Case 1:22-cv-00061-TSK-JPM Document 622 Filed 09/01/23 Page 1 of 34 PageID #: 48129
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`Exhibit 15
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`Case 1:22-cv-00061-TSK-JPM Document 622 Filed 09/01/23 Page 2 of 34 PageID #: 48130
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`CLARKSBURG DIVISION
`
`
`Plaintiff,
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`v.
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`REGENERON PHARMACEUTICALS, INC.,
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`MYLAN PHARMACEUTICALS INC.,
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`Defendant.
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`
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`Case No. 1:22-cv-00061-TSK
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`JURY TRIAL DEMANDED
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`HIGHLY CONFIDENTIAL –
`OUTSIDE COUNSEL’S EYES ONLY
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`REPLY EXPERT REPORT
`OF BERNHARDT L. TROUT, PH.D.
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`I declare that the following is, to the best of my knowledge and belief, true and correct.
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`Dated: March 30, 2023
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`
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`
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`Bernhardt L. Trout, Ph.D.
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`Case 1:22-cv-00061-TSK-JPM Document 622 Filed 09/01/23 Page 3 of 34 PageID #: 48131
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`
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`B.
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`I.
`II.
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`TABLE OF CONTENTS
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`Introduction ..........................................................................................................................1
`M710 infringes at least claims 4, 7, 9, 11, and 14-18 of the ’865 patent .............................1
`A.
`M710 contains an organic co-solvent comprising polysorbate 20...........................3
`1.
`Regeneron’s Construction ............................................................................4
`2.
`Mylan’s Construction...................................................................................6
`M710 comprises a VEGF antagonist, “wherein at least 98% of the VEGF
`antagonist is present in native conformation following storage at 5°C. for
`two months as measured by size exclusion chromatography”...............................13
`1.
`Regeneron’s Construction ..........................................................................14
`2.
`Mylan’s Construction.................................................................................15
`M710 infringes claim 18 of the ’865 patent...........................................................17
`C.
`Conclusion .........................................................................................................................20
`III.
`Appendix A ................................................................................................................................. A-1
`Appendix B ..................................................................................................................................B-1
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`i
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`Case 1:22-cv-00061-TSK-JPM Document 622 Filed 09/01/23 Page 4 of 34 PageID #: 48132
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`I.
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`Introduction
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`1.
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`I have been asked by counsel for Plaintiff Regeneron Pharmaceuticals, Inc.
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`(“Regeneron” or “Plaintiff”) to serve as an expert and provide my professional opinions
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`regarding certain issues relating to U.S. Patent Nos. 11,084,865 (the “’865 patent”) and
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`11,253,572 (the “’572 patent”).
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`2.
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`I understand Defendant Mylan Pharmaceuticals Inc. (“Mylan” or “Defendant”)
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`seeks FDA approval of Biologics License Application (“BLA”) No. 761274 to manufacture and
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`sell a biosimilar version of Regeneron’s EYLEA® (aflibercept) product (“M710”).
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`3.
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`On February 2, 2023, I submitted an expert report in which I explained the bases
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`for my opinion that Mylan infringes claims 4, 7, 9, 11, and 14-18 (i.e., the asserted claims of the
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`’865 patent, the “’865 Asserted Claims”) of the ’865 patent.
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`4.
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`In this report, I have been asked by counsel for Regeneron to respond to the
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`opinions expressed in the Responsive Expert Report of Gregory MacMichael Regarding
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`Noninfringement dated March 2, 2023.
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`II. M710 infringes at least claims 4, 7, 9, 11, and 14-18 of the ’865 patent
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`5.
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`In my Opening Report, I opined that M710 infringes claims 4, 7, 9, 11, and 14-18
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`of the ’865 patent. Opening Report ¶ 4.
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`6.
