A u g u s t 1 0 , 2 0 2 2
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`IPR2021-00880, -00881
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`U . S . P a t e n t N o s . 9 , 6 6 9 , 0 6 9 & 9 , 2 5 4 , 3 3 8
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`1
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`DEMONSTRATIVE EXHIBIT
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`Demonstrative Exhibit 2290
`Page 01 of 57
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`IPR2021-00880, -00881
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`U . S . P a t e n t N o s . 9 , 6 6 9 , 0 6 9 & 9 , 2 5 4 , 3 3 8
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`1
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`DEMONSTRATIVE EXHIBIT
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`Demonstrative Exhibit 2290
`Page 01 of 57
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`Overview
`• VEGF Trap-Eye: All Grounds, All Claims
`• IPR2021-00880—U.S. Patent No. 9,669,069
`• Ground 4 – All Claims: No Anticipation or Obviousness Based on Dixon’s
`Disclosure of VIEW Dosing Regimen
`• Ground 5 – Claim 8: No Anticipation or Obviousness Based on Heier-2009 in view
`of Mitchell or Dixon
`• IPR2021-00881—U.S. Patent No. 9,234,338
`• Claim Construction
`• Grounds 1-5 – All Claims: No Anticipation Based on Lack of “Treatment” Disclosure
`• Ground 6 – All Claims: No Obviousness Based on Prospective VIEW Dosing
`Regimen
`
`2
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`DEMONSTRATIVE EXHIBIT
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`VEGF Trap-Eye
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`3
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`DEMONSTRATIVE EXHIBIT
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`
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`Petitioner’s Grounds Do Not Disclose the Recited Amino
`Acid or Nucleic Acid Sequences
`
`Dixon Ex.1006
`
`Regeneron (28-April-2009)
`Ex.1028
`880 POR at 10-11; 880 Sur-reply at 5; 881 POR at 25-26; 881 Sur-reply at 14; 880 ID at 37; Ex.2129 at 109:15-110:3; Ex.2130 at 341:13-16; Ex.2049 at
`Section IX; Ex.2048 at Section X; Ex.1115 at ¶35
`
`Heier-2009 Ex.1020
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`4
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`DEMONSTRATIVE EXHIBIT
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`Petitioner’s Grounds Do Not Disclose the Recited Amino
`Acid or Nucleic Acid Sequences
`
`Regeneron (8-May-2008)
`Ex.1013
`881 POR at 25-26; 881 Sur-reply at 14; Ex.2129 at 109:15-110:3; Ex.2130 at 341:13-16; Ex.2049 at Section IX; Ex.2048 at Section X; Ex.1115 at ¶35
`
`NCT-795 Ex.1014
`
`NCT-337 Ex.1015
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`5
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`Petitioner’s Grounds Do Not Disclose the Recited Amino
`Acid or Nucleic Acid Sequences
`
`Dr. Gerritsen
`Petitioner’s Expert
`“Petitioner’s cited
`reference do not include a
`verbatim recitation of the
`amino acid sequence ….”
`Ex.1115 at ¶ 35.
`
`Dr. Albini
`Petitioner’s Expert
`Q: “Does Dixon provide
`any n[]ucleic acid or amino
`acid sequence information
`for any molecule? … A.
`Not directly.” Ex.2130 at
`341:13-16.
`
`“[W]e acknowledge that [Heier-
`2009] discloses only that ‘VEGF
`Trap-Eye is a purified formulation
`of VEGF Trap’.” ’880 ID at 37.
`
`6
`
`880 POR at 10-11, 880 Sur-reply at 5; 881 POR at 25-26; 881 Sur-reply at 14; 880 ID at 37; Ex.2129 at 109:15-110:3; Ex.2130 at 341:13-16; Ex.2049 at
`Section IX; Ex.2048 at Section X; Ex.1115 at ¶35
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`Inherency Requires That a Missing Limitation Necessarily Be
`Present
`
`•
`
`•
`
`“[A]nticipation by inherent disclosure is appropriate only when the
`reference discloses prior art that must necessarily include the
`unstated limitation.” Rexnord Indus., LLC v. Kappos, 705 F.3d
`1347, 1355 (Fed. Cir. 2013).
`“Inherency … may not be established by probabilities or
`possibilities.” Bettcher Indus., Inc. v. Bunzl USA, Inc., 661 F.3d
`629, 639 (Fed. Cir. 2011).
