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 IPR2021-00816
`Patent 9,220,631
`
`__________
`
`DECLARATION OF MARIE PICCI IN SUPPORT OF NOVARTIS’S
`PATENT OWNER PRELIMINARY RESPONSE
`
`Novartis Exhibit 2002.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`__________
`
`Case IPR2021-00816
`Patent 9,220,631
`
`__________
`
`DECLARATION OF MARIE PICCI IN SUPPORT OF NOVARTIS’S
`PATENT OWNER PRELIMINARY RESPONSE
`
`Novartis Exhibit 2002.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`TABLE OF CONTENTS
`INTRODUCTION ................................................................................................................. 1
`I.
`INVENTION OF THE CLAIMED SUBJECT MATTER............................................. 2
`II.
`III. REDUCTION TO PRACTICE ...................................................................................... 14
`IV. DILIGENCE ..................................................................................................................... 14
`V.
`DECLARATION.............................................................................................................. 31
`
`ii
`
`Novartis Exhibit 2002.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`I.
`
`INTRODUCTION
`1.
`I, Marie Picci, have personal knowledge of the facts set forth in this
`
`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
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`PFS, which includes the syringe components. My work focused on the
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`development of the integral parts of the device, including siliconization and
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`sterilization of the PFS. I worked on the PFS project until late 2018, when I
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`transitioned to my current role as the Delivery Systems Strategy Director for
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`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.
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`5.
`
`The documents cited in this document were generated as part of the
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`Page 1
`
`Novartis Exhibit 2002.003
`Regeneron v. Novartis, IPR2021-00816
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`
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`ordinary course of business at Novartis AG (“Novartis”). Through my
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`employment with Novartis, I am familiar with Novartis’s practices regarding the
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`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
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`subject matter relevant to the document. The documents were kept in the course of
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`Novartis’s regularly conducted research and development activities, and making
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`these documents was a regular practice of these activities.
`
`II.
`
`INVENTION OF THE CLAIMED SUBJECT MATTER
`6.
`I, along with my co-inventors, Juergen Sigg, Christophe Royer,
`
`Andrew Mark Bryant, and Heinrich Martin Buettgen conceived of the invention
`
`claimed in the ’631 patent by no later than July 2012.1 Specifically, by 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,
`
`
`1 I understand that “conceived” means that the inventors had in their minds a
`
`definite and permanent idea of the complete and operative invention.
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`Page 2
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`Novartis Exhibit 2002.004
`Regeneron v. Novartis, IPR2021-00816
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`
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`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
`
`October 2011, entitled RFB002 (Lucentis) Pharmaceutical Development Technical
`
`Review (“Development Technical Review” or “DTR”). Ex. 2063. Ex. 2063 is a
`
`true and correct copy of the Development Technical Review PowerPoint slide
`
`deck.
`
`8.
`
`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. The Development Technical Review slide deck is a summary
`
`and review document and thus reflects work that we had accomplished prior to the
`
`drafting of the PowerPoint itself. The work that is described in that document was
`
`therefore completed before October 2011, the date of the meeting for which the
`
`slide deck was drafted. This shows that we had conceived of the invention prior to
`
`October 2011.
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`9.
`
`The Development Technical Review describes
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`
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`Page 3
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`Novartis Exhibit 2002.005
`Regeneron v. Novartis, IPR2021-00816
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`
`
`
`
`
` 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).
`
`
`
`10.
`
`-
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`
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`11.
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`
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`Page 4
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`Novartis Exhibit 2002.006
`Regeneron v. Novartis, IPR2021-00816
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`
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`12.
`
` Ex. 1034.002.
