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
`
`__________
`
`
`PATENT OWNERS’ CONTINGENT MOTION TO AMEND
`UNDER 37 C.F.R. § 42.121
`
`
`
`
`
`
`__________
`
`
`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
`
`__________
`
`
`PATENT OWNERS’ CONTINGENT MOTION TO AMEND
`UNDER 37 C.F.R. § 42.121
`
`
`
`
`
`
`TABLE OF CONTENTS
`INTRODUCTION ............................................................................................... 1
`I.
`STATEMENT OF RELIEF REQUESTED ..................................................... 2
`II.
`III. THE REQUIREMENTS OF 35 U.S.C. § 316(d)(3) and 37 C.F.R. § 42.121
`ARE MET .................................................................................................................. 2
`IV. THE SUBSTITUTE CLAIMS ARE SUPPORTED BY THE WRITTEN
`DESCRIPTION .......................................................................................................... 5
`V. THE SUBSTITUTE CLAIMS ARE PATENTABLE ...................................12
`A. The Person of Ordinary Skill in the Art (POSA) ........................................12
`B. The Substitute Claims Are Patentable Over All Prior Art of Record .........13
`C. The Patent Owner Is Not Aware of Other Material Prior Art .....................25
`VI. CONCLUSION ..............................................................................................25
`
`
`
`
`
`
`
`ii
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Aqua Prods., Inc. v. Matal,
`872 F.3d 1290 (Fed. Cir. 2017) (en banc) .......................................................... 13
`AstraZeneca AB v. Mylan Pharm. Inc.,
`19 F.4th 1325 (Fed. Cir. 2021) ........................................................................... 18
`Lectrosonics v. ZAXCOM, Inc.,
`IPR2018-001129, Paper 15 (PTAB Feb. 25, 2019) .................................. 3, 4, 5, 6
`Statutes
`35 U.S.C. § 316(d) ..................................................................................................... 2
`35 U.S.C. § 316(d)(1)(B) ........................................................................................... 4
`35 U.S.C. § 316(d)(3)....................................................................................... 1, 2, 25
`Other Authorities
`37 C.F.R. § 42.11 ..................................................................................................... 25
`37 C.F.R. § 42.121 ........................................................................................... 1, 2, 25
`37 C.F.R. § 42.121(a)(3) ............................................................................................ 4
`
`
`
`
`
`
`
`
`iii
`
`
`
`
`
`I.
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`
`INTRODUCTION
`Patent Owner1 files this contingent Motion to Amend pursuant to 35 U.S.C.
`
`§ 316(d)(3) and 37 C.F.R. § 42.121, and requests preliminary guidance pursuant to
`
`the Motion to Amend Pilot Program, 84 Fed. Reg. 9497; 86 Fed. Reg. 51656.
`
`Patent Owner maintains its position that the ’631 patent claims are not
`
`unpatentable under any of the instituted grounds. In the event that the Board
`
`accepts Petitioner’s obviousness arguments and concludes otherwise, Patent Owner
`
`contingently moves to amend the original claims with corresponding proposed
`
`substitute claims. The substitute claims further distinguish the prior art of record
`
`in this proceeding by proposing two amendments to original independent claim 1:
`
`(1) reducing the upper level of silicone oil that is present in the syringe barrel to an
`
`amount of about 25 µg, and (2) additionally requiring that the terminally sterilized
`
`syringe have a shelf-life of at least twelve months after terminal sterilization. The
`
`substitute claims meet the requirements of 35 U.S.C. § 316(d)(3) insofar as they
`
`narrow the claims, have express support in the disclosures of the ’631 patent
`
`application as originally filed, and address an issue of patentability raised by the
`
`Board in the Institution Decision.
`
`None of the prior art cited by Petitioner renders the substitute claims
`
`unpatentable. None of the references teach the lowered amount of silicone oil in
`
`
`1 Novartis Pharma AG, Novartis Technology LLC, Novartis Pharmaceuticals Corp.