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`Dr. MacMichael has not offered any response or otherwise disagreed with my
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`opinion that M710 meets the specific limitations set forth in dependent claims 7, 9, 11, and 14-17
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`of the ’865 patent. The only limitations addressed by Dr. MacMichael are “organic co-solvent”
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`(as recited in claim 1, from which the ’865 Asserted Claims depend), “native conformation” (as
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`recited in claim 1), and “wherein said formulation does not contain phosphate” (as recited in
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`claim 18). MacMichael Responsive ¶¶ 38-96.
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`1
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`7.
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`The ’865 Asserted Claims, and the claims from which they depend, are set forth
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`below:
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`1. A vial comprising an ophthalmic formulation suitable for
`intravitreal administration that comprises:
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`a vascular endothelial growth factor (VEGF) antagonist
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`an organic co-solvent,
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`a buffer, and
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`a stabilizing agent,
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`wherein said VEGF antagonist fusion protein is glycosylated and
`comprises amino acids 27-457 of SEQ ID NO:4; and
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`wherein at least 98% of the VEGF antagonist is present in native
`conformation following storage at 5° C. for two months as
`measured by size exclusion chromatography.
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`2. The vial of claim 1, wherein the concentration of said VEGF
`antagonist fusion protein is 40 mg/ml, and wherein said organic
`co-solvent comprises polysorbate.
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`4. The vial of claim 2, wherein said organic co-solvent comprises
`about 0.03% to about 0.1% polysorbate 20.
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`5. The vial of claim 2, wherein said organic co-solvent comprises
`0.01% to 3% polysorbate 20.
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`7. The vial of claim 5, wherein said buffer comprises 5-25 mM
`buffer.
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`9. The vial of claim 5, wherein said buffer comprises a pH about
`6.2-6.3.
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`10. The vial of claim 5, wherein said stabilizing agent comprises a
`sugar.
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`11. The vial of claim 10, wherein said sugar is selected from the
`group consisting of sucrose, sorbitol, glycerol, trehalose, and
`mannitol.
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`14. The vial of claim 5, wherein said VEGF antagonist fusion
`protein is glycosylated at asparagine residues corresponding to
`asparagine residues 62, 94, 149, 222 and 308 of SEQ ID NO: 4.
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`2
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`15. The vial of claim 5, wherein said formulation is capable of
`providing a turbidity of 0.01 or lower at OD405 after 2 month
`storage at 5° C.
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`16. The vial of claim 5, wherein at least 99% of said VEGF
`antagonist fusion protein is present in native conformation after 2
`month storage at 5° C. as measured by size exclusion
`chromatography.
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`17. The vial of claim 5, wherein at least 98% of said VEGF
`antagonist fusion protein is present in native conformation
`following storage at 5° C. for 24 months as measured by size
`exclusion chromatography.
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`18. The vial of claim 5, wherein said formulation does not contain
`phosphate.
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`A. M710 contains an organic co-solvent comprising polysorbate 20
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`8.
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`With respect to “organic co-solvent,” I understand that Regeneron has proposed
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`that the term be construed according to its plain and ordinary meaning in view of the claims and
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`specification, and to include the substances polysorbate 20, polysorbate 80, polyethylene glycol,
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`propylene glycol, or a combination thereof, as disclosed in the ’865 patent. ’865 patent, 2:39-43,
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`2:33-38, 2:49-52, 3:11-16, 3:28-31, 4:11-17, 7:2-7. Specifically, I understand that Regeneron’s
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`proposed construction is: “Plain and ordinary meaning in view of the claims and specification;
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`to the extent there is a dispute as to claim scope, ‘organic co-solvent’ includes polysorbate 20,
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`polysorbate 80, polyethylene glycol, or propylene glycol, or a combination thereof.” I
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`understand that Mylan has proposed that the term be construed as “an organic substance added to
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`a primary solvent to increase the solubility of said VEGF antagonist.” I understand that the
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`Court has not yet issued a claim construction of this term.
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`9.
