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 IPR2021-00816
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF JAMES E. MALACKOWSKI, IN SUPPORT OF
`PATENT OWNER RESPONSE
`
`
`
`
`
`Novartis Exhibit 2205.001
`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 Owner
`
`__________
`
`
`Case IPR2021-00816
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF JAMES E. MALACKOWSKI, IN SUPPORT OF
`PATENT OWNER RESPONSE
`
`
`
`
`
`Novartis Exhibit 2205.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 2
`
`Qualifications and Compensation .................................................................... 2
`
`Summary of Opinions ...................................................................................... 6
`
`Industry Background ....................................................................................... 7
`
`A.
`
`Treatments for Wet AMD ..................................................................... 7
`
`i.
`
`ii.
`
`Avastin ........................................................................................ 9
`
`Lucentis .....................................................................................10
`
`iii.
`
`Eylea ..........................................................................................12
`
`B. Market Transition from Vials to Prefilled Syringes ............................13
`
`V.
`
`The ʼ631 Patent ..............................................................................................17
`
`VI. Legal Principles .............................................................................................21
`
`VII. Secondary Considerations Supporting the Non-Obviousness of the ʼ631
`Patent .............................................................................................................23
`
`A.
`
`B.
`
`Commercial Success............................................................................23
`
`Licensing .............................................................................................32
`
`VIII. Declaration .....................................................................................................37
`
`
`
`
`
`
`Novartis Exhibit 2205.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I, James E. Malackowski, have been retained by Novartis Pharma AG,
`
`Novartis Technology LLC, and Novartis Pharmaceuticals Corp. (collectively,
`
`“Patent Owner” or “Novartis”) as an independent expert witness in the above-
`
`captioned inter partes review (“IPR”), in which Petitioner Regeneron
`
`Pharmaceuticals, Inc. (“Petitioner” or “Regeneron”) has requested that the U.S.
`
`Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent No.
`
`9,220,631 (“the ʼ631 Patent”). This declaration sets forth my opinions based on
`
`the materials I have considered and my knowledge, education, skills, training, and
`
`experience.
`
`2.
`
`I provide this declaration to provide my opinions regarding certain
`
`secondary considerations of non-obviousness concerning the ʼ631 Patent,
`
`specifically commercial success and licensing. In order to perform this evaluation,
`
`I have reviewed certain accounting, financial, marketing, licensing, and other
`
`business data and related information in connection with this litigation.
`
`II. QUALIFICATIONS AND COMPENSATION
`
`3.
`
`I am the Co-Founder and Chief Executive Officer of Ocean Tomo,
`
`LLC, the Intellectual Capital Merchant Banc™ firm providing industry leading
`
`financial products and services related to intellectual property including financial
`
`expert testimony, valuation, strategy consulting, patent analytics, investment
`
`Novartis Exhibit 2205.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`management, and transaction brokerage. Ocean Tomo assists clients –
`
`corporations, law firms, governments and institutional investors – in realizing
`
`Intellectual Capital Equity® value broadly defined. Subsidiaries of Ocean Tomo
`
`include Ocean Tomo Investments Group, LLC, a registered broker dealer, and
`
`Ocean Tomo International (HK) Ltd.
`
`4.
`
`I am a founding and continuous member of the IP Hall of Fame
`
`Academy. I have been recognized annually since 2007 by leading industry
`
`publications as one of the “World’s Leading IP Strategists.” Significantly, I have
`
`been listed among “50 Under 45” by IP Law & Business™; included in the
`
`National Law Journal’s inaugural list of 50 Intellectual Property Trailblazers &
`
`Pioneers; and named as one of “The Most Influential People in IP” by Managing
`
`Intellectual Property™. I was named as 1 of 50 individuals, companies and
`
`institutions that framed the first 50 issues of IAM Magazine as well as 1 of 60
`
`leading global Economics Expert Witnesses by the same publication in 2014. In
`
`2011, I was selected by the World Economic Forum as one of less than twenty
`
`members of the Network of Global Agenda Councils to focus on questions of IP
`
`policy. In 2013, I was inducted into the Chicago Area Entrepreneurship Hall of
`
`Fame by the Institute for Entrepreneurial Studies at the University of Illinois at
`
`Chicago College of Business Administration. In 2018, I joined the Standards
`
`Development Organization Board of the Licensing Executives Society (USA &
`
`Novartis Exhibit 2205.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Canada), Inc. governing voluntary consensus-based professional practices that are
`
`guided in their development by the American National Standards Institute’s
`
`(ANSI’s) Essential Requirements. LES standards are designed to encourage and
`
`teach consensus practices in many of the business process aspects of intellectual
`
`capital management.