`
`7
`
`880 POR at 10-12; 880 Sur-reply at 5-6; 881 POR at 26; 881 Sur-reply at 14, 17
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`Multiple Sequences Could Satisfy Dixon’s Description of VEGF
`Trap-Eye
`
`Dixon, Ex.1006
`880 POR at 15-16, 18-20; 880 Sur-reply at 13-15; 881 POR at 30-33; 881 Sur-reply at 15-16, 21-24; Ex.1006 at 1576; Ex.1010 at 10:3-18, 26:5-20; Ex.2049 at ¶¶ 67-89;
`Ex.1033; Ex.2009; Ex.1008; Ex.1022; Ex.1023; Ex.1039; Ex.2288 at 16:3-7, 132:7-133:6, 142:6-20, 21:6-23, 27:9-28:8, 24:25-26:2, 95:17-19, 129:11-20, 127:4-13
`
`8
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`Multiple VEGF TrapR1R2 Molecules Were Disclosed in the Art
`
`• Both Flt1D2.Flk1D3.Fc∆C1(a) and
`VEGFR1R2-Fc∆C1(a) are chimeric
`molecules identified as “R1R2” in the prior
`art
`• Both Flt1D2.Flk1D3.Fc∆C1(a) and
`VEGFR1R2-Fc∆C1(a) satisfy the structural
`description set forth in Dixon
`
`9
`
`880 POR at 15-16, 18-20; 880 Sur-reply at 13-15; 881 POR at 30-33; 881 Sur-reply at 15-16, 21-24; Ex.1006 at 1576; Ex.1010 at 10:3-18, 26:5-20; Ex.2049 at ¶¶ 67-89;
`Ex.1033; Ex.2009; Ex.1008; Ex.1022; Ex.1023; Ex.1039; Ex.2288 at 16:3-7, 132:7-133:6, 142:6-20, 21:6-23, 27:9-28:8, 24:25-26:2, 95:17-19, 129:11-20, 127:4-13
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`Multiple VEGF TrapR1R2 Molecules Correspond to Dixon’s
`Structural Description of VEGF Trap-Eye
`
`But Flt1D2.Flk1D3.Fc∆C1(a) and VEGFR1R2-Fc∆C1(a)
`have different sequences and the POSA would not have
`known which—if either—was necessarily the sequence
`for VEGF Trap-Eye
`
`10
`
`880 POR at 15-16, 18-20; 880 Sur-reply at 13-15; 881 POR at 30-33; 881 Sur-reply at 15-16, 21-24; Ex.1006 at 1576; Ex.1010 at 10:3-18, 26:5-20; Ex.2049 at ¶¶ 67-89;
`Ex.1033; Ex.2009; Ex.1008; Ex.1022; Ex.1023; Ex.1039; Ex.2288 at 16:3-7, 132:7-133:6, 142:6-20, 21:6-23, 27:9-28:8, 24:25-26:2, 95:17-19, 129:11-20, 127:4-13
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`Mylan Argues That Molecular Structure Means Amino Acid
`Sequence
`
`11
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`880 POR at 13-15; 880 Sur-reply at 12-13; 881 POR at 28-30; 881 Sur-reply at 20-21; Ex.1006 at 1575-76; Ex.2049 at ¶¶55-66; Ex.2048 at ¶¶66-72;
`Ex.1115 at ¶65; Ex.2228 at 29:8-30:4, 32:10-15, 33:2-20; Ex.2129 at 73:25-74; Ex.2130 at 107:16-22; 337:17-21; Ex.1108 at 119:23-120:8
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`Molecular Structure Is Commonly Understood to Describe a
`Protein’s Three-Dimensional Structure
`
`Dr. Gerritsen
`Petitioner’s Expert
`
`Q. So the protein’s molecular
`structure will refer to its
`secondary structure, correct?
`A. I would – yes, I – I think
`that it would refer to the
`structural information. That’s
`what it says, “structure.”
`Ex.2129 at 73:25-74:4
`
`Dr. Klibanov
`
`“[T]he term ‘molecular
`structure’ was often used in the
`protein literature to refer to the
`three-dimensional structure of
`the protein molecule, rather
`than its amino acid sequence.”
`Ex.2049 at ¶57
`
`12
`
`880 POR at 13-15; 880 Sur-reply at 12-13; 881 POR at 28-30; 881 Sur-reply at 20-21; Ex.1006 at 1575-76; Ex.2049 at ¶¶50-66; Ex.2048 at ¶¶66-72;
`Ex.1115 at ¶65; Ex.2228 at 29:8-30:4, 32:10-15, 33:2-20; Ex.2129 at 73:25-74; Ex.2130 at 107:16-22; 337:17-21; Ex.1108 at 119:23-120:8
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`The POSA Could Understand Dixon to Refer to Domain
`Structure, Not an Amino Acid Sequence
`
`Dr. Gerritsen
`Petitioner’s Expert
`Figure 1 in Dixon depicts
`the “domain composition
`of the molecule” and it is
`not a “precise example[]
`of, you know, the
`sequence, per se; it’s a
`cartoon.” Ex.2288 at 29:8-
`30:4
`
`Dr. Klibanov
`
`“Dixon … suggests that the
`‘molecular structure’ of
`VEGF Trap-Eye refers to
`the selection and
`arrangement of receptor
`binding domains … not to
`the amino acid sequence.”
