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 Owners
`
`__________
`
`
`Case IPR2020-1318
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF MARIE PICCI IN SUPPORT OF NOVARTIS’S
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`
`
`Novartis Exhibit 2030.001
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`__________
`
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`__________
`
`
`Case IPR2020-1318
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF MARIE PICCI IN SUPPORT OF NOVARTIS’S
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`
`
`Novartis Exhibit 2030.001
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`
`
`
`TABLE OF CONTENTS
`INTRODUCTION ................................................................................................................. 1
`I.
`INVENTION OF THE CLAIMED SUBJECT MATTER............................................. 2
`II.
`III. REDUCTION TO PRACTICE ...................................................................................... 13
`IV. DILIGENCE ..................................................................................................................... 14
`V.
`DECLARATION.............................................................................................................. 22
`
`
`
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`
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`ii
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`Novartis Exhibit 2030.002
`Regeneron v. Novartis, IPR2020-01318
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`
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`I.
`
`INTRODUCTION
`I, Marie Picci, have personal knowledge of the facts set forth in this
`1.
`
`Declaration and am competent to testify concerning the same.
`
`2.
`
`I joined Novartis AG, the owner of United States Patent No.
`
`9,220,631 (the “’631 patent”), in 2006. I work at Novartis AG’s Basel,
`
`Switzerland location. From 2006–2014, I held the title of Senior Project
`
`Leader/Principal Device Engineer/ Team Lead for Device Development. In 2014,
`
`I became the Group Head of Portfolio Management for Device Development. I
`
`started working on the Lucentis® pre-filled syringe (“PFS”) project around April
`
`2011. As Device Team Leader, I was responsible for the device constituent of the
`
`PFS, which includes the syringe components. My work focused on the
`
`development of the integral parts of the device, including siliconization and
`
`sterilization of the PFS. I worked on the PFS project until late 2018, when I
`
`transitioned to my current role as the Delivery Systems Strategy Director for
`
`Device Development & Life Cycle Management (“LCM”).
`
`3.
`
`I am familiar with the subject matter claimed in the ’631 patent. I am
`
`a named inventor of the ’631 patent.
`
`4.
`
`I have been asked to provide this declaration to explain the facts and
`
`circumstances surrounding the invention described in the ’631 patent.
`
`5.
`
`The documents cited in this document were generated as part of the
`
`IPR2020-01318
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`
`
`Novartis Exhibit 2030.003
`Regeneron v. Novartis, IPR2020-01318
`
`
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`ordinary course of business at Novartis AG (“Novartis”). Through my
`
`employment with Novartis, I am familiar with Novartis’s practices regarding the
`
`creation and maintenance of such documents. The documents cited were made at
`
`or near the time referenced in the document by someone with knowledge of the
`
`subject matter relevant to the document. The documents were kept in the course of
`
`Novartis’s regularly conducted research and development activities, and making
`
`these documents was a regular practice of these activities.
`
`II.
`
`INVENTION OF THE CLAIMED SUBJECT MATTER
`I, along with my co-inventors, Juergen Sigg, Christophe Royer,
`6.
`
`Andrew Mark Bryant, and Heinrich Martin Buettgen conceived of the invention
`
`claimed in the ’631 patent by no later than July 2012. Specifically, no later than
`
`October 2011, we had conceived of, e.g., a terminally sterilized PFS for intravitreal
`
`injection, the syringe components comprising a glass barrel, a stopper and a
`
`plunger rod, and containing a solution comprising a VEGF antagonist. The PFS
`
`we conceived of also had, e.g., a maximum fill volume of either 0.5 mL or 1 mL,
`
`the syringe barrel included from about 1 µg to 100 µg silicone oil, the VEGF
`
`antagonist had no more than two particles greater than 50 µm in diameter per mL,
`
`and the syringe had a stopper break loose force of less than about 11 N.
`
`7.