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`I have not been asked by counsel to offer an opinion on the construction of
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`“organic co-solvent” as recited in the claims of the ’865 patent, nor have I offered such opinion.
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`I have instead sought to apply both parties’ construction and address whether M710 meets the
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`3
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`limitation under both parties’ constructions. Dr. MacMichael offers opinions as to the proper
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`construction of an “organic co-solvent.” MacMichael Responsive ¶¶ 51-56. However, Dr.
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`MacMichael’s claim construction opinions are not relevant to whether M710 infringes the ’865
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`Asserted Claims when applying either party’s construction.
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`1.
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`Regeneron’s Construction
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`10.
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`In my Opening Report, I explained my opinion that M710 contains “an organic
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`co-solvent,” “wherein said organic co-solvent comprises . . . polysorbate 20” at a concentration
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`within the claimed ranges. Opening Report ¶¶ 70-75.
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`11.
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`In applying Regeneron’s construction, Dr. MacMichael’s argument appears to be
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`that Mylan’s BLA categorizes polysorbate 20 as a “stabilizing agent” and not as an “organic co-
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`solvent.” MacMichael Responsive ¶¶ 58-59. However, I disagree with Dr. MacMichael’s
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`premise that because polysorbate 20 is described as a “stabilizing agent,” it cannot be an organic
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`co-solvent. As the POSA would recognize, it is common for excipients to fit into multiple
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`categories. For example, the Handbook of Pharmaceutical Excipients describes polysorbates as
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`falling into several categories: “Dispersing agent; emulsifying agent; nonionic surfactant;
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`solubilizing agent; suspending agent; wetting agent.” Handbook of Pharmaceutical Excipients
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`550 (6th ed. 2009). Chang & Hershenson likewise describe surfactants as examples both of
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`“stabilizer[s]” and “solubilizer[s].” B.S. Chang & S. Hershenson, Practical Approaches to
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`Protein Formulation Development, in Rational Design of Stable Protein Formulations 1, 14 (J.F.
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`4
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`Carpenter & M.C. Manning eds., 1st ed. 2002). Dr. MacMichael offers no support for the notion
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`that excipients may only fall within a single category. Nor does Dr. MacMichael contest that the
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`amount of polysorbate 20 falls within the ranges recited in the ’865 Asserted Claims, or that the
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`’865 patent describes that polysorbate 20 may be used as an organic co-solvent. MacMichael
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`Responsive ¶ 39 (agreeing that M710 contains “0.03% w/v polysorbate 20”). Thus, whether
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`Mylan refers to the polysorbate 20 in its formulation as an organic co-solvent is irrelevant; under
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`Regeneron’s construction, polysorbate 20 is an organic co-solvent as recited in the ’865 Asserted
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`Claims, and
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`Under Regeneron’s construction, polysorbate 20 is not, as Dr. MacMichael suggests
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`(MacMichael Responsive ¶ 56), sometimes an organic co-solvent and sometimes not.
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`12.
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`Dr. MacMichael also suggests that in order to be an organic co-solvent,
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`polysorbate 20 would have “to be added at a sufficiently high concentration.” MacMichael
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`Responsive ¶¶ 59-60. However, Dr. MacMichael provides no opinion about what that
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`concentration is. In my view, to meet the claim limitation, the amount of polysorbate must only
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`be within the concentration ranges claimed in the ’865 Asserted Claims: “about 0.03% to about
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`0.1%” for claim 4, or “0.01% to 3%” for claim 5 and the other ’865 Asserted Claims
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`And under Regeneron’s
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`construction, I understand that there is not a separate functional test for determining whether
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`polysorbate 20 is an “organic co-solvent.”
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`13.
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`Dr. MacMichael does not provide separate opinions addressing the ’865 Asserted
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`Claims, which all specifically require that the organic co-solvent comprises polysorbate.
