`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________________
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
`
`______________________
`
`Case No. IPR2021-00816
`U.S. Patent No. 9,220,631
`
`______________________
`
`DECLARATION OF DR. KENNETH S. GRAHAM
`
`Regeneron Exhibit 1102.001
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`EXHIBITS ....................................................................................................... 2
`
`III. DEVELOPMENT OF EYLEA PFS ................................................................ 2
`
`A.
`
`B.
`C.
`D.
`
`June 2010 Commercial Validation Batches of Terminally Sterilized
`EYLEA PFS .......................................................................................... 4
`Filing and Modification of BLA No. 125387 ..................................... 12
`EYLEA Approval in Australia and Europe ........................................ 14
`Clinical Studies, New Supply Chain, and Supplemental BLA for
`EYLEA PFS ........................................................................................ 15
`
`IV. DECLARATION ........................................................................................... 18
`
` i
`
`Regeneron Exhibit 1102.002
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`. 1155 REGITC00110725 — Regeneron Confidential Emails Filed Under Seal
`. 1156 REGITC00117031 — Regeneron Confidential FDA Correspondence
`
`EXHIBIT LIST
`EXHIBIT LIST
`
`Ex. 1019 U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`. 1019 U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 34 NF 29 (2011)
`Solutions, USP 34 NF 29 (2011)
`Ex. 1066 Australian Government, Department of Health and Ageing, Australian
`. 1066 Australian Government, Department of Health and Ageing, Australian
`Public Assessment Report for Aflibercept, (July 2012)
`Public Assessment Report for Aflibercept, July 2012)
`Ex. 1137 REGITC00114439 – Regeneron Confidential Report Filed Under Seal
`. 1137 REGITC00114439 — Regeneron Confidential Report Filed Under Seal
`Ex. 1138 REGITC00042686 – Vetter Confidential Report Filed Under Seal
`REGITC00042686 — Vetter Confidential Report Filed Under Seal
`. 1138
`Ex. 1139 REGITC00264748 – Regeneron Confidential Report Filed Under Seal
`REGITC00264748 — Regeneron Confidential Report Filed Under Seal
`. 1139
`Ex. 1140 REGITC00149282 – Regeneron Confidential Report Filed Under Seal
`. 1140 REGITC00149282 — Regeneron Confidential Report Filed Under Seal
`Ex. 1141 STERIS_00000489 – Steris Report Filed Under Seal
`STERIS_00000489 — Steris Report Filed Under Seal
`. 1141
`Ex. 1142 REGITC00122265 – Regeneron Confidential Report Filed Under Seal
`. 1142 REGITC00122265 — Regeneron Confidential Report Filed Under Seal
`Ex. 1143 REGITC00116953 – Vetter Confidential Report Filed Under Seal
`. 1143 REGITC001 16953 — Vetter Confidential Report Filed Under Seal
`Ex. 1144 REGITC01008782 – Vetter Confidential Report Filed Under Seal
`REGITC01008782 — Vetter Confidential Report Filed Under Seal
`. 1144
`Ex. 1145 REGITC00381349 – Regeneron Confidential Report Filed Under Seal
`REGITC00381349 — Regeneron Confidential Report Filed Under Seal
`. 1145
`Ex. 1146 REGITC00255816 – Bayer Correspondence with EMEA Filed Under
`. 1146 REGITC00255816 — Bayer Correspondence with EMEAFiled Under
`Seal
`Seal
`Ex. 1147 REGITC00883958 – Regeneron Confidential Memorandum Filed
`. 1147 REGITC00883958 — Regeneron Confidential Memorandum Filed
`Under Seal
`Under Seal
`Ex. 1148 REGITC00264472 – Regeneron Confidential Memorandum Filed
`. 1148 REGITC00264472 — Regeneron Confidential Memorandum Filed
`Under Seal
`UnderSeal
`Ex. 1149 REGITC01066319 – Regeneron Confidential Memorandum Filed
`REGITC01066319 — Regeneron Confidential Memorandum Filed
`. 1149
`Under Seal
`UnderSeal
`Ex. 1150 REGITC00149657 – EMA Assessment Report Filed Under Seal
`REGITC00149657 — EMA Assessment Report Filed Under Seal
`1150
`Ex.