`
`Our conception is corroborated by, for example, a PowerPoint
`
`presentation we presented to the Technical Development Review Committee in
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`IPR2020-01318
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`Novartis Exhibit 2030.004
`Regeneron v. Novartis, IPR2020-01318
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`
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`October 2011, entitled RFB002 (Lucentis) Pharmaceutical Development Technical
`
`Review (“Development Technical Review” or “DTR”). Ex. 2031. Ex. 2031 is a
`
`true and correct copy of the Development Technical Review PowerPoint slide
`
`deck. The Development Technical Review was authored by Juergen Sigg, and
`
`summarizes our work to that point on the development of an intravitreal PFS for
`
`Novartis’s Lucentis® product, which includes ranibizumab as an active ingredient,
`
`and provides details concerning the properties and features we intended the PFS to
`
`have. Id.
`
`8.
`
`The Development Technical Review describes
`
`
`
`
`
`
`
`
`
`
`
` Ranibizumab, the active ingredient in Lucentis®, is a VEGF
`
`antagonist administered by intravitreal injection. See Ex. 1027.001 and .004 (then-
`
`current Lucentis® prescribing information identifying Lucentis® (ranibizumab) as
`
`a monoclonal antibody fragment that binds to and inhibits VEGF and administered
`
`via intravitreal injection).
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`IPR2020-01318
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`Novartis Exhibit 2030.005
`Regeneron v. Novartis, IPR2020-01318
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`9.
`
`
`
`10.
`
`11.
`
`
`
` Ex. 1034.002.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`12. Other documents corroborate that we had conceived of certain
`
`additional limitations not expressly identified in the Development Technical
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`IPR2020-01318
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`Novartis Exhibit 2030.006
`Regeneron v. Novartis, IPR2020-01318
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`
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`Review.1 For example, another Novartis document
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`
`
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`
`
`
`
`
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`
`
`13. Furthermore, on July 3, 2012, we filed European Patent Application
`
`No. EP 12174860 (“EP ’860”) directed to our novel PFS, to which the ’631 patent
`
`claims priority. Ex. 1035. EP ’860 confirms that our PFS would have a “syringe
`
`barrel [with] an internal coating of silicone that has an average thickness of about
`
`450nm or less.” Ex. 1035.008 at 17–18. The PFS could include a “non-antibody
`
`VEGF antagonist,” such as “aflibercept,” Ex. 1035.009 at 8–13, including at a
`
`concentration of “40 mg/ml,” Ex. 1035.017 at 8–13. EP ’860 further indicates that
`
`
`A significant amount of effort went into developing the Lucentis PFS both
`
`1
`
`before and after the October 2011 Development Technical Review, and that work
`
`is reflected in the records maintained by Novartis. If it were required, many
`
`additional documents could be cited detailing the extensive research and
`
`development effort that went into the PFS and led to the Novartis patent filings.
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`IPR2020-01318
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`Novartis Exhibit 2030.007
`Regeneron v. Novartis, IPR2020-01318
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`
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`antibody VEGF antagonists had already “been approved for human use,”
`
`indicating that we intended that PFSs with non-antibody VEGF antagonists could
`
`be used with patients who had already received treatment with an antibody VEGF
`
`antagonist. Ex. 1035.009 at 5–7. Moreover, following terminal sterilization with
`
`ethylene oxide, the outer surface of the syringe would have “≤ 1 ppm … EtO
`
`residue,” which would be less than or equal to 0.1 mg outside the syringe and
`
`inside the blister pack. Ex. 1035.013 at 9–10. Also, “≤5% of the VEGF antagonist
`
`[would be] alkylated.” Ex. 1035.013 at 7–9; .017 at 26–27.