`
`1
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`the syringe barrel. Nor do any of the references support a reasonable expectation
`
`that such low amounts of silicone oil, even if suggested, could provide the recited
`
`break loose force and other properties for a pre-filled, terminally sterilized,
`
`intravitreal syringe comprising a VEGF therapeutic, let alone provide them over
`
`the course of a shelf-life of at least twelve months following terminal sterilization.
`
`Finally, Patent Owner is not aware of any prior art or teaching that a person of
`
`ordinary skill in the art (POSA) would combine with Petitioner’s prior art, Sigg,
`
`Lam or Boulange (or any other art of record), to render the proposed substitute
`
`claims obvious.
`
`II. STATEMENT OF RELIEF REQUESTED
`To the extent the Board finds any original claim unpatentable in this
`
`proceeding, Patent Owner respectfully requests that the Board grant this contingent
`
`motion to amend with respect to each corresponding substitute claim below for
`
`which the original claim was found unpatentable. The Board should not consider
`
`this motion for any original claim that it determines is patentable.
`
`III. THE REQUIREMENTS OF 35 U.S.C. § 316(d)(3) and 37 C.F.R. §
`42.121 ARE MET
`To satisfy 35 U.S.C. § 316(d) and 37 C.F.R. § 42.121, this Motion to Amend
`
`must (1) not present substitute claims that enlarge the scope of the claims of the
`
`challenged patent or introduce new subject matter; (2) propose a reasonable
`
`number of substitute claims; and (3) respond to a ground of unpatentability
`
`2
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`involved in this trial. See Lectrosonics v. ZAXCOM, Inc., IPR2018-001129, ,
`
`Paper 15 at 4 (PTAB Feb. 25, 2019) (Precedential). Patent Owners’ substitute
`
`claims meet all of the statutory and regulatory requirements.
`
`First, the proposed amendments narrow the scope of the original claims in two
`
`respects. Patent Owner proposes amending sole independent claim 1 to (1) narrow
`
`the range in amount of silicone oil in element (b); and (2) require that the claimed
`
`pre-filed, terminally sterilized syringe for intravitreal injection has a shelf life of at
`
`least twelve months after terminal sterilization. The following language highlights
`
`the proposed changes to claim 1, presented as substitute claim 27, in red text:
`
`27. A pre-filled, terminally sterilized syringe for intravitreal injection,
`the syringe comprising a glass body forming a barrel, a stopper and a
`plunger and 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 ug about 25
`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 and has a shelf life of at least
`twelve months after terminal sterilization.
`
`3
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`In addition, corresponding changes have been made to dependent claims 3 and 22
`
`(presented as substitute claims 29 and 48) to make them consistent with the upper
`
`limit of silicone oil in substitute claim 27:
`
`29. A pre-filled syringe according to claim [[1]] 27, wherein the
`syringe barrel has an internal coating of from about 3 µg to about 100
`ug 25 µg silicone oil.
`48. A pre-filled syringe according to claim [[1]] 27, wherein the
`syringe barrel has an internal coating of from about 1 50 to about 25
`µg silicone oil.
`
`The remaining dependent claims have not been amended other than by virtue of
`
`their reliance on proposed substitute claim 27.
`
`Second, Patent Owner proposes a reasonable number of substitute claims.
`
`See 35 U.S.C. § 316(d)(1)(B). “There is a rebuttable presumption that a reasonable
`
`number of substitute claims per challenged claim is one (1) substitute claim.”
`
`Lectrosonics, Paper 15 at 4 (citing 37 C.F.R. § 42.121(a)(3)). Patent Owner’s
`
`Motion proposes no more than one substitute claim for each challenged claim,
`
`which satisfies the requirements of 37 C.F.R. § 42.121(a)(3). See also 84 Fed.
`
`Reg. 9497, 9500. Indeed, only three claims have any substantive amendment from
`
`the originally issued claims.