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`MacMichael Responsive ¶¶ 63, 65, 67-68. For the same reasons as above and as explained in
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`my Opening Report, I disagree with Dr. MacMichael’s view that an organic co-solvent that
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`5
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`“comprises . . . polysorbate 20” could somehow exclude polysorbate 20 from meeting the claim
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`limitation.
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`2.
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`Mylan’s Construction
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`14. Mylan’s construction of “organic co-solvent” is “an organic substance added to a
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`primary solvent to increase the solubility of said VEGF antagonist.”
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`construction of “organic co-solvent” because this amount of polysorbate 20 reduced the
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`formation of insoluble aggregates of aflibercept in Mylan’s formulation. Opening Report ¶¶ 76-
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` under Mylan’s proposed
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`83.
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`15.
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`First, Dr. MacMichael appears to agree that polysorbate 20 is “an organic
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`substance” (as I explained, Opening Report ¶ 77) and that it is “added to a primary solvent”
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`(Opening Report ¶ 78). I addressed these aspects of Mylan’s construction in my Opening Report
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`and Dr. MacMichael has not disagreed.
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`16.
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` As I explained in my
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`Opening Report, “[t]he hydrophobic portion of non-ionic surfactants can bind to hydrophobic
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`patches on proteins. This naturally causes the surfactant to order itself so that more hydrophilic
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`groups are solvent exposed, resulting in a ‘hydrophobicity reversal’.” T.W. Randolph & L.S.
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`Jones, Surfactant-Protein Interactions, in Rational Design of Stable Protein Formulations 159,
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`167-68 (J.F. Carpenter & M.C. Manning eds., 1st ed. 2002); Opening Report ¶ 79. The
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`consequence of this interaction is that “the protein-surfactant complex is more hydrophilic tha[n]
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`either the surfactant or protein alone, and effectively increases the solubility of the complex” and
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`“reduce[s] the propensity of the protein to form higher-order aggregates.” Randolph & Jones at
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`168. Dr. MacMichael suggests that such an “effective[] increase” in solubility as described in
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`6
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`Randolph & Jones would not fall within Mylan’s proposed construction because an organic co-
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`solvent must involve “changing the physiochemistry of the primary solvent.” MacMichael
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`Responsive ¶ 47. However, that requirement is not set forth in Mylan’s proposed construction,
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`which only requires an increase in solubility, not a particular way of doing so.
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`17.
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`Dr. MacMichael criticizes Randolph & Jones because it “is not cited in Mylan’s
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`M710 BLA.” MacMichael Responsive ¶ 40. However, Dr. MacMichael does not express any
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`specific disagreement with the teachings from that publication as to how nonionic surfactants
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`affect the solubility of proteins.
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`18.
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`Dr. MacMichael also argues that my opinion “squarely contradicts the sworn
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`testimony of Dr. Eric Furfine.” MacMichael Responsive ¶ 40. I disagree. Dr. Furfine was asked
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`“what was the role of the 0.01 percent polysorbate 20 in” International Patent Publication No.
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`WO 2006/047325 (“Shams”) (describing a 10 mg/ml ranibizumab formulation, Shams 31:29-
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`30), and Dr. Furfine answered “I don’t know what role it played specifically because there is no
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`data associated with it, but I can tell you that polysorbate is often used as a stabilizer to agitation
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`and like stresses.” Furfine Dep. 191:16-192:4. Dr. Furfine’s statement regarding a different
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`formulation of a different protein (ranibizumab) does not shed light on whether the polysorbate
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`20 in Mylan’s M710 product meets Mylan’s proposed construction of “organic co-solvent” in the
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`context of aflibercept and the ’865 patent and, in any event, is consistent with the function of
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`polysorbate 20 in M710 in reducing aggregation and therefore increasing solubility. The studies
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`and data in Mylan’s BLA show that the polysorbate 20 in M710 reduces the formation of
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`aggregates and thus increases the solubility of the VEGF antagonist. Based on dynamic light
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`scattering data showing the existence of multiple peaks only in a formulation lacking polysorbate
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`20 (indicating the formation of aggregates), Mylan’s BLA states that “[i]ncreased M710 stability
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`7
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`with inclusion of polysorbate 20 compared to absence of polysorbate 20 was also demonstrated.”