`
`14. The following table summarizes the corroborating support
`
`demonstrating that we had conceived of all of the claimed subject matter of the
`
`’631 patent no later than July 18, 2012:
`
`Claim 1
`
`1. A pre-filled, terminally
`sterilized syringe for intravitreal
`injection,
`
`the syringe comprising a glass
`body forming a barrel, a stopper
`and a plunger and
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`IPR2020-01318
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`
`
`Novartis Exhibit 2030.008
`Regeneron v. Novartis, IPR2020-01318
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`
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`containing an ophthalmic solution
`which comprises a VEGF-
`antagonist, wherein:
`
`
`(a) the syringe has a nominal
`maximum fill volume of between
`about 0.5 ml and about 1 ml,
`
`
`(b) the syringe barrel comprises
`from about 1 µg to 100 µg
`silicone oil,
`
`(c) the VEGF antagonist solution
`comprises no more than 2
`particles >50 μm in diameter per
`ml
`
`and wherein the syringe has a
`stopper break loose force of less
`than about 11N.
`
`
`IPR2020-01318
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`
`
`Novartis Exhibit 2030.009
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`Claim 2
`
`2. The syringe barrel has an
`internal coating of silicone oil that
`has an average thickness of about
`450 nm or less.
`
`“syringe barrel [with] an internal coating of
`silicone that has an average thickness of
`about 450nm or less.” Ex. 1035.008 at 17–
`18.
`
`See claim 1(b).
`
`
`See claim 1(c).
`
`
`Claim 3
`
`3. A pre-filled syringe according
`to claim 1, wherein the syringe
`barrel has an internal coating of
`from about 3 μg to about 100 ug
`silicone oil.
`
`Claim 4
`
`4. A pre-filled syringe according
`to claim 1, wherein the silicone
`oil is DC365 emulsion.
`
`Claim 5
`
`5. A pre-filled syringe according
`to claim 1, wherein the VEGF
`antagonist solution further
`comprises one or more of (i) no
`
`diameter per ml, and (ii) no more
`
`more than 5 particles ≧25 μm in
`than 50 particles ≧10 μm in
`
`diameter per ml.
`
`Claim 6
`
`6. A pre-filled syringe according
`to claim 1, wherein the VEGF
`
`See claim 1(c).
`
`
`IPR2020-01318
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`
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`
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`
`
`Novartis Exhibit 2030.010
`Regeneron v. Novartis, IPR2020-01318
`
`
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`antagonist solution meets
`USP789.
`
`Claim 7
`
`7. A pre-filled syringe according
`to claim 1, wherein the VEGF
`antagonist is an anti-VEGF
`antibody.
`
`Claim 8
`
`8. A pre-filled syringe according
`to claim 7, wherein the anti-
`VEGF antibody is ranibizumab.
`
`Claim 9
`
`9. A pre-filled syringe according
`to claim 8, wherein the
`ranibizumab is at a concentration
`of 10 mg/ml.
`
`Claim 10
`
`10. A pre-filled syringe according
`to claim 8, wherein the silicone
`oil has a viscosity of about 350
`cP,
`
`
`
`
`
`
` Ex. 1034.002.
`
`See claim 1(c).
`
`and the VEGF antagonist solution
`further comprises one or more of
`
`μm in diameter per ml, and (ii) no
`
`(i) no more than 5 particles ≧25
`more than 50 particles ≧10 μm in
`
`diameter per ml.
`
`Claim 11
`
`11. A pre-filled syringe according
`to claim 1 wherein the VEGF
`
`The PFS could include a “non-antibody
`VEGF antagonist,” such as “aflibercept,”
`
`IPR2020-01318
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`
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`
`
`Novartis Exhibit 2030.011
`Regeneron v. Novartis, IPR2020-01318
`
`
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`antagonist is a non-antibody
`VEGF antagonist.
`
`including at a concentration of “40 mg/ml.”
`Ex. 1035.009 at 8–13; .017 at 8–13.
`
`Claim 12
`
`12. A pre-filled syringe according
`to claim 11, wherein the non-
`antibody VEGF antagonist is
`aflibercept or conbercept.
`
`See claim 11.
