
`congestive heart failure
`
`CHF
`DSS rat
`Dahl salt-sensitive rat
`EP Patent Application No. 0726072A2 (Ex. 1002)
`EP ’072
`Gomez-Monterrey Gomez-Monterrey et al., “NEW THIOL INHIBITORS OF
`NEUTRAL ENDOPEPTIDASE EC 3.4.24.11:
`vi
`
`

`

`
`
`Ksander
`
`Lam Decl.
`LVEDP
`LVSP
`MAP
`Merriam-
`Webster’s
`
`NEP
`Novartis
`Pet.
`
`POSA
`SHRsp rat
`Tabrizchi Decl.
`Trippodo
`
`SYNTHESIS AND ENZYME ACTIVE-SITE
`RECOGNITION,” Journal of Medicinal Chemistry, Vol. 37,
`Issue 12, June 1, 1994, 1865–73 (Ex. 1005)
`Ksander et al., “DICARBOXYLIC ACID DIPEPTIDE
`NEUTRAL ENDOPEPTIDASE INHIBITORS,” Journal of
`Medicinal Chemistry, Vol. 38, Issue 10, May 1, 1995,
`1689–700 (Ex. 1006)
`
`Declaration of Prof. Y.W. Francis Lam (Ex. 1018)
`left ventricular end diastolic pressure
`left ventricular systolic pressure
`mean arterial pressure
`
`Merriam Webster’s Medical Dictionary (1995), cover page
`and pages 97, 174, 278, 308, 684 (Entries for
`cardiomyopathy, diastole, heart failure, hypertension, and
`systole) (Ex. 2001)
`
`neutral endopeptidase
`Novartis Pharmaceuticals Corporation
`Petition for Inter Partes Review of U.S. Patent No.
`8,101,659 filed by Biocon
`
`person of ordinary skill in the art
`
`stroke-prone spontaneously hypertensive rat
`
`Declaration of Dr. Reza Tabrizchi (Ex. 2004)
`
`Trippodo et al., “REPRESSION OF ANGIOTENSIN II
`AND POTENTIATION OF BRADYKININ
`CONTRIBUTE TO THE SYNERGISTIC EFFECTS OF
`DUAL METALLOPROTEASE INHIBITION IN HEART
`FAILURE,” Journal of Pharmacology and Experimental
`Therapeutics, Vol. 272, No. 2, February 1, 1995, 619–27
`(Ex. 1003)
`
`vii
`
`

`

`Roques
`
`Shetty
`
`Roques et al., “NEUTRAL ENDOPEPTIDASE 24.11:
`STRUCTURE, INHIBITION, AND EXPERIMENTAL
`AND CLINICAL PHARMACOLOGY,” Pharmacological
`Reviews, Vol. 45, Issue 1, March 1, 1993, 87–146 (Ex.
`1013)
`Shetty et al., “DIFFERENTIAL INHIBITION OF THE
`PREJUNCTIONAL ACTIONS OF ANGIOTENSIN II IN
`RAT ATRIA BY VALSARTAN, IRBESARTAN,
`EPROSARTAN, AND LOSARTAN,” Journal of
`Pharmacology and Experimental Therapeutics, Vol. 294,
`No. 1, July 1, 2000, 179–86 (Ex. 1004)
`
`Smits
`
`Smits et al., “EFFECT OF ENDOPEPTIDASE 24.11
`INHIBITION IN CONSCIOUS CARDIOMYOPATHIC
`HAMSTERS,” Journal of Pharmacology and Experimental
`Therapeutics, Vol. 254, No. 1, April 2, 1990, 176–79 (Ex.
`2003)
`Webb Declaration May 11, 2006 declaration under 37 C.F.R. § 1.132 of
`inventor Randy Lee Webb (Ex. 1015 at 884–919)
`
`
`
`
`
`
`
`viii
`
`