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`MYL-AFL-BLA0002879, at -2913; see Opening Report ¶¶ 80-81. Dr. MacMichael does not
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`address this data and agrees that surfactants like polysorbate 20 “prevent[] aggregation.”
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`MacMichael Responsive ¶ 41. As I explained in my Opening Report, and as Dr. MacMichael
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`explained at his deposition (Opening Report ¶ 82), this is consistent with the known property of
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`polysorbates in preventing aggregation, which by extension increases solubility by preventing
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`the formation of insoluble aggregates. Dr. MacMichael does not provide any analysis or point to
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`any data contradicting these findings in Mylan’s BLA.
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`19.
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` Dr. MacMichael also appears to add additional limitations to Mylan’s
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`construction. For example, Dr. MacMichael argues that an “organic co-solvent” must increase
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`solubility of the VEGF antagonist in a specific way: by “changing the physiochemistry of the
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`primary solvent.” MacMichael Responsive ¶ 47. Dr. MacMichael does not explain what that
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`means, nor does he explain where those requirements are found in Mylan’s construction. To the
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`contrary, Mylan’s construction does not specify how an organic co-solvent increases solubility; it
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`only requires that an “organic co-solvent” is “an organic substance added to a primary solvent to
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`increase the solubility of said VEGF antagonist.” That is the construction I applied in my
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`Opening Report.
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`20.
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`Dr. MacMichael asserts that because “aflibercept is highly soluble in water
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`alone,” polysorbate 20 cannot increase the solubility of aflibercept. MacMichael Responsive
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`¶ 48. That is incorrect. Solubility is not a binary property. A molecule could be soluble in
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`water, but have increased solubility in the presence of an organic co-solvent. Consistent with
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`that basic principle, Mylan’s proposed construction does not require that the organic co-solvent
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`is necessary for the VEGF antagonist’s solubility; it requires that the organic co-solvent
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`8
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`“increase[s] the solubility” of the VEGF antagonist. As explained above and in my Opening
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`Report, the polysorbate 20 in M710 does so by reducing insoluble aggregates.
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`21.
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`Dr. MacMichael suggests that aflibercept does not have “‘hydrophobic patches’
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`that would render it prone to hydrophobic aggregation.” MacMichael Responsive ¶ 48. I
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`disagree. Aflibercept does contain patches of hydrophobic amino acid residues, which the POSA
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`would understand to include alanine, leucine, valine, isoleucine, proline, phenylalanine,
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`methionine, and tryptophan. As is evident from the aflibercept amino acid sequence of SEQ ID
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`NO:4, there are multiple such residues among amino acids 27-457 of SEQ ID NO:4. The POSA
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`would understand that an amphiphilic molecule like polysorbate 20 would orient itself so that the
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`hydrophobic portion would be exposed to these hydrophobic portions of aflibercept, while the
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`hydrophilic portion of polysorbate 20 would expose itself to the solvent (water).
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`22.
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`I have also considered the three-dimensional structure of a substituent of
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`aflibercept, VEGFR1, domain 2. In doing so, I used the Protein Data Bank (rcsb.org) and
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`downloaded the pdb file of 5ABD, entitled, “CRYSTAL STRUCTURE OF VEGFR-1 DOMAIN
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`2 IN PRESENCE OF CU.” I confirmed via sequence alignment using BLAST
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`(https://blast.ncbi.nlm.nih.gov/) that there was 100% sequence alignment for SEQ ID NO:4 of
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`the ’865 patent, residues 30-124. Using Visual Molecular Dynamics (VMD) v. 1.9.4, I
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`visualized the structure using the Van der Waals setting, and labeled the hydrophobic residues
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`red and the hydrophilic residues blue. (Hydrophobic residues are ALA LEU VAL ILE PRO PHE
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`MET TRP,1 and I confirmed that the residues with surfaces exposed in red are those residues.)