`
`Claim 13
`
`13. A pre-filled syringe according
`to claim 12, wherein the non-
`antibody VEGF antagonist is
`aflibercept at a concentration of
`40 mg/ml.
`
`Claim 14
`
`14. A pre-filled syringe according
`to claim 1, wherein the syringe
`has a stopper break loose force of
`less than about 5N, and wherein
`the syringe has a stopper slide
`force of less than about 5N.
`
`Claim 15
`
`15. A pre-filled syringe according
`to claim 14, wherein the stopper
`break loose force or stopper slide
`force is measured using a filled
`syringe, at a stopper travelling
`speed of 190 mm/min, with a 30
`G×0.5 inch needle attached to the
`syringe.
`
`Claim 16
`
`IPR2020-01318
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`
`
`See claim 12.
`
`
`
`
`
`Novartis Exhibit 2030.012
`Regeneron v. Novartis, IPR2020-01318
`
`
`
`See claim 14.
`
`16. A pre-filled syringe according
`to claim 1, wherein the syringe
`has a stopper slide force of less
`than about 11N.
`
`Claim 17
`
`17. A blister pack comprising a
`pre-filled syringe according to
`claim 1, wherein the syringe has
`been sterilised using H2O2 or EtO.
`
`Claim 18
`
`Following terminal sterilization with
`ethylene oxide, the outer surface of the
`syringe would have “≤ 1 ppm … EtO
`residue,” which would be less than or equal
`to 0.1 mg outside the syringe and inside the
`blister pack. Ex. 1035.013 at 9–10.
`
`See claim 18. <1 ppm would be less than or
`equal to 0.1 mg EtO outside the syringe and
`inside the blister pack. Ex. 1035.013 at 9–
`10.
`
`18. A blister pack comprising a
`pre-filled syringe according to
`claim 17, wherein the outer
`
`surface of the syringe has ≦1 ppm
`
`EtO or H2O2 residue.
`
`Claim 19
`
`19. A blister pack comprising a
`pre-filled syringe according to
`claim 17, wherein the syringe has
`been sterilised using EtO or H2O2
`and the total EtO or H2O2 residue
`found on the outside of the
`syringe and inside of the blister
`
`pack is ≦0.1 mg.
`
`Claim 20
`
`IPR2020-01318
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`
`
`Novartis Exhibit 2030.013
`Regeneron v. Novartis, IPR2020-01318
`
`
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`“≤5% of the VEGF antagonist [would be]
`alkylated.” Ex. 1035.013 at 7-9; .017 at 26–
`27.
`
`See claim 1(b).
`
`
`
`
`
`
` Ex. 1034.002.
`
`20. A blister pack comprising a
`pre-filled syringe according to
`
`VEGF antagonist is alkylated.
`
`claim 18, wherein ≦5% of the
`
`Claim 21
`
`21. A blister pack comprising a
`pre-filled syringe according to
`claim 17, wherein the syringe has
`been sterilised using EtO or H2O2
`with a Sterility Assurance Level
`of at least 10−6.
`
`Claim 22
`
`22. A pre-filled syringe according
`to claim 1, wherein the syringe
`barrel has an internal coating of
`from about 1-50 μg silicone oil.
`
`Claim 23
`
`23. A pre-filled syringe according
`to claim 1, wherein the silicone
`oil has a viscosity of about 350
`cP.
`
`Claim 24
`
`24. A method of treating a patient
`suffering from of an ocular
`disease selected from choroidal
`neovascularisation, wet age-
`related macular degeneration,
`macular edema secondary to
`retinal vein occlusion (RVO)
`including both branch RVO
`(bRVO) and central RVO
`(cRVO), choroidal
`
`IPR2020-01318
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`
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`Novartis Exhibit 2030.014
`Regeneron v. Novartis, IPR2020-01318
`
`
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`neovascularisation secondary to
`pathologic myopia (PM), diabetic
`macular edema (DME), diabetic
`retinopathy, and proliferative
`retinopathy, comprising the step
`of administering an ophthalmic
`solution to the patient using a pre-
`filled syringe according to claim
`1.