`

`
`
`I.
`
`INTRODUCTION
`Patent Owner Novartis Pharmaceuticals Corporation (“Novartis”)
`
`respectfully requests denial of Biocon Pharma Limited’s (“Biocon”) Petition for
`
`inter partes review of U.S. Patent No. 8,101,659 (“the ’659 Patent,” Ex. 1001).
`
`The ’659 Patent covers compositions comprising about a 1:1 ratio of
`
`valsartan (an angiotensin-receptor blocker (“ARB”) (also called an AT 1-
`
`antagonist)) and sacubitril (a neprilysin inhibitor (“NEP inhibitor”)), or their
`
`pharmaceutically acceptable salts.
`
`Biocon’s arguments are premised on self-evident misrepresentations of the
`
`prior art, particularly EP ’072 (Ex. 1002) and Gomez-Monterrey (Ex. 1005), and
`
`Biocon repeatedly fails to credibly support its allegations, leaving large
`
`unexplained gaps. As a result of these fundamental flaws that pervade both of
`
`Biocon’s Grounds, its challenge to the ’659 Patent cannot succeed for two
`
`independent reasons.
`
`First, the Board should exercise its discretion to deny institution under 35
`
`U.S.C. § 325(d). Biocon’s argument that the Examiner overlooked EP ’072 in
`
`finding unexpected results is premised on Biocon’s unsupported and erroneous
`
`interpretation of EP ’072, and fails to demonstrate that the Office erred in a manner
`
`material to patentability. Indeed, EP ’072, read as a whole, bolsters the unexpected
`
`
`
`1
`
`

`

`
`
`nature of the Webb Declaration synergistic antihypertensive results. Thus, it is
`
`Biocon, not the Office, that has erred.
`
`Biocon contends that the antihypertensive data in the May 11, 2006
`
`declaration under 37 C.F.R. § 1.132 of inventor Randy Lee Webb (“Webb
`
`Declaration”) (Ex. 1015 at 884–919) was expected in view of EP ’072, which
`
`according to Biocon, reported the “same synergistic effect.” Pet. at 5, citing Ex.
`
`1002, p. 2, ll. 29–31. The data Biocon compares are not, however, the same — far
`
`from it. The EP ’072 data in Example 1(b) that Biocon relies on was from a heart
`
`failure model and involves the cardiac parameters left ventricular end diastolic
`
`pressure (LVEDP) and left ventricular systolic pressure (LVSP). In contrast, the
`
`Webb Declaration reports blood pressure lowering data in hypertension models.
`
`Biocon makes no effort to explain how the EP ’072 data in a heart failure model,
`
`let alone LVEDP and LVSP data, has any relevance to the Webb Declaration’s
`
`blood pressure data, or why it would be appropriate to compare these data to
`
`evaluate unexpected results.
`
`Biocon’s failure to explain the relevance of EP ’072 Example 1(b) to
`
`hypertension is alone a sufficient basis to deny institution. But Biocon’s complete
`
`failure to acknowledge, let alone address, the blood pressure data in EP ’072
`
`Example 2 is even more damning. Example 2 reports blood pressure data in a
`
`hypertension model and shows that the ARB and NEP inhibitor combination tested
`
`2
`
`

`

`
`
`was no better at lowering blood pressure than the placebo (vehicle). Viewed
`
`against this prior art failure to lower blood pressure, the Webb Declaration’s
`
`synergistic blood pressure lowering results are all the more unexpected.
`
`Second, in arguing there was a motivation to combine, Biocon fails to
`
`advance any credible explanation for why a person of ordinary skill in the art
`
`(“POSA”) would (as opposed to could) have combined Ksander (Ex. 1006) or the
`
`’996 Patent (Ex. 1009) with Biocon’s other prior art. As confirmed by Novartis’s
`
`expert Dr. Reza Tabrizchi, Biocon’s only rationale is based upon a
`
`misunderstanding of Gomez-Monterrey (Ex. 1005), a reference that expressly
`
`contradicts Biocon’s arguments.
`
`Biocon’s additional Ground 2 arguments also fail. Biocon argues that it
`
`would be “obvious to try” combining valsartan with any other active compound
`
`with a different mechanism for treating hypertension, but Biocon fails to even
`
`argue that the possible options a POSA would have encountered were “finite,”
`
`“small,” or “easily traversed,” or “that skilled artisans would have had a reason to
`
`select the route that produced the claimed invention,” as the law requires. Biocon
`
`also argues it would have been obvious to combine two known compounds for
`
`their known function (especially when used to treat the same condition by different
`
`mechanisms), but Biocon fails to identify any reason why a person of ordinary skill
`
`would have chosen the ’996 Patent, as required under the law.
`
`3
`
`