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`The rendering below shows that there are solvent-exposed hydrophobic patches on aflibercept,
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`shown in red:
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`1 See https://www.ks.uiuc.edu/Research/vmd/mailing_list/vmd-l/11894.html.
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`Additional orientations also show surface-exposed hydrophobic patches, see Appendix A.
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`23.
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`Furthermore, I used the Protein Data Bank (rcsb.org) and downloaded the pdb file
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`of 4CHD, entitled, “Crystallographic structure of the Human IgG1 alpha 2-6 sialilated Fc-
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`Fragment.” I confirmed via sequence alignment using BLAST (https://blast.ncbi.nlm.nih.gov/)
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`that there was 100% sequence alignment for SEQ ID NO:4 of the ’865 patent, residues 249-454.
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`Using Visual Molecular Dynamics (VMD) v. 1.9.4, I visualized the structure using the van der
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`Waals setting, and labeled the hydrophobic residues red and the hydrophilic residues blue. (As
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`above, hydrophobic residues labeled are ALA LEU VAL ILE PRO PHE MET TRP, and I
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`10
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`confirmed that the residues with surfaces exposed in red are those residues.) The rendering
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`below shows that there are solvent exposed hydrophobic patches on aflibercept, shown in red:
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`Additional orientations also show surface-exposed hydrophobic patches, see Appendix B.
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`24.
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`I also tried to find a crystal structure for VEGFR2 Domain 3, but was not able to
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`find one. Nevertheless, the analyses of the domains above provide sufficient information
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`demonstrating a significant amount of exposed hydrophobic patches.
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`25.
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`As above, the POSA would understand that a surfactant would favorably interact
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`with these hydrophobic patches, consistent with the teachings of Randolph & Jones. More
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`specifically, as the surfactant concentration increases in a solution, the transfer free energy is
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`negative and the protein in the surfactant-containing solution becomes more thermodynamically
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`stable; i.e., it has lower free energy. In a solid, by contrast, the free energy does not change.
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`11
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`Thus, in the presence of the surfactant, the thermodynamic barrier for the solid to form is higher,
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`or in other words, the surfactant makes the protein more soluble.
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`26.
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`Dr. MacMichael argues that “aflibercept was sufficiently in solution and stable in
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`an aqueous formulation without the presence of polysorbate.” MacMichael Responsive ¶ 49.
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`Again, however, polysorbate 20 would increase solubility even if aflibercept is water soluble at a
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`given concentration without polysorbate 20. As above, and as explained in my Opening Report,
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`the dynamic light scattering data in Mylan’s BLA indicates that polysorbate 20 increased
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`solubility by inhibiting aggregation. Dr. MacMichael acknowledges that polysorbate 20 was
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`added “to increase stability,” MacMichael Responsive ¶ 49—and in doing so, it increases
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`solubility. Dr. MacMichael agreed with this basic principle at his deposition, explaining that “a
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`protein that is soluble can either absorb or fall out of solution in the form of aggregates or . . .
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`change its tertiary structure and lose its solubility. Adding a surfactant, such as polysorbate 80,
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`shields some of that nonspecific absorption and shields hydrophobic and hydrophilic patches on
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`the molecule preventing aggregation.”2 MacMichael Dep. 86:8-21; see MacMichael Dep.
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`228:10-20 (“Once you have achieved a certain level of aggregation, [a protein] will fall out of
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`solution.”); Opening Report ¶ 82. In other words, aggregation reflects the lack of solubility of a
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`protein.
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`27.