`Ex.2049 at ¶66
`
`13
`
`880 POR at 13-15; 880 Sur-reply at 12-13; 881 POR at 28-30; 881 Sur-reply at 20-21; Ex.2049 at ¶¶55-66; Ex.1006 at 1575-7; Ex.2048 at ¶¶66-72;
`Ex.1115 at ¶65; Ex.2228 at 29:8-30:4, 32:10-15, 33:2-20; Ex.2129 at 73:25-74; Ex.2130 at 107:16-22; 337:17-21; Ex.1108 at 119:23-120:8
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`Post-Filing Evidence May Not Be Used to Establish the
`Identity of the Claimed Sequence
`
`14
`
`880 POR at 18; 880 Sur-reply at 6-10; 881 POR at 31; 881 Sur-Reply at 14-18; Ex.1024
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`DEMONSTRATIVE EXHIBIT
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`Post-Filing Evidence May Not Be Used to Establish the
`Identity of the Claimed Sequence
`
`•
`
`“The role of extrinsic evidence is to educate the decision-maker to
`what the reference meant to [the POSA], not to fill gaps in the
`reference.” Scripps Clinic v. Genentech, Inc., 927 F.2d 1565, 1576-77
`(Fed. Cir. 1991).
`• Prior art disclosure of an “incomplete description … denie[s] skilled
`artisans from having access to that composition, thereby precluding
`the use of the inherency doctrine to fill in [the] disclosure ….”
`Endo Pharms. Sols., Inc. v. CustoPharm Inc., 894 F.3d 1374, 1383
`(Fed. Cir. 2018).
`“There is no support … for Petitioner’s contention that the very
`‘identity’ or ‘structure’ of a claimed compound that was only known
`in the prior art by an experimental code name can be established
`using post-filing evidence ….” Bayer Cropscience LP v. Syngenta
`Ltd., IPR2017-01332, Paper 15, 4-6 (P.T.A.B. Apr. 2, 2018).
`
`•
`
`15
`
`880 POR at 12-13, 22; 880 Sur-reply at 5-9, 16; 881 POR at 26-27, 34; 881 Sur-reply at 14-18, 24
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`DEMONSTRATIVE EXHIBIT
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`VEGF Trap-Eye Was Not Publicly Available
`
`Dr. Do
`
`“In my experience, VEGF
`Trap-Eye was not
`publicly available … until
`after it was approved by
`FDA on November 18,
`2011.” Ex.2051 at ¶172
`
`Dr. Brown
`
`“Regeneron required its clinical
`investigators to sign a
`confidentiality agreement and
`clinical trial agreement that
`limited disclosure of information
`regarding its investigational
`drug.” Ex.2050 at ¶71
`
`16
`
`880 POR at 9-10; 880 Sur-reply at 10-11; 881 POR at 24-25; 881 Sur-reply at 18-19; Ex.2050 at ¶¶ 70-72, Ex. 2051 at ¶¶ 171-72; Ex.2130 at 319:16-
`320:9; Ex.2096, Ex.2128
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`DEMONSTRATIVE EXHIBIT
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`
`
`’069 Patent
`Ground 4
`
`17
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`DEMONSTRATIVE EXHIBIT
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`
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`Dixon’s Disclosure of VIEW Does Not Anticipate the Claims
`of the ’069 Patent
`’069 Patent (Ex.1001)
`
`Dixon (Ex.1006)
`
`VIEW required “each tertiary dose” to be administered on an 8-week interval, not on a
`PRN basis as required by the ’069 Patent claims.
`880 POR at 22-25; 880 Sur-reply at 18-20; Ex.1001; Ex. 1006 at 1576; Ex.2050 at ¶131; Ex.1017 at 136-137; Ex.1018 at 10; Ex.1002 at 84-85, Ex.2287 at
`147:21-148:20
`
`18
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`Modification of VIEW Requires Elimination of Q8 Dosing
`
`VIEW Dosing
`Regimen
`
`Modification of
`VIEW to Arrive at
`Claim 8 PRN
`Dosing Regimen
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`PRN
`
`19
`
`880 POR at 25-28, 880 Reply at 21-24, Ex.1001 at 3; Ex.2050 at ¶¶131-138
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`There Would Have Been No Motivation to Modify a Q8
`Dosing Regimen to PRN
`
`Q. PRN dosing would still require monthly office visits; correct?
`A. That’s the common understanding. That’s [the] PRN protocol.
`***
`Q: Would you agree that regular interval dosing on a Q8 dosing
`regimen would be less burdensome than monthly PRN?
`A. I – I agree … it sounds certainly less burdensome.
`Q. It would be less burdensome; correct?
`A. Yes.