`
`Third, the proposed amendments respond to a ground of unpatentability
`
`involved in this IPR. The Board instituted trial on all grounds presented in the
`
`4
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`Petition, which include combinations of Boulange, Lam and Sigg. See Decision
`
`(Paper 13) at 73-74. The Panel noted that “Sigg does not disclose any particular
`
`break loose force,” but credited Petitioner’s reading of Boulange. Id. at 60. The
`
`Panel noted that “it [found persuasive] on this record and for institution the Table 7
`
`disclosure of the results of syringe B1, which was also siliconized with 40 µg of
`
`silicone oil on the internal surface but (unlike A and C) also has a coating of
`
`Parylene C on the piston” and that “in each case, Table 7 shows that the break
`
`loose force at time zero was below the claimed 11 N.” Id. at 61.
`
`The substitute claim amendments directly respond to at least these issues and
`
`more clearly distinguish from the syringes described in Boulange and the results
`
`provided in Tables 5 and 7. No syringe in Boulange has less than 40 µg of silicone
`
`oil. And even if the syringes in Boulange could be terminally sterilized, no syringe
`
`in Boulange has a VEGF antagonist. Nor do the Boulange syringes have a break
`
`loose force of less than 11N twelve months after sterilization. Therefore, the
`
`proposed amendments eliminate any supposed motivation to combine Boulange
`
`with Sigg or Lam, and any other prior art such as USP 789, and eliminate any
`
`reasonable expectation of success in doing so.
`
`IV. THE SUBSTITUTE CLAIMS ARE SUPPORTED BY THE WRITTEN
`DESCRIPTION
`The substitute claims must be supported by the original applications and may
`
`not introduce new subject matter. A motion to amend will meet this requirement if
`
`5
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`it “set[s] forth written description support in the originally filed disclosure of the
`
`subject patent for each proposed substitute claim, and also set forth support in an
`
`earlier filed disclosure for each claim for which benefit of the filing date of the
`
`earlier filed disclosure is sought.” See Lectrosonics, at 7. Support for proposed
`
`substitute claims can be found in the specification of the original application, No.
`
`13/750,352 (“’352 Application), which ultimately issued at the ’631 patent, as well
`
`as the priority application EP 12189649 (“EP ’649”), as evidenced in the table
`
`below:
`
`SUBSTITUTE CLAIM
`Claim 27 (Substitute For Claim 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 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,
`
`6
`
`WRITTEN DESCRIPTION
`
`See Ex. 2227 (’352
`Application), Claim 1; Ex.
`2227.0007, ll. 7-8; .0017, ll.
`1-2, ll. 9- 13, l. 2; See Ex.
`2014 (EP ’649), Claims 1, 3,
`9, and 12, and .004, ll. 5-6;
`.0013, ll. 7-9 , l. 15-.0014, l.
`6.
`
`See Ex. 2227 at Claim 1;
`.006, l. 28-.007, l. 6; .019, ll.
`6 – 18; .027, Figs. 1-3; See
`Ex. 2014, at Claim 1; .004, ll.
`23-24; .0023, Figs. 1-3.
`
`See Ex. 2227 at Claim 1;
`.010, ll. 5-6. See, Ex. 2014 at
`Claim 3, see also, .007,, ll. 2-
`3.
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`See Ex. 2227 at Claim 1;
`.007, ll. 8-9; .011, ll. 13 – 20.
`See Ex. 2014 at Claim 9;
`.004, ll. 5-6 and .008, ll. 1-4.
`
`See Ex. 2227 at Claims 1, 20;
`.012, l. 10; .020, l. 26 – .021.,
`l. 3; .017, ll. 15-17. See Ex.
`2014 at claims 12, and 20;
`.008, l. 22, and .0016, l. 27-
`.0017, l. 3; .0013, ll. 19-21.
`
`
`
`See Ex. 2227 at Claim 6;
`.012, ll. 17-18. See Ex. 2014
`at Claim 8; .008, ll. 29-30.
`
`
`
`See Ex. 2227 at Claims 7, 8;
`p. 6, ll. 13 – 20. See Ex. 2014
`at Claim 9; p. 6, ll.1-4.