`

`
`
`II.
`
`BACKGROUND
` The Prior Art
`Below, Novartis addresses the prior art most relevant to this preliminary
`
`patent owner response, EP ’072 (Ex. 1002) and Gomez-Monterrey (Ex. 1005).
`
`1.
`
`EP ’072: Biocon improperly compares the heart failure
`model of EP ’072 Example 1(b) with the hypertension
`models in the Webb Declaration and ignores the failed
`hypertension model results of EP ’072 Example 2.
`Heart failure and hypertension are different medical conditions. Heart failure
`
`concerns the heart muscle and an inability to maintain an adequate circulation of
`
`blood to the body, whereas hypertension concerns the blood vessels and is
`
`characterized by elevated blood pressure. See, e.g., Ex. 2001, Merriam-Webster’s
`
`at 278, 308. Both the ’659 Patent and EP ’072 differentiate between heart failure
`
`and hypertension.1 And, in particular, precisely because heart failure and
`
`hypertension are different conditions, the EP ’072 applicants used separate animal
`
`models to study how certain drugs affect each of these conditions. Example 1(b)
`
`
`1 Ex. 1002, EP ’072, e.g., at 2 (referencing “treating hypertension and/or
`
`congestive heart failure”); see also id. at claim 1; Ex. 1001, U.S. ’659, e.g., at 1
`
`(referencing a method for the treatment or prevention of “a condition or disease
`
`selected from the group consisting of hypertension, heart failure . . .”).
`
`4
`
`

`

`
`
`uses a cardiomyopathic hamster heart failure model, whereas Example 2 uses a 1-
`
`kidney-1-clip (1K1C) dog hypertension model. Ex. 1002, EP ’072 at 6–9 and 9–10.
`
`As discussed further below, Biocon without explanation improperly equates
`
`the cardiomyopathic hamster heart failure model of EP ’072 Example 1(b)
`
`(wherein the animals had low blood pressure and were not tested for blood
`
`pressure-lowering effect) with the rat hypertension models of the Webb
`
`Declaration (wherein the animals actually had high blood pressure and were tested
`
`for blood pressure-lowering effect). From this comparison, Biocon concludes that
`
`the Webb Declaration hypertension results were expected in view of the EP ’072
`
`Example 1(b) heart failure results. Biocon, however, fails to even recognize the
`
`differences between the different animal models and the different conditions they
`
`represent, let alone provide any explanation as to how the heart failure results
`
`could be relevant to blood pressure lowering in a hypertension model.
`
`Moreover, Biocon and its expert Dr. Lam completely ignore the data in EP
`
`’072 that is plainly most relevant to the Webb Declaration data — the failed results
`
`of the 1-kidney-1-clip (1K1C) dog hypertension model2 in EP ’072 Example 2
`
`
`2 Ex. 2002, Böhm at Abstract (discussing 1K1C animal model as a model of
`
`hypertension and not heart failure: “In membranes of hypertrophic hearts from rats
`
`with different forms of experimentally induced hypertension without heart failure
`
`5
`
`

`

`
`
`(wherein the animals had high blood pressure and were tested for blood pressure-
`
`lowering effect). Even though EP ’072 discloses that the combination of irbesartan
`
`and the selective or dual-acting NEP inhibitor is useful in treating two distinct
`
`conditions, hypertension and heart failure,3 this statement does not address synergy
`
`and cannot supplant the blood pressure data in Example 2, which plainly shows the
`
`combination had no blood pressure-lowering activity. Biocon ignores this EP ’072
`
`Example 2 data and fails to explain how or why the failure to lower blood pressure
`
`in EP ’072 Example 2 equates with Webb’s synergistic hypertension-lowering
`
`results.
`
`EP ’072 contains two Examples, testing the same drug combination: (1)
`
`Example 1(b), involving a heart failure animal model, and (2) Example 2,
`
`involving a hypertension animal model.
`
`
`(one kidney, one clip rats, deoxycorticosterone-treated rats, and rats with reduced
`
`renal mass)…”(emphasis added)).
`
`3 Ex. 1002, EP ’072 at p. 2, ll. 31–33 (“[T]he combination of this particular
`
`angiotensin II antagonist [irbesartan] and the selective or dual acting neutral
`
`endopeptidase inhibitor is useful in treating hypertension and/or congestive heart
`
`failure.”).
`
`6
`
`