`Ex.2130 at 278:22-279:11, 285:15-286:3 (objections omitted)
`
`Dr. Albini
`Petitioner’s Expert
`
`20
`
`880 POR 25-28, 880 Reply 20-24 Ex.2130 at 278:22-279:11, 285:15-286:3; Ex. 2050 at ¶¶131-138, 45, 69, 82
`
`DEMONSTRATIVE EXHIBIT
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`’069 Patent
`Ground 5
`
`21
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`
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`The POSA Would Not Have Been Motivated to Eliminate the
`Fourth Loading Dose from CLEAR-IT-2
`
`• Mylan argues that the POSA
`would eliminate the fourth
`loading dose in CLEAR-IT-2
`based on either:
`•
`(a) Lucentis prior art
`dosing regimens disclosed
`in Mitchell; or
`(b) disclosure of PO’s
`prospective 2Q8 VIEW
`dosing regimen in Dixon
`
`•
`
`XX
`
`22
`
`880 Petition at 60-66; 880 POR at 28-43; 880 Sur-reply at 26-36; Ex.2095 at 3, Ex.1055 at 6
`
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`CLEAR-IT-2 Showed Visual Acuity Improvements with the
`Fourth Loading Dose
`
`Dr. Albini
`Petitioner’s Expert
`Q. … So in CLEAR-IT 2, both
`of these monthly treatment
`arms show visual acuity
`improvement with the
`administration of the fourth
`loading dose; correct?
`A. Correct.
`Ex.2130 at 207:22-208:4
`880 POR at 30-31; 36-41; 880 Sur-reply at 26-28; Ex.1055 at 16; Ex.2050 at ¶¶ 124-125, 143-145; Ex.2130 at 207:22-208:11; Ex.2287 at 66:8-67:22
`
`23
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`CLEAR-IT-2 Showed CRT Improvements with the Fourth
`Loading Dose
`
`Dr. Albini
`Petitioner’s Expert
`Q. … [T]he monthly treatment
`arms in CLEAR – in CLEAR-IT
`2, both of those treatment arms
`show average CRT reductions
`with the fourth monthly loading
`dose; correct?
`A. Yes.
`Ex.2130 at 209:8-13
`
`24
`
`880 POR at 36-41; 880 Sur-Reply at 26-27; Ex.2050 at ¶¶144-149; Ex.1055 at 18; Ex.2130 at 209:8-13
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`DEMONSTRATIVE EXHIBIT
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`Physicians Give Monthly Loading Doses until Visual Acuity
`Gains Have Plateaued
`
`Dr. Brown
`
`“[I]n the clinical practice of
`anti-VEGF injection was (and
`is) to give monthly loading
`does until retina drying and
`initial visual acuity gains have
`plateaued….” Ex.2050 at
`¶141
`
`Dr. Albini
`Petitioner’s Expert
`“I don’t disagree with Dr. Brown’s
`assessment that ‘most physicians
`would be guided in clinical practice
`by giving monthly loading doses
`until the patient’s fluid on retina had
`dried and visual acuity gains had
`plateaued….’” ’880 Ex.1114 at ¶40
`
`25
`
`880 POR at 41; 880 Sur-reply at 30-33; Ex.2050 at ¶141-149, Ex.1114 at ¶40
`
`DEMONSTRATIVE EXHIBIT
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`Mitchell Did Not Provide Motivation to Drop a Loading Dose
`
`• The clinical trial results of MARINA and
`ANCHOR showed no meaningful visual
`acuity benefit from a fourth monthly
`dose of ranibizumab.
`“Ranibizumab initiation with three
`consecutive monthly injections appears
`optimal as this is when the majority of
`patients experience most VA gain in all
`studies….” Ex.1030 at 4.
`
`•
`
`26
`
`880 POR at 34-36, 40; 880 Sur-reply at 29-33; Ex.2050 at ¶¶139-143, 146-148; Ex.2030, 6, 9
`
`DEMONSTRATIVE EXHIBIT
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`Dixon Does Not Provide Motivation to Drop a Loading Dose
`
`• The prospective VIEW trial was the first trial to
`test three monthly loading doses of VEGF Trap-
`Eye in one of the three dosing arms
`• There is no clinical trial data reported in Dixon for
`three loading doses
`• Dixon discloses clinical trial data from CLEAR-IT-
`2 that showed that 4 loading doses were needed
`to dry the retina and achieve maximum initial VA
`gains
`
`27
`
`880 POR at 41-43; Reply 33-36; Ex.2050 at ¶¶73-82, 131-138
`
`DEMONSTRATIVE EXHIBIT
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`
`
`’338 Patent
`Claim Construction
`
`28
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`The Preamble Is a Positive Limitation
`
`•
`
`•
`
`•
`
`“[T]he claims are directed to methods of
`administering, i.e., using, a VEGF
`antagonist for the specific purpose of
`treating an angiogenic eye disorder in a
`patient.”
`“[W]e agree with Patent Owner that the
`preamble sets forth the essence of the
`invention.”