`
`
`
`See Ex. 2227 at Claim 10; p.
`6, ll. 23-26. See Ex. 2014 at
`Claim 10; p. 6, ll. 7-10.
`
`
`
`See Ex. 2227 at Claim 12;
`.011, l. 32- .012, l. 2. See Ex.
`2014 at Claim 12; .009, ll. 9-
`11.
`
`(b) the syringe barrel comprises from about 1 µg
`to 100 ug about 25 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 and has a
`shelf life of at least twelve months after terminal
`sterilization.
`Claim 28 (Proposed Substitute for Claim 2)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating
`of silicone oil that has an average thickness of
`about 450 nm or less.
`Claim 29 (Proposed Substitute for Claim 3)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating
`of from about 3 µg to about 100 ug 25 µg
`silicone oil.
`Claim 30 (Proposed Substitute for Claim 4)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the silicone oil is DC365 emulsion.
`
`Claim 31 (Proposed Substitute for Claim 5)
`A pre-filled syringe according to claim [[1]] 27,
`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.
`
`7
`
`
`
`Claim 32 (Proposed Substitute for Claim 6)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the VEGF antagonist solution meets
`USP789.
`
`Claim 33 (Proposed Substitute for Claim 7)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the VEGF antagonist is an anti-VEGF
`antibody.
`
`Claim 34 (Proposed Substitute for Claim 8)
`A pre-filled syringe according to claim [[7]] 33,
`wherein the anti-VEGF antibody is ranibizumab
`
`Claim 35 (Proposed Substitute for Claim 9)
`A pre-filled syringe according to claim [[8]] 34,
`wherein the ranibizumab is at a concentration of
`10 mg/ml.
`Claim 36 (Proposed Substitute for Claim 10)
`A pre-filled syringe according to claim [[8]] 34,
`wherein the silicone oil has a viscosity of about
`350 cP, and 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 37 (Proposed Substitute for Claim 11)
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`
`
`
`See Ex. 2227 at Claim 13;
`.007, ll. 12-14 and .013, ll. 4-
`5. See Ex. 2014 at Claim 13;
`.009, ll. 11-13.
`
`
`
`See Ex. 2227 at Claim 14;
`.013, ll. 7-10, and .020, l. 26.
`See Ex. 2014 at Claim 14;
`.009, ll. 15-19, and .0016, l.
`27.
`
`
`
`See Ex. 2227 at Claim 15;
`.013, l. 9. See Ex. 2014 at
`Claim 15; .009, l. 17.
`
`
`
`See Ex. 2227 at Claim 16;
`.010, ll. 21-22; p. 8, l. 19. See
`Ex. 2014 at .007, ll. 18-19.
`
`
`
`See Ex. 2227 at Claim 12,
`.012, l. 32 – .013, l. 2; .011,
`ll. 23-25. See Ex. 2014 at
`Claim 12; .009, ll. 9-11 and
`.0012, l. 7-9.
`
`
`
`8
`
`
`
`A pre-filled syringe according to claim [[1]] 27
`wherein the VEGF antagonist is a non-antibody
`VEGF antagonist.
`
`Claim 38 (Proposed Substitute for Claim 12)
`A pre-filled syringe according to claim [[11]] 37,
`wherein the non-antibody VEGF antagonist is
`aflibercept or conbercept.
`
`Claim 39 (Proposed Substitute for Claim 13)
`A pre-filled syringe according to claim [[12]] 38,
`wherein the non-antibody VEGF antagonist is
`aflibercept at a concentration of 40 mg/ml.
`Claim 40 (Proposed Substitute for Claim 14)
`A pre-filled syringe according to claim [[1]] 27,
`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 41 (Proposed Substitute for Claim 15)
`A pre-filled syringe according to claim [[14]] 40,
`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 Gx0.5 inch needle attached to the syringe.
`Claim 42 (Proposed Substitute for Claim 16)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe has a stopper slide force of
`less than about 11N.
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`See Ex. 2227 at Claim 13;
`.013, l. 11 - .014, l. 32. See
`Ex. 2014 at Claim 16; .009, l.