`
`13. Other documents corroborate that we had conceived of certain
`
`additional limitations of dependent claims not expressly identified in the
`
`Development Technical Review.2 For example, another Novartis document
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A significant amount of effort went into developing the Lucentis PFS both
`
`2
`
`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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`
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`Page 5
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`Novartis Exhibit 2002.007
`Regeneron v. Novartis, IPR2021-00816
`
`
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`
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`14. Furthermore, on July 3, 2012, we filed European Patent Application
`
`No. EP 12174860 (“EP ’860”) directed to our novel PFS. Ex. 1035. EP ’860
`
`confirms that the PFS we conceived would have a syringe barrel with an internal
`
`coating of silicone that has an average thickness of about 450nm or less (as in
`
`claim 2 of the ’631 patent). 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 (as in claims 11-13 of the ’631 patent). Ex. 1035.017
`
`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 (as in claim 26). Ex. 1035.009 at 5–
`
`7. Moreover, following terminal sterilization with ethylene oxide, the outer
`
`surface of the syringe would have less than 1 ppm of EtO residue, which would be
`
`less than or equal to 0.1 mg outside the syringe and inside the blister pack (as in
`
`claims 18-19). Ex. 1035.013 at 9–10. Also, less than 5% of the VEGF antagonist
`
`would be alkylated. Ex. 1035.013 at 7–9; .017 at 26–27.
`
`15. The following table summarizes the corroborating support
`
`demonstrating that we had conceived of all of the claimed subject matter of the
`
`
`
`
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`
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`
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`Page 6
`
`Novartis Exhibit 2002.008
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`'63 1 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 fonning a barrel, a stopper
`and a plunger and
`
`containing an ophthalmic solution
`which comprises a VEGF(cid:173)
`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
`
`Page 7
`
`Novartis Exhibit 2002.009
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`and wherein the syringe has a
`stopper break loose force of less
`than about l lN.
`
`Claim 2
`
`2. The syringe barrel has an
`internal coating of silicone oil that
`has an average thickness of about
`450 run or less.
`
`"syringe barrel [with] an internal coating of
`silicone that has an average thickness of
`about 450run or less." Ex. 1035.008 at 17-
`18.
`
`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
`
`See claim l (b).
`
`Page 8
`
`Novartis Exhibit 2002.0010
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`See claim l (c).
`
`See claim I ( c).
`
`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
`more than 5 particles >25 µm in
`diameter per ml, and (ii) no more
`than 50 particles ~ 10 µm in
`diameter per ml.
`
`Claim 6
`
`6. A pre-filled syringe according
`to claim 1, wherein the VEGF
`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(cid:173)
`VEGF an tibody is ranibizumab.
`
`Claim 9
`
`9. A pre-filled syringe according
`to claim 8, wherein the
`
`Page 9
`
`Novartis Exhibit 2002.0011
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`ranibizumab is at a concentration
`of 10 mg/ml.
`
`Claim 10
`
`IO. A pre-filled syringe according
`to claim 8, wherein the silicone
`oil has a viscosity of about 350
`cP,
`
`and the VEGF antagonist solution See claim l(c).
`further comprises one or more of
`(i) no more than 5 particles >25
`µm in diameter per ml, and (ii) no
`more than 50 particles ~ 10 µm in
`diameter per ml.
`
`Claim 11
`
`11. A pre-filled syringe according
`to claim 1 wherein the VEGF
`antagonist is a non-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.
`
`Claim 12
`
`12. A pre-filled syringe according See claim 11.
`to claim 11, wherein the non-
`antibody VEGF antagonist is
`aflibercept or conbercept.
`
`Claim 13
`
`13 . A pre-filled syringe according See claim 12.
`to claim 12, wherein the non-
`antibody VEGF antagonist is
`aflibercept at a concentration of
`40 mg/ml.
`
`Claim 14
`
`Page 10
`
`Novartis Exhibit 2002.0012
`Regeneron v. Novartis, IPR2021-00816
`
`
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`14. A pre-filled syringe according
`to claim 1, wherein the syringe
`has a stopper break loose force of
`less than about SN, 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 nun/min, with a 30
`Gx0.5 inch needle attached to the
`syn nge.
`
`Claim 16
`
`16. A pre-filled syringe according See claim 14.
`to claim 1, wherein the syringe
`has a stopper slide force of less
`than about l lN.
`
`Claim 17
`
`17. A blister pack comprising a
`pre-filled syringe according to
`claim 1, wherein the syringe has
`been sterilised using H20 2 or EtO.
`
`Claim 18
`
`Page 11
`
`Novartis Exhibit 2002.0013
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`18. A blister pack comprising a
`pre-filled syringe according to
`claim 1 7, wherein the outer
`surface of the syringe has ~ 1 ppm
`EtO or H20 2 residue.
`
`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. < l 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.