`“[W]e preliminarily find that the
`preambles of claims 1 and 14 are
`limiting.”
`
`29
`
`881 ID 18-19; 881 POR at 7-12; 881 Sur-reply at 2-3, Ex. 1001 at Claim 1
`
`DEMONSTRATIVE EXHIBIT
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`
`
`A Positive Limitation Must Actually Be Practiced Where It Is
`Needed for Utility
`
`• “[M]ethod of growing and isolating” was a positive limitation that
`grounded the claim in its utility and, consequently, had to be practiced
`to satisfy the claim. See Boehringer Ingelheim Vetmedica, Inc. v.
`Schering-Plough Corp., 320 F.3d 1339, 1344-45 (Fed. Cir. 2003)
`• “[M]ethod for diagnosing an increased risk of thrombosis or a
`genetic defect causing thrombosis” was a positive limitation and
`that “diagnosis is thus the essence of the invention; its appearance in
`the count gives … ‘life, meaning, and vitality to the claims or counts.’”
`Griffin v. Bertina, 285 F.3d 1029, 1033 (Fed. Cir. 2002)
`
`Petitioner Identifies No Case Where “Treating” Is
`a Positive Limitation but Efficacy Is Not Required
`
`30
`
`881 POR at 9-12; 881 Sur-reply at 2-3
`
`DEMONSTRATIVE EXHIBIT
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`
`
`Claims Are Interpreted as They Would Have Been
`Understood by the POSA at the Time of the Filing
`
`• Claims “must be understood and interpreted by the
`court as they would be understood and interpreted by a
`person in that field of technology.” Multiform Desiccants,
`Inc. v. Medzam, Ltd., 133 F.3d 1473, 1477 (1998)
`“[T]his court interprets the claim[s]” from the perspective of
`the POSA “at the time of filing.” Schering Corp. v. Amgen
`Inc., 222 F.3d 1347, 1353 (Fed. Cir. 2000)
`
`•
`
`31
`
`881 POR at 32; 881 Sur-reply at 3, 8, 9
`
`DEMONSTRATIVE EXHIBIT
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`
`
`Highly Effective Anti-VEGF Agents Already Existed at the
`Time of Filing
`
`• January 13, 2011—Earliest priority date
`for the ’338 Patent
`• June 30, 2006—FDA approval of
`Lucentis
`• Lucentis established a high-level of
`efficacy for the treatment of
`angiogenic eye disorders
`• After Lucentis, slowing vision loss
`was not acceptable treatment
`
`32
`
`881 POR 12-17; 881 Sur-reply 3-9; Ex.2051 at ¶¶47-68; Ex.2050 ¶¶31-41; Ex.1001 1:49-59, 2:15-22
`
`DEMONSTRATIVE EXHIBIT
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`
`
`Lucentis Changed the Expectation of Efficacy in the Art
`
`Dr. Do
`
`“[R]etina doctors no longer believed
`that simply slowing vision decline
`was enough for effective treatment
`when therapy was now available
`that could actually produce visual
`acuity gains.” Ex.2051 at ¶66
`
`Dr. Brown
`“[A] gain of letters can translate into
`a meaningful real-world difference
`for patients. Once a therapy was
`available that could deliver visual
`acuity gains, physicians and their
`patients were no longer content to
`simply slow disease progression.”
`Ex.2050 at ¶39
`
`33
`
`881 POR, 3-4, 12-13, 20-22; 881 Sur-reply 3-4, Ex.2130, 155:3-9, 194:3-15; Ex.2287, 55:14-56:1, 240:18-242:4; Ex.2050 at ¶¶39-42; Ex.2051 ¶66
`
`DEMONSTRATIVE EXHIBIT
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`Lucentis Changed the Expectation of Efficacy in the Art
`
`• “… [W]ould you consider both Lucentis and off-label
`Avastin to have been standard of care at the time [the
`VIEW] trials were run? A. Very much so.” Ex.2130 at 153:2-9
`• “I think that anti-VEGF therapy with Ranibizumab had
`changed the efficacy of treatment …” Ex.2287 at 241:18-
`242:4
`• “Q. By 2011, Lucentis and off-label Avastin were able to
`provide visual acuity gain to patients with angiogenic eye
`disorders; correct? … THE WITNESS: By 2011, bevacizumab