`15 – .011, l. 6
`
`
`
`See Ex. 2227 at Claim 18;
`.013, l. 13 and .014, l. 8. See
`Ex. 2014 at Claim 12; .009, l.
`21 and .0010, l. 17.
`
`
`
`See Ex. 2227 at Claim 19,
`.010, ll. 22-23. See Ex. 2014
`at Claim 18; .007, ll. 19-20.
`
`
`
`See Ex. 2227 at Claims 21,
`23; .012, ll. 8-12; .020, l. 26 –
`.021, l. 3. See Ex. 2014 at
`Claims 21 and 23; .008, ll.
`21-24 and .0016, l. 27 –
`.0017, l. 3.
`
`
`
`See Ex. 2227 at Claim 24;
`.012, ll. 11-14 and .020, l. 24
`– .021, l. 3. See Ex. 2014 at
`.008, ll. 25-26; .0016, l. 27 –
`.0017, l. 3.
`
`
`
`See Ex. 2227 at Claim 22;
`.012, ll. 8 – 9. See Ex. 2014 at
`Claim 22; p. 6, ll. .008.
`
`9
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`
`
`
`See Ex. 2227 at Claim 25;
`.017, ll. 9-12 and ll. 19-22.
`See Ex. 2014 at Claim 24;
`.0013, ll. 15-18 and ll. 23-25.
`
`
`
`See Ex. 2227 at Claim 26; p.
`12, ll. 26-30. See Ex. 2014 at
`Claim 25; p. 11, l. 30 – p. 12,
`l. 12.
`
`
`
`See Ex. 2227 at Claim 26;
`.017, l. 30 – .018, l. 2. See Ex.
`2014 at Claim 26; .0014, ll.
`2-6.
`
`
`
`See Ex. 2227 at Claim 28. See
`Ex. 2014 at Claim 27.
`
`
`See Ex. 2227 at Claim 29;
`.017, ll. 19-22. See Ex. 2014
`at Claim 28; .0013, ll. 23-25.
`
`
`See Ex. 2227 at Claims 7,8;
`.011, ll. 13 – 20. See Ex. 2014
`
`Claim 43 (Proposed Substitute for Claim 17)
`A blister pack comprising a pre-filled syringe
`according to claim [[1]] 27, wherein the syringe
`has been sterilised using H2O2 or EtO.
`
`Claim 44 (Proposed Substitute for Claim 18)
`A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, wherein the outer
`surface of the syringe has ≤1 ppm EtO or H2O2
`residue.
`Claim 45 (Proposed Substitute for Claim 19)
`A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, 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 46 (Proposed Substitute for Claim 20)
`A blister pack comprising a pre-filled syringe
`according to claim [[18]] 44, wherein ≤5% of the
`VEGF antagonist is alkylated.
`Claim 47 (Proposed Substitute for Claim 21)
`A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, wherein the syringe
`has been sterilised using EtO or H2O2 with a
`Sterility Assurance Level of at least 10-6.
`Claim 48 (Proposed Substitute for Claim 22)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating
`of from about 1 50 to about 25 µg silicone oil.
`
`10
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`at Claim 9; .004, ll. 5-6 and
`.008., ll. 1-4.
`
`
`
`See Ex. 2227 at .011, ll. 23-
`25. See Ex. 2014 at .008, ll.
`7-9.
`
`
`
`See Ex. 2227 at Claim 30;
`.016, ll. 9-15. See Ex. 2014 at
`Claim 33; .0012, ll. 15-21.
`
`
`
`See Ex. 2227 at Claim 31;
`.016, ll. 15-17. See Ex. 2014
`at Claim 34; .0012, ll. 21-23.
`
`
`
`See Ex. 2227 at Claim 32;
`.016, ll. 18-24. See Ex. 2014
`at Claim 35; .0012, ll. 24-30.
`
`Claim 48 (Proposed Substitute for Claim 23)
`A pre-filled syringe according to claim [[1]] 27,
`wherein the silicone oil has a viscosity of about
`350 cP.