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`Dr. MacMichael cites the Integrity Bio Report, but this Report is consistent with
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`my conclusion that polysorbate 20 increases the solubility of aflibercept in M710.
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`2 Like polysorbate 20, the ’865 patent describes polysorbate 80 as an organic co-solvent. ’865
`patent, 3:28-30.
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`12
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`28.
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`For the reasons above and set forth in my Opening Report, my opinion is that
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`polysorbate 20 in M710 is an “organic co-solvent” under Mylan’s construction, because it is “an
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`organic substance added to a primary solvent to increase the solubility of said VEGF antagonist.”
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`I disagree with Dr. MacMichael’s view that an organic co-solvent that “comprises . . .
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`polysorbate 20” could somehow exclude polysorbate 20 from meeting the claim limitation.
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`B. M710 comprises a VEGF antagonist, “wherein at least 98% of the VEGF
`antagonist is present in native conformation following storage at 5°C. for two
`months as measured by size exclusion chromatography”
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`29. With respect to “[present in] native conformation,” I understand that Regeneron
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`has proposed that the term be given its plain and ordinary meaning in view of the claims and
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`specification and the full context in which the term appears, i.e., “wherein at least 98% of the
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`VEGF antagonist is present in native conformation following storage at 5°C. for two months as
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`measured by size exclusion chromatography.” I understand that Mylan has proposed that the
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`term be construed as “[present in] a form that does not exhibit chemical or physical instability.”
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`1.
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`Regeneron’s Construction
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`30.
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`In my Opening Report, I explained how M710 was in “native conformation . . . as
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`measured by size exclusion chromatography,” based on the understanding that “native
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`conformation” must be assessed using the technique set forth in the claims, “size exclusion
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`chromatography.” Opening Report ¶ 87. As I explained, Mylan’s BLA seeks approval for a
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`product that contains greater than 95% “monomer percentage,” which corresponds to “native
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`conformation” (or “native configuration”) in the ’865 patent, and thus falls within the scope of
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`the ’865 Asserted Claims. Opening Report ¶ 89. Furthermore,
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`31.
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`Dr. MacMichael does not dispute my evaluation of the data in Mylan’s BLA.
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`Instead, as with “organic co-solvent,” Dr. MacMichael argues about the meaning of the claim
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`term “wherein at least 98% of the VEGF antagonist is present in native conformation following
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`storage at 5°C. for two months as measured by size exclusion chromatography.” Dr.
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`MacMichael argues that even under Regeneron’s claim construction, “native conformation . . . is
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`tied to multiple stability considerations,” including aspects of physical and chemical stability that
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`could not be measured by size exclusion chromatography. MacMichael Responsive ¶¶ 76-77. I
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`disagree. While I understand that Mylan argues that its proposed construction encompasses
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`these other stability attributes, Regeneron’s proposed construction does not. Dr. MacMichael
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`does not challenge the evidence in Mylan’s BLA demonstrating that M710 is “present in native
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`conformation” under Regeneron’s proposed construction, which involves only one analytical
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`method—i.e., size exclusion chromatography. Thus, Dr. MacMichael does not offer any
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`noninfringement opinion under Regeneron’s claim construction.
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`32.
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` Dr. MacMichael does not address the specific limitations recited in claims 16 and
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`17. Accordingly, I disagree with Dr. MacMichael’s noninfringement opinions for the same
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`reasons expressed above and in my Opening Report.
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`2.
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`Mylan’s Construction
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`33.
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`As I explained in my Opening Report, M710 is also “present in native
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`conformation” under Mylan’s proposed construction of the term, which requires that the VEGF
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`antagonist is “[present in] a form that does not exhibit chemical or physical instability.” Opening
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`Report ¶¶ 95-108. As I explained, Mylan’s BLA includes data showing that aflibercept in M710
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`does not exhibit physical or chemical instability, using both size exclusion chromatography and
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`other techniques. Id.
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`34.