`and ranibizumab were both used to treat patients with
`angiogenic eye disorders and were resulting in visual
`gains ….” Ex.2287 at 55:14-56:1
`
`Dr. Albini
`Petitioner’s Expert
`
`34
`
`881 POR, 3-4, 12-13, 20-22, 38; 881 Sur-reply 3-4, Ex. 2130, 155:3-9, 194:3-15; Ex.2287, 55:14-56:1, 240:18-242:4
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 34 of 57
`
`
`
`Lucentis Changed the Expectation of Efficacy in the Art
`
`Ex.2114
`
`Ex.1006
`
`Ex.1043
`
`35
`
`881 POR, 3-4, 12-13, 20-22; 881 Sur-reply 3-4; Ex.2114 at 6;; Ex. 1006; Ex.1043; Ex. 2130, 155:3-9, 194:3-15; Ex.2287, 55:14-56:1, 240:18-242:4;
`Ex.2050 at ¶¶39-42, 179; Ex.2051 ¶66; Ex.1002 ¶50
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 35 of 57
`
`
`
`Lucentis Changed the Expectation of Efficacy in the Art
`
`• Macugen was approved in 2004 as the
`first anti-VEGF agent approved for the
`treatment of wAMD
`• But After Lucentis’ approval,
`Macugen use plummeted
`• Macugen merely slowed vision loss
`whereas Lucentis produced visual
`acuity gains
`
`36
`
`881 POR at 3-4, 12, 17; Ex.2051 ¶¶ 56-58, 66; Ex.2050 ¶¶ 29-32, 42, 165-170; Ex. 2038
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 36 of 57
`
`
`
`Lucentis Clinical Trial Results
`
`Efforts to Extend
`Lucentis Dosing
`Failed to Maintain
`Visual Acuity
`
`37
`
`881 POR at 3-6, 53-54, 58, 61-62; 881 Sur-reply at 32-33; Ex.2050 at ¶¶ 163, 46-69, 160-173
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 37 of 57
`
`
`
`The ’338 Patent Identifies a Need for Extended Dosing
`Regimens That Maintain the Efficacy Expected in the Art
`
`The specification expressly identifies the
`unsatisfactory Lucentis extended dosing
`regimen of PIER (US 2007/01900058) as
`leaving “a need in the art”
`
`38
`
`881 Sur-reply at 4-9; 881 POR at 6-7, 13-18; Ex.1001 at 1:49-59, 2:15-22; Ex.1135; Ex.1085
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 38 of 57
`
`
`
`The US 2007/01900058 Cited in the ’338 Patent Reflects
`the PIER Dosing Regimen
`
`Dr. Albini
`Petitioner’s Expert
`Q. … [I]s it fair to say that the dosing
`regimen set forth in Figure 2 [of US
`2007/01900058] is the same design
`… as the dosing regimen that was
`tested in the Pier study?
`A. It seems to be consistent.
`Ex.2287 at 40:3-14
`881 Sur-reply at 4-9; 881 POR at 13-18; Ex.1001 at 1:49-59, 2:15-22; Ex.1135; Ex.1085; Ex.2287, 40:3-14
`
`39
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 39 of 57
`
`
`
`PIER [US 2007/01900058] Was Unsatisfactory Because it Did
`Not Maintain Visual Acuity Gains
`
`Dr. Albini
`Petitioner’s Expert
`“… [M]ost of my colleagues by
`the time 2011 showed up would
`not have considered the results
`that were seen in the Pier study
`to be quote/unquote, highly
`effective.” Ex.2287 at 42:9-20.
`
`40
`
`881 Sur-reply at 4-9; 881 POR at 5, 13-18; Ex.1001 at 1:49-59, 2:15-22; Ex.1135; Ex.1085; Ex.1030; Ex. 2050 ¶¶47-52; Ex.2287 at 42:9-20
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 40 of 57
`
`
`
`The Intrinsic Record Establishes That the Claimed Dosing
`Regimen Maintains Visual Acuity Gains
`
`• Every example shows that administration
`with VEGF Trap, including on the claimed
`Q8 dosing regimen, produced visual acuity
`gains, not just slowed vision loss. Ex.1001
`at 7:35-15:15
`• Examples 4 and 5 show visual acuity gains
`and maintenance of those gains with a Q8
`dosing regimen. Ex.1001 at 9:10-14:34
`• The treatment group which received the
`drug far less frequently than the monthly
`dosing arm achieved remarkably similar
`improvements. Ex.1017 at 288-291.
`
`41
`
`881 POR at 6-7, 13-16; 881 Sur-reply 4-9, Ex.1001, 1:49-59, 2:15-22; Ex.2051 at ¶¶ 79-82; Ex.2050 at ¶ 83; Ex.1017 at 288-291.