`
`Claim 25
`
`25. The method of claim 24,
`further comprising an initial
`priming step in which the
`physician depresses the plunger of
`the pre-filled syringe to align the
`pre-determined part of the stopper
`with the priming mark.
`
`Claim 26
`
`26. A method according to claim
`24, wherein the VEGF antagonist
`administered is a non-antibody
`VEGF antagonist and wherein the
`patient has previously received
`treatment with an antibody VEGF
`antagonist.
`
`The PFS could include a “non-antibody
`VEGF antagonist,” such as “aflibercept,”
`including at a concentration of “40 mg/ml.”
`Ex. 1035.009 at 8-13; .017 at 8-13. EP ’860
`further indicates that antibody VEGF
`antagonists had already “been approved for
`human use,” indicating that we intended that
`PFSs with non-antibody VEGF antagonists
`could be used with patients who had already
`received treatment with an antibody VEGF
`antagonist. Ex. 1035.009 at 5–7.
`
`
`
`III. REDUCTION TO PRACTICE
`I and my co-inventors filed another European Patent Application, EP
`15.
`
`12189649 (“EP ’649”), on October 23, 2012. Ex. 2023. On January 23, 2013, we
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`IPR2020-01318
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`
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`Novartis Exhibit 2030.015
`Regeneron v. Novartis, IPR2020-01318
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`
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`filed U.S. Patent Application No. 13/750,352 (Ex. 2044), which I understand
`
`issued as the ’631 patent. I executed an inventor declaration on February 8, 2013,
`
`and it was filed on March 27, 2013. Ex. 1002.0700.
`
`IV. DILIGENCE
`16. From July 2012 through January 2013, we worked diligently
`
`
`
`
`
`
`
`meetings,
`
` At these
`
`
`
` The minutes from
`
`these meetings reflect that ongoing work. I regularly attended these meetings with
`
`other inventors.
`
`17. These team meetings are
`
` meeting minutes are identified and summarized in the
`
`following table:
`
`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
`
`Novartis Exhibit 2030.016
`Regeneron v. Novartis, IPR2020-01318
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`
`
`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
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`Novartis Exhibit 2030.017
`Regeneron v. Novartis, IPR2020-01318
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`
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`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
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`Novartis Exhibit 2030.018
`Regeneron v. Novartis, IPR2020-01318
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`
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`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
`
`
`
`
`Novartis Exhibit 2030.019
`Regeneron v. Novartis, IPR2020-01318
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`
`
`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
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`Novartis Exhibit 2030.020
`Regeneron v. Novartis, IPR2020-01318
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`
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`Meeting Date
`
`Activities described in Meeting Minutes
`
`IPR2020-01318
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`
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`Novartis Exhibit 2030.021
`Regeneron v. Novartis, IPR2020-01318
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`Meeting Date
`
`Activities described in Meeting Minutes
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`IPR2020-01318
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`Novartis Exhibit 2030.022
`Regeneron v. Novartis, IPR2020-01318
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`Meeting Date
`
`Activities described in Meeting Minutes
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`
`
`
`
`IPR2020-01318
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`Novartis Exhibit 2030.023
`Regeneron v. Novartis, IPR2020-01318
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`
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`V. DECLARATION
`18. I hereby declare tlrat all statements made herein of my own
`
`knowledge axe true and that all statements made on information and belief are
`
`believed to be true. I finttrer declare that all of my statements are made with the
`
`knowledge that willful false statements are punishable by fine or imprisonment, or
`
`both, under Section 1001 of Title 18 of the United States Code.
`
`Dated: 2-LorJ*lr^ Z*7- ,r,W
`
`rPR2020-01317
`ACTr\,lEll05557172.6
`
`Novartis Exhibit 2030.024
`Regeneron v. Novartis, IPR2020-01318
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`
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