`

`
`
`EP ’072 Example 1(b), heart failure: Example 1(b) was conducted in
`
`cardiomyopathic hamsters, a heart failure animal model. “These animals develop a
`
`genetic form of cardiomyopathy4 [disease of the heart muscle] that progresses
`
`uniformly among animals through different stages of heart failure.” Ex. 1002, EP
`
`’072 at p. 6, ll. 36–40 (emphasis added). These animals do not have hypertension
`
`(elevated blood pressure) and therefore are not hypertension models. “[T]he
`
`cardiomyopathic hamsters are characterized (as compared with control hamsters)
`
`by low mean arterial pressure” (id. at p. 6, ll. 39–43 (emphasis added)),5 and
`
`therefore do not have hypertension (elevated blood pressure).
`
`As Biocon’s expert Dr. Lam acknowledges (Ex. 1018, Lam Decl. ¶ 118), EP
`
`’072 Example 1(b) is based on the same work described more fully in Trippodo, a
`
`heart failure (not a hypertension) study. The Trippodo title evidences this:
`
`“Repression of Angiotensin II and Potentiation of Bradykinin Contribute to the
`
`
`4 Ex. 2001, Merriam-Webster’s at 97 (defining “cardiomyopathy” as “a typically
`
`chronic disorder of heart muscle that may involve hypertrophy and obstructive
`
`damage to the heart”).
`
`5 Ex. 1013, Roques at 128 (“[C]ardiomyopathic hamsters … have a significantly
`
`lower basal mean arterial pressure compared to normal hamsters (90 versus 135
`
`mmHg)”); see also Ex. 2003, Smits at Abstract.
`
`7
`
`

`

`
`
`Synergistic Effects of Dual Metalloprotease Inhibition in Heart Failure.” Ex.
`
`1003, Trippodo at 619 (emphasis added). Moreover, the purpose of Trippodo was
`
`to evaluate cardiovascular effects in cardiomyopathic hamsters with heart failure.
`
`Id. at 620.
`
`Both Example 1(b) and Trippodo describe a series of experiments in which
`
`LVEDP and LVSP were determined in cardiomyopathic hamsters. LVEDP is the
`
`pressure within the left ventricle of the heart following the completion of diastolic
`
`filling,6 just prior to systole7 (when the heart contracts and ejects its contents into
`
`the aorta). LVSP is the pressure in the left ventricle of the heart at any point prior
`
`to systole. Importantly, unlike with Example 2 (which is explained below), the EP
`
`’072 applicants did not measure blood pressure in Example 1(b), even though they
`
`had the ability to do so (as explained below for Example 1(a)).
`
`The Discussion of Results of Example 1(b) in EP ’072 states that:
`
`
`6 Ex. 2001, Merriam-Webster’s at 174 (defining “diastole” as “the passive
`
`rhythmical expansion or dilation of the cavities of the heart during which they fill
`
`with blood”).
`
`7 Ex. 2001, Merriam-Webster’s at 684 (defining “systole” as “the contraction of the
`
`heart by which the blood is forced onward and the circulation kept up”).
`
`8
`
`