`Claim 50 (Proposed Substitute for Claim 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 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] 27.
`Claim 51 (Proposed Substitute for Claim 25)
`The method of claim [[24]] 50, 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 52 (Proposed Substitute for Claim 26)
`A method according to claim [[24]] 50, wherein
`the VEGF antagonist administered is a non-
`antibody VEGF antagonist and wherein the
`patient has previously received treatment with an
`antibody VEGF antagonist.
`
`11
`
`
`
`U.S. Patent No. 9,220,631
`IPR2021-00816
`Written description support for the substitute claims is corroborated by the
`
`testimony of named inventor Dr. Juergen Sigg. In his declaration, Dr. Sigg
`
`explains that he developed terminally sterilized syringes containing VEGF
`
`antagonists and measured their break loose forces at manufacture, i.e., time zero, as
`
`well as at several time points thereafter for at least twelve months. Ex. 2206, ¶¶
`
`50-51. Dr. Sigg further explains that these terminally sterilized syringes were
`
`manufactured such that their syringe barrels comprised silicone oil of about 1 µg to
`
`about 25 µg.
`
`
`
`
`
` These
`
`syringes showed break loose forces of less than 11N, and a slide force of less than
`
`5N, at time zero and after storage for at least twelve months following terminal
`
`sterilization, with minimal change in such forces between these timepoints. Ex.
`
`2206,¶ 51; Ex. Ex. 2224.041. Thus, consistent with the express disclosure of the
`
`’631 patent application, Dr. Sigg was in possession of the claimed subject matter of
`
`the substitute claims by at least the filing date. Ex. 2206, ¶¶ 49-51.
`
`V. THE SUBSTITUTE CLAIMS ARE PATENTABLE
`A. The Person of Ordinary Skill in the Art (POSA)
`As noted above, the substitute claims are supported by EP ’649, entitling
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`them to a priority date of at least October 23, 2012. As of that date, a POSA would
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`have had an advanced degree (i.e., an M.S., a Ph.D., or equivalent) in mechanical
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`engineering, biomedical engineering, materials science, chemistry, chemical
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`engineering, or a related field, and at least 2–3 years of professional experience,
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`including in the design of a PFS and/or the development of ophthalmologic drug
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`products or drug delivery devices. Such a person would have been a member of a
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`product development team and would have drawn upon not only his or her own
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`skills, but also the specialized skills of team members in complementary fields
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`including ophthalmology, microbiology and toxicology. Ex. 2201 ¶ 16.
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`Even if the Panel were to adopt Petitioner’s proposed definition of a POSA,
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`the substitute claims would be patentable in view of the prior art. Ex. 2208, ¶ 21.
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`B. The Substitute Claims Are Patentable Over All Prior Art of Record
`The Board must assess the patentability of proposed substitute claims
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`“without placing the burden of persuasion on the patent owner.” Aqua Prods., Inc.
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`v. Matal, 872 F.3d 1290, 1328 (Fed. Cir. 2017) (en banc). None of the prior art
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`known to Patent Owner anticipates or renders obvious the substitute claims for the
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`reasons set forth in the Patent Owner Response (“POR”), and for the additional
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`reasons set forth below. With regard to anticipation, Petitioner has not proposed
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`any grounds based on anticipation, and Patent Owner is not aware of any
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`anticipatory prior art. With regard to obviousness, Petitioner has asserted
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`obviousness based upon prior art references, including Sigg, Lam and Boulange,
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`but none of those references provide any motivation to use the claimed subject
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`matter, or any reasonable expectation of success in doing so.
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`1.