`Ex. 1151 REGITC00381924 – Regeneron Confidential Memorandum Filed
`Ex. 1151 REGITC00381924 — Regeneron Confidential Memorandum Filed
`Under Seal
`Under Seal
`Ex. 1152 REGITC00041726 – Regeneron Confidential Presentation Filed Under
`Ex. 1152 REGITC00041726 — Regeneron Confidential Presentation Filed Under
`Seal
`Seal
`Ex. 1153 REG_SDNY_02214433 – EMA Correspondence Filed Under Seal
`REG_SDNY_02214433 — EMA Correspondence Filed Under Seal
`. 1153
`Ex. 1154 REGITC00160863 – Regeneron Confidential Memorandum Filed
`REGITC00160863 — Regeneron Confidential Memorandum Filed
`. 1154
`Under Seal
`UnderSeal
`Ex. 1155 REGITC00110725 – Regeneron Confidential Emails Filed Under Seal
`Ex. 1156 REGITC00117031 – Regeneron Confidential FDA Correspondence
`Filed Under Seal
`Filed UnderSeal
`
`ii
`ii
`
`Regeneron Exhibit 1102.003
`Regeneron v. Novartis
`IPR2021-00816
`
`Regeneron Exhibit 1102.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`
`I, Kenneth S. Graham, declare as follows:
`I.
`Introduction
`1.
`I am Senior Director at Regeneron Pharmaceuticals, Inc. (“Regeneron”)
`
`and I have been employed at Regeneron since January 21, 2002.
`
`2.
`
`I earned a B.S. in Animal Bioscience from Penn State University in
`
`1983 and an M.S. in Veterinary Science from Penn State University in 1986. I then
`
`earned a Ph.D in Bioorganic Chemistry from the California Institute of Technology
`
`in 1992.
`
`3.
`
`I have worked on Regeneron’s biologic drug EYLEA® (aflibercept)
`
`(“EYLEA”) since 2003. My initial involvement was developing fit for purpose
`
`analytical methods that were used to characterize the protein and ensure its quality.
`
`While working in the Regeneron pilot manufacturing facility at Tarrytown, New
`
`York, I helped to produce and ensure the release of the first clinical batches that were
`
`used during development of the drug. In 2005, I transferred pilot manufacturing into
`
`pre-clinical development and joined the Formulation Development Group (“FDG”).
`
`4.
`
`In 2005, I became the FDG Program Lead of EYLEA and was
`
`responsible for the development of EYLEA in both vial and pre-filled syringe
`
`presentations. My role in the development of EYLEA pre-filled syringe included
`
`defining quality attributes, studying the stability of the product, evaluating syringe
`
`offerings and specifications from Vetter, evaluating particulate matter and
`
`
`
`1
`
`Regeneron Exhibit 1102.004
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`siliconization, and evaluating and developing methods of terminally sterilizing the
`
`pre-filled syringes.
`
`5.
`
`I have personal knowledge of the facts set forth below.
`
`II. Exhibits
`6.
`Exs. 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146,
`
`1147, 1148, 1149, 1150, 1151, 1152, and 1153 are true and correct copies of records
`
`that were either created or received by an employee of Regeneron as part of that
`
`employee’s job duties relating to the development of EYLEA and regulatory
`
`submissions for EYLEA. The records were maintained by Regeneron in the
`
`ordinary course of business.
`
`7.
`
`Exs. 1154 and 1155 are true and correct copies of records of email or
`
`letter correspondence sent by an employee of Regeneron as part of that employee’s
`
`job duties relating to the development of EYLEA and regulatory submissions for
`
`EYLEA. The records were maintained by Regeneron in the ordinary course of
`
`business.
`
`III. Development of EYLEA PFS
`8.
`EYLEA is a biotherapeutic product developed for intravitreal injection
`
`that is designed to treat diseases of the eye, such as Wet Age-related Macular
`
`Degeneration (“wAMD”).
`
`
`
`2
`
`Regeneron Exhibit 1102.005
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`9.
`
`In 2004, Regeneron began its clinical development of Eylea® for use
`
`in treating eye disease. Regeneron began developing the pre-filled syringe
`
`presentation of EYLEA (“EYLEA PFS”) in 2005 in collaboration with Vetter
`
`Pharma-Fertigung GmbH & Co. KG (“Vetter”).
`
`10. On December 1, 2005, Regeneron and Vetter entered into a
`
`development agreement to develop an EYLEA PFS.
`
`11. At the time, Vetter offered both sprayed and baked-on options for
`
`siliconization of a 1 ml syringe barrel. Ex. 1152 (3/16/2006 presentation identifying
`
`syringes examined as being prepared with “sprayed silicone” or “baked emulsion
`
`silicon treatment”). Regeneron ultimately selected the baked-on siliconization
`
`option.