`
`":s:5% of the VEGF antagonist r would be l
`alkylated." Ex. 1035.013 at 7-9; .017 at 26-
`27.
`
`Claim 19
`
`19. A blister pack comprising a
`pre-filled syringe according to
`claim 1 7, wherein the syringe has
`been sterilised using EtO or H20 2
`and the total EtO or H20 2 residue
`found on the outside of the
`syringe and inside of the blister
`pack is ~ 0. 1 mg.
`
`Claim 20
`
`20. A blister pack comprising a
`pre-filled syringe according to
`claim 18, wherein <5% of the
`VEGF antagonist is alkylated.
`
`Claim 21
`
`21 . A blister pack comprising a
`pre-filled syringe according to
`claim 1 7, wherein the syringe has
`been sterilised using EtO or H20 2
`with a Sterility Assurance Level
`of at least 10- 6.
`
`Claim 22
`
`22. A pre-filled syringe according See claim l (b).
`to claim 1, wherein the syringe
`barrel has an internal coating of
`from about 1-50 µg silicone oil.
`
`Page 12
`
`Novartis Exhibit 2002.0014
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`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(cid:173)
`related macular degeneration,
`macu lar edema secondary to
`retinal vein occlusion (RVO)
`including both branch RVO
`(bRVO) and central RVO
`(cRVO), choroidal
`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(cid:173)
`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.
`
`Page 13
`
`Novartis Exhibit 2002.001 5
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Claim 26
`
`26. A method according to claim
`The PFS could include a "non-antibody
`24, wherein the VEGF antagonist VEGF antagonist," such as "aflibercept,"
`including at a concentration of "40 mg/ml."
`administered is a non-antibody
`VEGF antagonist and wherein the Ex. 1035.009 at 8-13; .017 at 8-13. EP '860
`patient has previously received
`further indicates that antibody VEGF
`treatment with an antibody VEGF antagonists had already "been approved for
`human use," indicating that we intended that
`antagonist.
`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
`
`16.
`
`I and my co-inventors filed another European Patent Application, EP
`
`12 1 89649 ("RP ' 649"), on October 21, 201 2. Ex. 2014. On .T :muary 21, 201 1, we
`
`filed U.S. Patent Application No. 13/750,352 (Ex. 2032), 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
`
`17.
`
`From Octob er 2011 through January 20 13, we worked diligently
`
`these meetings,
`
`At
`
`The minutes from
`
`Page 14
`
`Novartis Exhibit 2002.0016
`Regeneron v. Novartis, IPR2021-00816
`
`
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`these meetings reflect that ongoing work. I regularly attended these meetings with
`
`other inventors.
`
`18. These team meetings are
`
`· meeting minutes are identified and summarized in the
`
`following table:
`
`Activities described in Meeting Minutes
`
`Page 15
`
`Novartis Exhibit 2002.0017
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 16
`
`Novartis Exhibit 2002.0018
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 17
`
`Novartis Exhibit 2002.0019
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 18
`
`Novartis Exhibit 2002.0020
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`Activities described in Meeting Minutes
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`Page 19
`
`Novartis Exhibit 2002.0021
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 20
`
`Novartis Exhibit 2002.0022
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 21
`
`Novartis Exhibit 2002.0023
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 22
`
`Novartis Exhibit 2002.0024
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 23
`
`Novartis Exhibit 2002.0025
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 24
`
`Novartis Exhibit 2002.0026
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 25
`
`Novartis Exhibit 2002.0027
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 26
`
`Novartis Exhibit 2002.0028
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 27
`
`Novartis Exhibit 2002.0029
`Regeneron v. Novartis, IPR2021 -00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 28
`
`Novartis Exhibit 2002.0030
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 29
`
`Novartis Exhibit 2002.0031
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Activities described in Meeting Minutes
`
`Page 30
`
`Novartis Exhibit 2002.0032
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`V. DECLARA TJON
`
`19.
`
`I hereby declare that all statements made herein ofmy own
`
`knowledge are true and that all statements made on infonnation and belief are
`
`believed to be true. l further 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:
`
`tR J½'~ 2 c2 -1
`
`By
`
`~ MariePicci
`
`Novartis Exhibit 2002.0033
`Regeneron v. Novartis, IPR2021-00816
`
`
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