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`None of the prior art teaches the use of “about 1 µg to about 25 µg
`silicone oil” in the barrel of a syringe
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`
`Petitioner concedes that “the disclosure of Sigg” and “the disclosure of
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`Lam” are “silent as to the amount of silicone oil used in the tested pre-filled
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`syringes.” Ex. 1003. ¶¶ 128, 138. Petitioner relies exclusively on Boulange for the
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`purported teaching that syringe barrels having lower silicone oil amounts also will
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`have low stopper forces. Petitioner essentially contends that a POSA would have
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`been motivated to modify the syringes in Boulange to fill them with a VEGF
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`antagonist solution, terminally sterilize them, and expect them to exhibit the same
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`functional forces that Boulange reports for unmodified syringes filled with
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`demineralized water. There are several shortcomings with Petitioner’s alleged
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`teachings of Boulange. To posit that one could combine Boulange with Sigg or
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`Lam and have a reasonable expectation of success in achieving the recited break
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`loose and glide forces claimed in the ’631 patent is nothing short of hindsight. Ex.
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`2208, ¶ 111; POR at 9-26, 42-44. But even if the Board credits Petitioner’s
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`arguments regarding Boulange generally, the substitute claims recite a syringe with
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`an amount of silicone oil that Boulange simply fails to disclose or teach.
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`Boulange describes syringe barrels with coatings of silicone oil in amounts
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`of only 40 µg and 500 µg. Boulange does not describe a syringe with any other
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`amount of silicone oil. Exhibit 1008.22, ll. 16, 19. And Boulange certainly does
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`not describe any syringe whose barrel is coated with silicone oil in an amount
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`“from of about 1 µg to about 25 µg.” Thus, there is no explicit disclosure or
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`teaching in Boulange of syringes whose barrels are coated with 1 µg to about 25
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`µg of silicone oil in accordance with the proposed amended claim element. Ex.
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`2208, ¶¶ 75-81.
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`Dr. Koller opines that applying the ratio of 4 µg/cm2 in Boulange to a 0.5
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`mL syringe would provide the syringe approximately 28 µg of silicone oil coating.
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`Ex. 1003 ¶ 200. First, this ratio is speculative based on the disclosures of
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`Boulange, which discloses 40 µg of silicone oil as its lowest amount. Second, that
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`speculation is further compounded when considered in combination with the non-
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`descript syringes mentioned in Sigg and Lam. Ex. 2208, ¶¶ 65-66, 71-72 Third,
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`even crediting Dr. Koller’s position, applying that ratio to the 0.5 and 1.0 mL
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`syringes of the substitute claims would result in in a syringe having anywhere from
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`~28-43 µg of silicone oil. Ex. 1003.129-.130; Ex. 2208. ¶¶ 78-79. That is still
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`outside the bounds of the substitute claims. And, given the specific test parameters
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`and syringes used in Boulange, a POSA would have appreciated the absence of
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`teachings on the break loose and glide force for amounts of silicone oil less than 40
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`µg. Ex. 2208, ¶¶ 95-99. A POSA would not have understood Boulange as
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`teaching that an amount of about 1 µg to about 25 µg silicone oil would be
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`U.S. Patent No. 9,220,631
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`appropriate for a syringe with a VEGF antagonist for intravitreal injection. Ex.
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`2208, ¶¶ 94-104.
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`2.
`
`A POSA would have had no motivation or reasonable expectation
`of success in achieving the stopper forces of Boulange by using
`“about 1 µg to about 25 µg silicone oil” in the barrel of a syringe
`A POSA would not have been motivated to use nearly half the amount of the
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`silicone oil disclosed in Boulange (as claimed), nor would the POSA have had any
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`reasonable expectation that such a reduced amount of silicone oil in a syringe
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`barrel could achieve the stopper break loose and glide forces as claimed in the
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`substitute claims. Ex. 2208. ¶¶ 94-95.
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`First, the data of Boulange would have steered the POSA away from using
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`amounts of silicone oil below those described in Boulange. Boulange reports data
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`showing that syringes with 40 μg (or 4 µg/cm2) of baked-on silicone oil performed
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`worse than the syringes with 500 μg (or 50 µg/cm2) of sprayed-on silicone oil. Ex.