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`Furthermore, I explained that I applied Mylan’s proposed construction consistent
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`with its meaning to a POSA and the explanation from Dr. MacMichael. Opening Report ¶ 108.
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`However, Dr. MacMichael’s discussion of this claim limitation applies the construction in
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`inconsistent ways. In particular, it is unclear whether Dr. MacMichael believes that infringement
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`under Mylan’s construction requires only using size exclusion chromatography (the technique
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`recited in the claims) or other techniques. Dr. MacMichael states that a VEGF antagonist – “may
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`be able to comply with the SEC test found in the claims without independently satisfying the
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`‘native conformation’ standard,” suggesting that more than size exclusion chromatography is
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`necessary to evaluate whether a protein is “present in native conformation.” MacMichael
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`Responsive ¶ 72. However, two paragraphs later, Dr. MacMichael argues that all of the other
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`data in Mylan’s BLA that I addressed in my Opening Report (¶¶ 97-106) using other techniques
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`to evaluate the stability of aflibercept is irrelevant even under Mylan’s claim construction
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`because “none of these tests is SEC,” which is required to “show infringement according to the
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`Asserted Claims.” MacMichael Responsive ¶ 74. Thus, Dr. MacMichael apparently views the
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`claims as paradoxical: “native conformation” simultaneously requires testing of attributes that
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`size exclusion chromatography cannot detect, while also requiring that size exclusion
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`chromatography be used exclusively to detect them. Even Dr. MacMichael appears to be
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`confused by what methods may be used to evaluate “native conformation,” as he also argues,
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`under Regeneron’s construction, that size exclusion chromatography would not be sufficient.
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`MacMichael Responsive ¶¶ 76-77.
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`35.
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`Regardless, as I explained in my Opening Report, M710 is “present in native
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`conformation” according to each technique applied in Mylan’s BLA, and thus meets the claim
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`limitation. If proving that Mylan’s M710 meets this claim limitation requires the use of only size
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`exclusion chromatography, then M710 meets the claim limitation because the size exclusion
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`chromatography data in Mylan’s BLA after 2 months demonstrates that M710 does not exhibit
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`chemical or physical instability as measured by size exclusion chromatography, as the %
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`monomer remains above 98% for over two months in the batches evaluated. Opening Report
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`¶ 95. If, on the other hand, other tests are required to show that M710 meets this limitation, then
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`the results in the BLA evaluating Appearance, Color, Clarity, pH, Particulate Matter, Identity by
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`SDS-PAGE, Purity by Non-Reduced CE-SDS, Charge Heterogeneity by cIEF, and Relative
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`Potency confirm that aflibercept in M710 is present in native conformation. Opening Report
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`¶¶ 96-107. Dr. MacMichael does not address these results in Mylan’s BLA, and he does not
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`disagree with my conclusion that they confirm that aflibercept in M710 is present in native
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`conformation.
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`16
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`36.
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` As above, Dr. MacMichael does not address the specific limitations of claims 16
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`and 17. Accordingly, I disagree with Dr. MacMichael’s noninfringement opinions for the same
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`reasons expressed above and in my Opening Report.
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`C. M710 infringes claim 18 of the ’865 patent.
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`37.
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`In my Opening Report, I explained that M710 does not have any excipients that
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`include phosphate and thus the M710 “formulation does not contain phosphate.” Opening
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`Report ¶¶ 141-42.
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`38.
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`Dr. MacMichael does not point to any ingredients in the M710 formulation that
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`include phosphate.
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` I disagree.
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`39.
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`In my opinion, trace phosphate-containing molecules which incidentally make it
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`into a vial of M710 would not be part of the M710 “formulation.” Such molecules would instead
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`be extraneous and unwanted impurities.
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`not contain phosphate”—even if the vial also contained some miniscule amount of unwanted
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`phosphate-containing impurity.
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`17
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`Case 1:22-cv-00061-TSK-JPM Document 622 File