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 41 of 57
`
`
`
`Petitioner Argues That the Inventor Redefined “Treating”
`Through the Use of Lexicography
`
`• An inventor must clearly express an intent to redefine the meaning
`of claim terms for lexicography to apply
`• Lexicography requires that any special meaning given to a term
`“must be sufficiently clear in the specification that any
`departure from common usage would be so understood by a
`[POSA].” Multiform Desiccants, Inc. v. Medzam, Ltd., 133 F.3d
`1473, 1477 (Fed. Cir. 1998)
`“When a patentee acts as his own lexicographer in redefining the
`meaning of particular claim terms away from their ordinary
`meaning, he must clearly express that intent in the written
`description.” Merck & Co. v. Teva Pharmaceuticals USA, Inc., 395
`F.3d 1364, 1370 (Fed. Cir. 2005)
`
`•
`
`42
`
`881 Sur-reply at 8-9; 881 Petition at 15, 880 Reply at 30, 36
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 42 of 57
`
`
`
`It Is Undisputed That the POSA Would Not Have Considered
`“Treating” to Be Loss of ≤15 Letters by 2011
`
`Dr. Do
`
`Dr. Brown
`
`The POSA would not
`“accept any treatment
`that merely prevented a
`patient from losing
`‘fifteen or fewer
`letters….’” Ex.2051 at
`¶83
`
`By 2011, average retinal
`specialist would not have
`thought that simply achieving
`‘loss of less than 15 letters
`…’ in a patient would be
`effective treatment.” Ex.2050
`at ¶ 80
`
`Dr. Albini
`Petitioner’s Expert
`By 2011 loss of 14
`letters “would not have
`been considered
`sufficiently efficacious.”
`Ex.2130 at 194:3-15
`
`43
`
`881 POR at 20-22; 881 Sur-reply 8-9; Ex.2051 at ¶83; Ex.2050 at ¶80; Ex.2130 at 194:3-15; Ex.1001 at 7:15-32,
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 43 of 57
`
`
`
`Column 7 Does Not Redefine “Treating” as Recited in Claims
`
`• The POSA would have understood that
`“treating” in the context of the ’338 Patent
`means to achieve and maintain the efficacy
`expected in the art
`• Lexicography does not apply because:
`1. There is no express definition of “treating”
`and “efficacy” is not a claim term
`It would not be clear to the POSA that the
`inventor intended to redefine “treating”
`
`2.
`
`44
`
`881 POR at 13-18, 20-22; 881 Sur-reply 4-9; Ex.1001, 7:15-32; Ex.2051 ¶¶ 69-84
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 44 of 57
`
`
`
`The POSA Would Not Understand Column 7 to Redefine the
`Meaning of “Treating”
`
`Q. … [T]he 338 patent which you cite in your declaration, lines 15 to
`32 of Column 7, do you agree that the inventor is providing a
`definition for the term “efficacy” here?
`A. In that paragraph, the skilled artisan reviewing those words would
`understand that those lines refer to clinical trial endpoints, such as
`the loss of 15 letters or less.
`Q. So do you disagree with my question that this is where the
`inventor provides a definition for the term –the claim term “efficacy”?
`A. In my experience, I interpret this statement as referring to
`clinical trial endpoints. And I believe the person of ordinary skill
`in the art would also interpret it the same way.
`Ex.1109 at 91:12-23 (objections omitted)
`
`45
`
`881 POR at 20-22, 881 Sur-reply at 4-9; Ex.1109, 91:12-23; Ex.2051 at ¶¶ 69-84
`
`Dr. Do
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 45 of 57
`
`
`
`Dr. Albini Acknowledged the Column 7 Reference to
`“Efficacy” is Unclear
`
`[I]n this sentence here where it says, “In the context of the methods
`for treating angiogenic eye disorders such as AMD, CRVO, and
`DME, ‘efficacy’ means that, from the initiation of treatment, the
`patient exhibits a loss of 15 or fewer letters on the ETDRS visual
`acuity chart.” And that part --- that was confusing to me was that,
`one, that’s not a great demonstration of efficacy if you have 14 letters
`of vision loss; and that would be included in that definition. So it
`seems like a sort of misguided definition.
`***
`So I – I – I thought it was – I didn’t really understand from reading
`the patent how this efficacy criteria were to be used when
`employing the treatment strategy.
`Ex.2130 at 177:20-180:5
`
`46
`
`881 POR at 20-22, 881 Sur-reply at 4-9; Ex.2130 at 177:20-180:5
`
`Dr. Albini
`Petitioner’s Expert
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 46 of 57
`
`
`
`Loss of ≤15 Letters Is a Clinical Trial Endpoint, Not a
`Definition of Effective Treatment
`
`Dr. Do
`
`The POSA “reviewing Column 7
`would understand that loss of 15
`or fewer letters … correspond[s]
`to clinical trial endpoints that
`were used to measure or assess
`the clinical results of anti-VEGF
`agents in the art.” Ex.2051 at ¶70
`
`Dr. Albini
`Petitioner’s Expert
`“I think that most retina
`specialists would recognize” a
`loss of 15 letters or fewer “as an
`often used metric in clinical trials”
`for anti-VEGF Agents. Ex.2130 at
`181:11-22.