`

`
`
`The combination of [irbesartan] and SQ 28603 produced
`cardiovascular effects that were greater than those with
`either treatment alone. Specifically, the combination
`caused significant decreases in left ventricular end
`diastolic pressure [LVEDP] and left ventricular systolic
`pressure [LVSP] with no significant change in heart rate.
`SQ 28603 produced
`smaller decreases, whereas
`[irbesartan] had no significant effects on the measured
`cardiovascular pressures. Thus, the combination of
`[irbesartan] and SQ 28603 produced beneficial
`hemodynamic effects in cardiomyopathic hamsters with
`compensated heart failure.
`
`Ex. 1002, EP ’072 at p. 9, ll. 22–27 (emphasis added). It is these LVEDP and
`
`LVSP results, which are also mentioned on page 2 of EP ’072 (p. 2, ll. 26–33),8
`
`that Biocon alleges show synergy. See Pet. at 27, 61. The “cardiovascular effects,”
`
`“hemodynamic effects” and “measured cardiovascular pressures” discussed on
`
`page 9 of EP ’072 (reproduced above) refer to LVEDP and LVSP; blood pressure
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`is not reported. EP ’072 Example 1(b) concludes that the combination “produced
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`beneficial hemodynamic effects in animals with compensated heart failure,”
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`8 Page 2 of EP ’072 refers to “cardiac preload” and “cardiac afterload,” terms that
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`Trippodo uses interchangeably with LVEDP and LVSP, respectively. Ex. 1003,
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`Trippodo at Abstract.
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`9
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`
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`which did not have elevated blood pressure (Ex. 1002, EP ’072 at p. 9, ll. 27–28
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`(emphasis added)); it does not conclude that the combination produced beneficial
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`effects in animals with hypertension (elevated blood pressure). And Biocon never
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`alleges that LVEDP or LVSP relate to blood pressure in heart failure or
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`hypertension, let alone explains the nature of that potential relationship, if any.
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`Here, there is no reason to consider whether LVEDP or LVSP serve as a surrogate
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`for blood pressure because Example 2 directly measures the blood pressure-
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`lowering effect of the drug combination and shows the combination is no different
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`from the placebo (vehicle).
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`Although EP ’072 and Trippodo disclose that the cardiomyopathic hamsters
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`had catheters placed that allowed measurement of mean arterial pressure (“MAP”),
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`which is the average blood pressure in a subject’s arteries (as was done in Example
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`1(a)) (Ex. 1002, EP ’072 at p. 6, l. 45 – p. 7, l. 25; Ex. 1003, Trippodo at 620),
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`blood pressures are not reported in Example 1(b) or the corresponding experiment
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`in Trippodo.9
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`9 Blood pressures are, however, measured and reported in Example 2. To
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`determine the amount of ARB to use in Example 1(b), Example 1(a) reports an
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`experiment where the ARB was administered alone (not in combination) and mean
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`10
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`EP ’072 Example 2, hypertension: In contrast to the heart failure
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`experiments in Example 1(b), EP ’072 Example 2 describes studies in an animal
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`model of hypertension, 1-kidney-1-clip (1K1C) hypertensive dogs. Example 2
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`discloses that the experiments “were conducted in dogs that had been rendered
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`hypertensive by prior unilateral nephrectomy and constriction of the remaining
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`renal artery.” Ex. 1002, EP ’072 at p. 9, ll. 31–32 (emphasis added). These animals
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`have hypertension.10 An arterial catheter was used “for measurement of blood
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`pressure” and “[m]ean arterial pressure (MAP) was continuously recorded….”
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`Ex. 1002, EP ’072 at p. 9, ll. 37–38 (emphasis added). Cardiac measurements such
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`as LVEDP and LVSP are not reported.
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`Example 2 reports data in hypertensive dogs that were administered one of
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`four treatments: (1) vehicle, (2) the NEP inhibitor SQ 28603 (30 µmol/kg), (3) the
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`ARB BMS186295 (irbesartan) (30 µmol/kg), and (4) the combination of irbesartan
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`(30 µmol/kg) and SQ 28603 (30 µmol/kg). Mean arterial pressure is reported in
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`Table 1 (blue labels added for clarity):
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`arterial pressure was reported. No other blood pressure data was reported in
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`Example 1. Ex. 1002, EP ’072 at 6–9.
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`10 See, e.g., Ex. 2002, Böhm at Abstract (describing a 1K1C rat model as having
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`“hypertension without heart failure”).
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`11
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`

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`Ex. 1002, EP ’072 at 10. Based on these data, the applicants concluded that while
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`“BMS 186295 [i.e., irbesartan] significantly reduced mean arterial pressure (MAP)
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`(Table 1) in the conscious 1K1C hypertensive dogs . . . [t]he effects of the
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`combination BMS 186295 [i.e., irbesartan] and SQ 28603 were not consistently
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`different from those of vehicle.” Ex. 1002, EP ’072 at p. 10, ll. 33–35 (emphasis
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`added). Thus, whereas irbesartan administered alone significantly reduced mean
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`arterial pressure in these hypertensive animals compared to the vehicle (see
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`asterisks), the combination of the ARB irbesartan and NEP inhibitor SQ 28603 was
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`no more effective at lowering blood pressure than the vehicle (0.84% sodium
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`bicarbonate), i.e., a placebo.
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`12
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`