`
`12. By October 2007, Regeneron and Vetter had manufactured batches of
`
`1 ml EYLEA PFS for clinical use. Ex. 1137 is a batch status form confirming the
`
`manufacture of 5,629 prefilled 1 ml syringes containing EYLEA on October 24,
`
`2007. Ex. 1138 shows that the syringe barrels were siliconized using a baked-on
`
`silicone process on Vetter’s CR01 production line that involved application of
`
`DC365 emulsion diluted to 1.75% silicone oil (also referred to as a 1:20 emulsion).
`
`In paragraphs 22-30 below, I provide more detail regarding the amount of silicone
`
`oil applied using this baked-on process.
`
`
`
`3
`
`Regeneron Exhibit 1102.006
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`13. With respect to sterilization, the FDA informed Regeneron in 2008 that
`
`terminally sterilizing the outside of the prefilled syringe would be a requirement for
`
`launching a prefilled syringe containing EYLEA. Ex. 1155 is November 2008 email
`
`from
`
`, who was regulatory lead at Regeneron on EYLEA at the
`
`time, relaying the FDA’s requirement for sterilization of the outside of the prefilled
`
`syringe within the blister pack. Based on this requirement specified by FDA,
`
`Regeneron proceeded to develop a commercial terminal sterilization process for the
`
`EYLEA PFS.
`
`A.
`
`14.
`
`June 2010 Commercial Validation Batches of Terminally
`Sterilized EYLEA PFS
`In June 2010, three consecutive validation batches of terminally
`
`sterilized EYLEA PFS were manufactured. The syringes were filled at Vetter in
`
`March and April 2010, and then terminally sterilized at Steris in Syracuse, NY in
`
`June 2010 using vaporized hydrogen peroxide (“VHP”). The table below is an
`
`excerpt from Ex. 1139, which is a portion of the Biologics Licensing Application
`
`(“BLA”) No. 125387 submitted to FDA in February 2011. The commercial scale
`
`validation batch numbers are C08011M640N11, C08012M640N11, and
`
`C08014M640N11.
`
`
`
`4
`
`Regeneron Exhibit 1102.007
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`Ex. 1139.019
`
`15. The table below is an excerpt from Ex. 1140, which is another portion
`
`of BLA No. 125387, showing that the number of syringes manufactured in these
`
`commercial scale validation batches was roughly 25,000 syringes each.
`
`Ex. 1140.005
`
`16. These commercial scale validation batches were sterilized in a VHP
`
`
`
`chamber developed with Steris as shown in exemplary pictures below from Ex.
`
`1141.010, .012, .01, which is a Cycle Development Report dated 12/7/2010
`
`
`
`5
`
`Regeneron Exhibit 1102.008
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`regarding VHP sterilization of the EYLEA PFS. As depicted below, each tray
`
`contains 54 blister packs, with each blister pack containing a prefilled syringe. The
`
`trays are loaded onto skids, and the skids are then placed into the sterilization
`
`chamber. The cycle report explains that a
`
` Id. at .020.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`6
`
`Regeneron Exhibit 1102.009
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`
`
`17. Ex. 1142 contains excerpts from the official batch record for
`
`commercial validation batch no. C08012M640N11. The Quality Assurance Batch
`
`Status Form identifies the product as “VEGF Trap ITV Drug Product, 40 mg/mL
`
`(50 µL/1 mL syringe)” and confirms the batch size of 25,063 prefilled syringes. Ex.
`
`1142.001.
`
`18. Page .005 of Ex. 1142 is titled “Summary of Analysis” and includes an
`
`assessment as to whether commercial validation batch no. C08012M640N11 met
`
`certain acceptance criteria. Ex. 1142.005.
`
`
`
`. The “Summary of Analysis” describes that the syringes
`
`manufactured in the batch were “pre-filled syringes” that included an “aqueous
`
`solution of VEGF Trap recombinant protein for injection [at] 40 mg/mL.” Id. The
`
`pre-filled syringes were also “subjected to the Vaporized Hydrogen (VHP)
`
`sterilization process.” Id.
`
`19. The Summary of Analysis confirms that commercial validation batch
`
`no. C08012M640N11 met the requirement of no more than 50 particles greater than
`
`10 µm in diameter per mL, no more than 5 particles greater than 25 µm in diameter
`
`
`
`
`
`
`
`
`
`7
`
`Regeneron Exhibit 1102.010
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`per mL, and no more than 2 particles greater than 50 µm in diameter per mL. Ex.