`
`47
`
`881 POR at 20-22; 881 Sur-reply 4-9; Ex.2051 ¶69-73, Ex.2130, 181:11-22, 169:16-20
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 47 of 57
`
`
`
`Terms Should Be Construed in a Manner That Renders the
`Patent Internally Consistent
`
`“In construing terms used in patent claims, it is necessary to
`consider the specification as a whole, and to read all portions
`… in a manner that renders the patent internally
`consistent. In addition, it is important to construe claim
`language through the ‘viewing glass’ of a person skilled in
`the art.” Budde v. Harley-Davidson, Inc., 250 F.3d 1369, 1379-
`80 (Fed. Cir. 2001)
`
`48
`
`881 POR at 20; 881 Sur-Reply 8-9
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 48 of 57
`
`
`
`’338 Patent
`Ground 6
`
`49
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 49 of 57
`
`
`
`There Was No Reasonable Expectation of Success of
`Arriving at the Claimed Invention
`
`•
`
`“[T]here can be little better evidence negating an
`expectation of success than actual reports of failure.”
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough
`Corp., 320 F.3d 1339, 1354 (Fed. Cir. 2003).
`
`50
`
`881 Sur-reply at 32-33
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 50 of 57
`
`
`
`Lucentis Clinical Trial Results
`
`Efforts to Extend
`Lucentis Dosing
`Failed to Maintain
`Visual Acuity
`
`51
`
`881 POR at 3-6, 53-54, 58, 61-62; 881 Sur-reply at 32-33; Ex.2050 at ¶¶ 163, 46-69, 160-173
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 51 of 57
`
`
`
`The Prior Art Taught That Q8 Dosing Was Ineffective
`
`Q. …Why wouldn’t [the POSA] just use three monthly
`loading doses followed by Q8 dosing if they saw the protocol
`for the VIEW study?
`A. I think that because of the relative lack of efficacy seen
`with quarterly dosing and less frequent regular dosing, that
`PRN dosing at the time was considered to be a better strategy.
`***
`Q. Were people doing a Q8 maintenance dosing at the time?
`A. I’ve already answered that many times, but the answer is no.
`Ex.2130 at 283:13-284:7 (objections omitted)
`
`Dr. Albini
`Petitioner’s Expert
`
`52
`
`881 POR at 53-54, 58, 5-6; 881 Sur-reply at 32-33; Ex.2130 at 283:13-284:7; Ex.2050 at ¶¶109-113, 153-67
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 52 of 57
`
`
`
`CLEAR-IT-2 Suggested That VEGF Trap-Eye Would Not Be
`Effective on an Eight-Week Dosing Regimen
`
`Dr. Brown
`
`“I recall that, looking at the rise
`in mean CRT [in CLEAR-IT-2],
`we … thought that VEGF Trap-
`Eye might last six weeks, but
`had great skepticism that it
`would be noninferior to
`Lucentis on an 8-week fixed
`dosing regimen.” Ex.2050 at
`¶126
`
`53
`
`881 POR 55-58, 881 Sur-reply at 30; Ex.2050 ¶122-126; Ex.2130 at 211:1-5; 214:15-22; Ex.1055 at 18; Ex.2094 at 5
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 53 of 57
`
`
`
`Fluid Re-Accumulation Indicates the Need for Retreatment
`
`Dr. Brown
`
`“[A]n increase in CRT
`corresponds to fluid re-
`accumulation on the retina and
`indicates a need for
`retreatment.” Ex.2050 at ¶122
`
`Dr. Albini
`Petitioner’s Expert
`Q. Fluid reaccumulation on the retina
`or an increase in CRT, as measured
`by OCT, is typically an indication that
`retreatment with an anti-VEGF agent
`is necessary; correct?
`A. Correct
`Ex.2130 at 211:1-5
`
`54
`
`881 POR at 55-57; 881 Sur-reply at 30; Ex.2050 at ¶122-126; Ex.2130 at 211:1-5
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 54 of 57
`
`
`
`There Was a Long-Felt but Unmet Need for Extended Dosing
`That Maintained a High Level of Efficacy
`
`55
`
`881 POR 2, 5-6, 12-13 60-62; 881 Sur-Reply 33-34; Ex.2050 ¶¶ 69, 82, 151-159, Ex.1018, 1, 9, 10.
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 55 of 57
`
`
`
`There Was a Long-Felt but Unmet Need for Extended Dosing
`That Maintained a High Level of Efficacy
`
`56
`
`881 POR 2, 5-6, 12-13 60-62; 881 Sur-Reply 33-34; Ex.2050 ¶¶84, 151-159; Ex.2116; Ex.1018, 1,9.
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 56 of 57
`
`
`
`Eylea Is a Commercial Success
`
`Eylea achieved $5.8 billion in net
`sales in the U.S.
`
`Eylea’s Growth in sales has come from
`patients who would have otherwise
`received Lucentis and Avastin
`
`57
`
`881 POR 1-2, 54, 58, 61-62; Sur-reply at 34-37; Ex.2052 ¶¶ 52, 70-76
`
`DEMONSTRATIVE EXHIBIT
`
`Demonstrative Exhibit 2290
`Page 57 of 57
`
`
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