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`Example 2 is the only example in EP ’072 to measure blood pressure-
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`lowering activity of a drug combination. Astonishingly, both Biocon and its expert
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`Dr. Lam failed to address Example 2 or its results, which demonstrate that the
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`combination of the ARB irbesartan and the NEP inhibitor SQ 28603 failed to lower
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`blood pressure compared to the placebo vehicle — let alone in a synergistic
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`manner. Thus, in arguing that EP ’072 discloses a synergistic antihypertensive
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`combination,11 Biocon and Dr. Lam either misunderstand or ignore the
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`hypertension teachings of EP ’072 Example 2.
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`Biocon and Dr. Lam similarly either misunderstand or mischaracterize the
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`teachings of Trippodo, by alleging it confirms the expectation that an AT 1-
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`11 See Pet. at 1–2 (citing Ex. 1018, Lam Decl. ¶¶ 112–18) (“EP ‘072 discloses the
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`combination of an AT-1 antagonist (i.e. irbesartan) and a NEP inhibitor (i.e. SQ
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`28603) in a 1:1 ratio and that this combination provides a synergistic
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`antihypertensive effect.”); Pet. at 4–5 (citing Ex. 1018, Lam Decl. ¶ 213) (same);
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`Pet. at 39 (citing Ex. 1018, Lam Decl. ¶ 154) (“EP ‘072 would have reasonably
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`suggested to a POSA that an AT 1-antagonist and a NEP inhibitor could be
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`successfully combined into a single pharmaceutical composition which provided
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`positive synergistic effects in hypertensive animals without any negative reported
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`effects.”); Pet. at 61–62 (citing Ex. 1018, Lam Decl. ¶ 232).
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`13
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`

`

`
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`antagonist and a NEP inhibitor could be successfully combined into a single
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`pharmaceutical composition that provided positive synergistic effects in
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`hypertensive animals.12 As discussed above, pp. 7–8, 10, Trippodo involved a heart
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`failure study that did not include hypertensive animals. The potential hypertension-
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`lowering effect, if any, of the combination was not even measured in Trippodo.
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`2. Gomez-Monterrey
`Gomez-Monterrey studies the enzyme neutral endopeptidase (“NEP”), also
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`known as neprilysin, which was thought to be involved in the metabolism of
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`various peptides. Ex. 2004, Tabrizchi Decl. ¶ 15; Ex. 1005, Gomez-Monterrey at
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`1865. The purpose of Gomez-Monterrey was to better understand the structure of
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`NEP’s active site using a series of new NEP inhibitors, not SQ 28603 or sacubitril.
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`Ex. 1005, Gomez-Monterrey at Title, Abstract, 1865–68; Pet. at 22, 31–32; Ex.
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`1018, Lam Decl. ¶¶ 87–88, 90, 127, 129; section III.B.1.a. While Gomez-
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`Monterrey is limited to evaluating NEP’s active site with this new series of NEP
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`inhibitors, the prior art reported over a hundred NEP inhibitors that were
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`individually identified. See, e.g., Ex. 2004, Tabrizchi Decl. ¶ 17; Ex. 1013, Roques
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`at 93–96.
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`12 See Pet. at 39 (citing Ex. 1018, Lam Decl. ¶ 154).
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`14
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`

`

`
`
`The Claimed Invention
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`The ’659 Patent specification discloses pharmaceutical compositions
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`comprising valsartan and sacubitril and their use to treat cardiovascular conditions
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`including hypertension and heart failure. Ex. 1001, ’659 Patent at Abstract, col. 10,
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`ll. 3–7. Representative Claim 1 of the ’659 Patent covers pharmaceutical
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`compositions of sacubitril and valsartan in a ratio of about 1:1. Id. at Claim 1.
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`1.
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`The ’659 Patent specification discloses the antihypertensive
`activity of sacubitril and valsartan and cites EP ’072.
`The ’659 Patent specification explains that valsartan is an angiotensin II type
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`1 receptor antagonist (ARB or Ang II antagonist) and cites U.S. Patent No.
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`5,399,578 (“the ’578 Patent,” Ex. 1008), which discloses that valsartan is an
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`antihypertensive agent. Ex. 1001, ’659 Patent at col. 3, ll. 30–53; Ex. 1008, ’578
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`Patent at col. 7, ll. 15–29. The specification explains that sacubitril is a neprilysin
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`(NEP) inhibitor and cites U.S. Patent No. 5,217,996 (“the ’996 Patent,” Ex. 1009),
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`which discloses sacubitril (among many NEP inhibi