`
`1142.005. These criteria are a requirement of USP789 for ophthalmic solutions
`
`using the microscopic method. Ex. 1019.005-.006.
`
`20. The Summary of Analysis confirms that commercial validation batch
`
`no. C08012M640N11 also met the requirements for break out force (also known as
`
`break loose force) and sustaining force (also known as glide force or slide force). A
`
`break out force of
`
` and a sustaining force of
`
` were reported for syringes
`
`from the batch. Ex. 1142.005.
`
`21. The Summary of Analysis confirms that commercial validation batch
`
`no. C08012M640N11 met the sterility requirement.
`
`. Ex. 1142.005.
`
` Ex. 1151.002 (
`
`”).
`
`
`
`
`
`
`
`
`
`
`
`
`
`22. As detailed below, the commercial validation batches included syringe
`
`barrels that were siliconized at Vetter using a baked-on process with a 1.75% diluted
`
`DC365 emulsion that results in the application of between
`
` and
`
` µg of silicone
`
`oil to the glass barrel.
`
`
`
`8
`
`Regeneron Exhibit 1102.011
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`23. Ex. 1140.004
`
`24. Ex. 1143 is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`25. Page .011 of Ex. 1143 confirms that a DC365 emulsion diluted to
`
`1.75% (i.e., 1:20 emulsion) is used to siliconize the syringe barrel, which is the same
`
`diluted emulsion used for the October 2007 batches.
`
`26.
`
`
`
`
`
`
`
`
`
`
`
`9
`
`
`
`Regeneron Exhibit 1102.012
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`27.
`
`NN20N
`
`28.
`
`29.
`Ny s©
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`— So
`
`Regeneron Exhibit 1102.013
`Regeneron Exhibit 1102.013
`Regeneron v. Norvatis
`Regeneron v. Norvatis
`IPR2021-00816
`IPR2021-00816
`
`

`

`30.
`bo S
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11
`11
`
`Regeneron Exhibit 1102.014
`Regeneron Exhibit 1102.014
`Regeneron v. Norvatis
`Regeneron v. Norvatis
`IPR2021-00816
`IPR2021-00816
`
`

`

`
`
`B.
`Filing and Modification of BLA No. 125387
`31. On February 11, 2011, Regeneron filed BLA No. 125387 with FDA
`
`seeking approval of EYLEA. The BLA included four vial presentations and two
`
`pre-filled syringe presentations for EYLEA shown in the table below.
`
`Presentation
`Vial
`Vial
`Vial
`Vial
`PFS (VHP)
`PFS (EtO)
`
`32.
`
`
`
`Dose Concentration
`10 mg/ml
`40 mg/ml
`10 mg/ml
`40 mg/ml
`40 mg/ml
`40 mg/ml
`
`Manufacturer
`Vetter
`Vetter
`JHP
`JHP
`Vetter
`Vetter
`
`
`
`
`
`However, when it became apparent that FDA would not be able to timely complete
`
`review of the BLA given the large number of presentations, Regeneron made a
`
`decision to formally withdraw three vial presentations and both prefilled syringe
`
`presentations, thereby leaving one vial presentation in the BLA. The decision to
`
`withdraw the prefilled syringe presentations was based on facilitating FDA’s review
`
`and approval of EYLEA, and not because of any safety concerns regarding the
`
`prefilled syringe presentation.
`
`33. Ex. 1156 is an August 10, 2011 letter from
`
` at Regeneron to
`
` at FDA regarding BLA No. 125387. This letter informs FDA
`
`of Regeneron’s “intention to withdraw all dosage forms except the 40 mg/mL Vetter
`
`
`
`12
`
`Regeneron Exhibit 1102.015
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`vials from consideration in the initial BLA” in order “[t]o streamline completion of
`
`the BLA review.” Ex. 1156.001 (emphasis in original).
`
`34. Ex. 1146 is a document that Bayer2 submitted to the European
`
`Medicines Evaluation Agency (“EMA”) as part of its regulatory filing for EYLEA.
`
`Bayer’s submission to the EMA retained the pre-filled syringe presentation. Ex.
`
`1146 explains that “[t]he reason for the withdrawal of the PFS presentation [from
`
`the U.S. FDA regulatory application] was to facilitate completion of the BLA
`
`review. The withdrawal of the PFS was not related to safety concerns.” Ex.