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`2208. ¶¶ 96-100. Specifically, Boulange observed significantly greater increases in
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`break loose force in the syringes with 40 μg of baked-on silicone oil than in the
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`syringes with spray-on silicone oil (500 μg). The only exception was stopper A,
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`which had a merely proportional increase in break loose force in the syringe with
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`baked-on silicone oil due to a greater break loose force at T=0 in that syringe. For
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`pistons A and C, at all timepoints, the glide force was also much higher in the
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`syringes with 40 µg of silicone oil than in the syringes with 500 µg of silicone oil.
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`U.S. Patent No. 9,220,631
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`Compare Ex. 1008.020 (Table 4) with Ex. 1008.021 (Table 5). Boulange taught a
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`POSA that syringes with lower amounts of silicone oil (e.g., 40 μg) perform worse
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`than syringes with the higher amounts of silicone oil (e.g., 500 μg). A POSA,
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`faced with that data, would not have chosen to further reduce the amount of
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`silicone oil in the syringe barrel from the lowest amount disclosed in Boulange (40
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`µg) to a range nearly half of that disclosed in Boulange. Ex. 2208. ¶¶ 103.
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`Moreover, a POSA would have understood that the break loose and glide
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`force data from Boulange could not have been extrapolated to a syringe with a
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`VEGF antagonist. Petitioner does not dispute that Boulange obtained its break
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`loose and glide forces by utilizing syringes filled with demineralized water. Ex.
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`1008.016. In contrast, the claims of the ’631 patent require that the terminally
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`sterilized syringe comprise a VEGF antagonist. As Dr. Koller concedes, a VEGF
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`antagonist would be at least 30% more viscous than water. Ex. 1003.117. The use
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`of a solution at least 30% more viscous that water, such as a VEGF antagonist,
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`would affect the forces on the syringe such that a POSA would not have expected
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`the test results in Boulange to be the same when conducted on a syringe filled with
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`a VEGF antagonist solution. Ex. 2208, ¶ 107. In sum, Boulange would not have
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`motivated a POSA to use about 1 µg to about 25 µg silicone oil in a terminally
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`sterilized syringe comprising a VEGF antagonist. Nor would the POSA have had
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`any reasonable expectation of success in achieving the claimed break loose force
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`of less than 11N with such an amount of silicone oil.
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`3.
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`None of the prior art taught “a shelf life of at least twelve months”
`for a terminally-sterilized syringe comprising a VEGF antagonist
`with “about 1 µg to about 25 µg silicone oil”
`The subject matter of the substitute claims is also not obvious because the
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`
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`prior art failed to teach that a terminally sterilized syringe comprising about 1 µg to
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`about 25 µg of silicone oil could have a shelf-life of at least twelve months after
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`terminal sterilization. Indeed, Petitioner’s main prior art reference on the impact of
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`storage on terminally sterilized syringes with varied amounts of silicone oil,
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`Boulange, would have taught a POSA away from the subject matter of the
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`substitute claims. See AstraZeneca AB v. Mylan Pharm. Inc., 19 F.4th 1325, 1337
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`(Fed. Cir. 2021) (affirming a judgment of nonobviousness based in part on a prior
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`art reference teaching away). A POSA would have understood that, in order for a
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`terminally sterilized syringe with a VEGF antagonist to have twelve months of
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`shelf life, that product would need to be stable over that period of time, including
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`in its stopper functionality. Ex. 2208. ¶ 110; Ex. 2209, ¶¶ 29-30. Yet nothing in
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`the prior art taught that a terminally sterilized syringe comprising about 1 µg to
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`about 25 µg of silicone oil would function with the appropriate break loose and
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`glide forces after twelve months of shelf life. Ex. 2208. ¶ 111. Nor has Petitioner
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`pointed to any such evidence.
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`U.S. Patent No. 9,220,631
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`A POSA developing a terminally sterilized syringe a for a VEGF antagonist
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`would have desired it to be stable for storage for an extended period of time, e.g.,
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`at least twelve months. Ex. 2208. ¶ 110. Pharmaceutical products require long-
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`term storage for FDA approval. As of the priority date, the FDA speci
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