`
`1146.001. The document also notes that “[i]t was discussed with the FDA that to
`
`facilitate completion of review, it would make sense to focus on a single presentation
`
`for initial approval and request approval of the additional configurations in
`
`supplemental applications. The vial presentation was deemed to be the most straight-
`
`forward in terms of data available at the time in the six month priority review cycle.
`
`FDA concurred with this determination.” Id.
`
`35. FDA approved EYLEA in the vial presentation in November 2011, and
`
`it achieved greater success than anticipated. Regeneron was anticipating EYLEA
`
`would have sales
`
`product.
`
`, but within a year it was a billion dollar
`
`
`2 Bayer partnered with Regeneron to commercialize EYLEA outside the United
`States.
`
`
`
`13
`
`Regeneron Exhibit 1102.016
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`C. EYLEA Approval in Australia and Europe
`36. The terminally sterilized EYLEA prefilled syringe was approved in
`
`Australia and Europe in March 2012 and November 2012, respectively. Ex. 1149 is
`
`a document detailing Regeneron’s EYLEA “AMD Program Global Development
`
`Plan” and confirms that approval in Australia was granted in March 2012. Ex. 1150
`
`is the EMA’s Assessment Report of Bayer’s EYLEA registration filing, dated
`
`September 20, 2012, and states that “in the light of the overall data submitted and
`
`the scientific discussion within the Committee, issued a positive opinion for granting
`
`a Marketing Authorisation to Eylea.” Ex. 1150.007; see also Ex. 1153.005
`
`(“Aflibercept was officially approved for use in the European Union (EU) by the
`
`European Commission (EC) on November 22, 2012”).
`
`37. The Therapeutic Goods Authority (“TGA”) of Australia issued an
`
`Australian Public Assessment Report for Aflibercept that published on July 30,
`
`2012. Ex. 1066. The report identifies the product as “Eylea” and with both “Pre-
`
`filled syringe and vial” containers. Id. at .005. The report further describes that
`
`“[t]he syringe presentation is supplied in glass 1 mL syringes…One blister package
`
`contains one syringe…[and] [b]listers containing the syringe are either hydrogen
`
`peroxide (H2O2)-sterilised or ethylene oxide (ETO)-sterilised.” Id. at .007.
`
`38. The EMA Assessment report on September 20, 2012 identifies the
`
`product as Aflibercept, and identifies both a vial presentation and “a pre-filled
`
`
`
`14
`
`Regeneron Exhibit 1102.017
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`syringe that is terminally sterilised.” Ex. 1150.010; Id. at .012 (“The [drug product]
`
`appears in two presentations differing in terms of primary container type: 2 ml type
`
`I glass vials and 1ml pre-filled syringes.”). The report further explains that “[i]n
`
`2007, a pre-filled syringe has been developed [and] [i]n 2009, an external
`
`sterilization step was added to the proposed pre-filled syringe manufacturing process
`
`after secondary packaging to render the external surface of the syringe and the
`
`internal surface of the blister as sterile.” Id. at .012.
`
`D. Clinical Studies, New Supply Chain, and Supplemental BLA for
`EYLEA PFS
`39. After EYLEA was approved in a vial presentation in November 2011,
`
`Regeneron continued to use and pursue commercialization of the pre-filled syringe
`
`presentation.
`
`40.
`
`41.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`15
`
`Regeneron Exhibit 1102.018
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`
`
`|
`
`42.
`
`
`
`43.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`16
`16
`
`Regeneron Exhibit 1102.019
`Regeneron Exhibit 1102.019
`Regeneron v. Norvatis
`Regeneron v. Norvatis
`IPR2021-00816
`IPR2021-00816
`
`

`

`
`
` Regeneron ultimately filed a supplemental BLA seeking approval of the
`
`EYLEA prefilled syringe in June 2018, and it was approved in August 2019.
`
`
`
`
`
`
`
`17
`
`Regeneron Exhibit 1102.020
`Regeneron v. Norvatis
`IPR2021-00816
`
`

`

`IV. Declaration
`
`44.
`
`I declare that all statements made herein of my own knowledgeare true
`
`and that all statements made on information and belief are believed to be true; and
`
`further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Dated:
`
`// Apr: / ZOZZ
`
`By:
`
`18
`
`Regeneron Exhibit 1102.021
`Regeneron Exhibit 1102.021
`Regeneron v. Norvatis
`Regeneron v. Norvatis
`IPR2021-00816
`IPR2021-00816
`
`