`
`5.
`
`On more than fifty occasions, I have served as an expert in U.S.
`
`Federal Court, U.S. Bankruptcy Court, State Court, the Ontario Superior Court of
`
`Justice, and global arbitrations on questions relating to intellectual property
`
`economics, including the subject of valuation, reasonable royalty, lost profits, price
`
`erosion, commercial success, corrective advertising, creditor allocations, Hatch-
`
`Waxman Act market exclusivity, business significance of licensing terms including
`
`RAND obligations, venture financing, and equities of a potential injunction. My
`
`experience extends to matters of general business valuation and commercial
`
`disputes, both domestic and foreign. I have publicly addressed policy issues
`
`affecting international trade and have provided expert opinions concerning
`
`antidumping and countervailing duties imposed by the U.S. Department of
`
`Commerce as well as testimony on domestic industry, bond, and remedies before
`
`the International Trade Commission.
`
`6.
`
`I have substantial experience as a Board Director for leading
`
`technology corporations and research organizations as well as companies with
`
`Novartis Exhibit 2205.005
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`critical brand management issues. I am Past President of The Licensing
`
`Executives Society International, Inc. as well as its largest chapter, LES USA &
`
`Canada, Inc. Today, I focus my not-for-profit efforts with organizations
`
`leveraging science and innovation for the benefit of children, including those
`
`located in lesser developed countries. I am a Director of the Stanley Manne
`
`Children’s Research Institute and have served since 2002 as a Trustee or Director
`
`of the National Inventors Hall of Fame, Inc., an organization providing summer
`
`enrichment programs for more than 160,000 students annually.
`
`7.
`
`I am a frequent speaker on emerging technology markets and related
`
`financial measures. I have addressed mass media audiences including Bloomberg
`
`Morning Call, Bloomberg Evening Market Pulse, Bloomberg Final Word, CNBC
`
`Closing Bell, CNBC On the Money, CNBC Street Signs, CNBC World Wide
`
`Exchange, CBS News Radio, and Fox Business National Television as well as
`
`other recognized news-based internet video channels. I am a judge on behalf of the
`
`Illinois Technology Association’s CityLIGHTS™ Innovation Awards program, 1st
`
`Source Faculty Commercialization Awards, and have also appeared as a judge on
`
`PBS’s Everyday Edisons.
`
`8.
`
`As an inventor, I have more than twenty issued U.S. patents. I am a
`
`frequent instructor for graduate studies on IP management and markets and a
`
`Summa Cum Laude graduate of the University of Notre Dame majoring in
`
`Novartis Exhibit 2205.006
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`accountancy and philosophy. I am Certified/Accredited in Financial Forensics,
`
`Business Valuation, and Blockchain Fundamentals. I am a Certified Licensing
`
`Professional and a Registered Certified Public Accountant in the State of Illinois.
`
`9. My curriculum vitae is provided as Appendix 1, and provides further
`
`information about my experience, expertise, and presentations.
`
`10. My payment is not contingent upon my testimony or outcome of this
`
`investigation. I have no personal interest in the outcome of this investigation.
`
`III. SUMMARY OF OPINIONS
`
`11.
`
`In my opinion, the antibody drug product Lucentis (active ingredient
`
`ranibizumab) is an anti-vascular endothelial growth factor (“anti-VEGF”)
`
`treatment sold in a pre-filled syringe (“PFS”) presentation incorporating the
`
`claimed inventions of the ʼ631 Patent that has been commercially successful. The
`
`commercial success of the Lucentis PFS is demonstrated by significant sales in the
`
`relevant market, rapid conversion of sales from vial to PFS presentation, the
`
`reversal from declining sales to increasing sales, and positive effects on market
`
`share. Additionally, it is my opinion that a nexus exists between the technology of
`
`the claimed inventions and the commercial success of the Lucentis PFS, which
`
`incorporates the patented technologies.
`
`Novartis Exhibit 2205.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`12. The claimed inventions of the ʼ631 Patent have also been licensed by
`
`third-parties. Additionally, it is my opinion that a nexus exists between the
`
`technology of the claimed inventions and the licenses entered into by third-parties.
`
`13. As a result, these secondary considerations of non-obviousness tend to
`
`indicate that the ʼ631 Patent is not obvious.
`
`IV.
`
`INDUSTRY BACKGROUND
`
`A. Treatments for Wet AMD
`
`14. Wet age-related macular degeneration (“wet AMD”) is an eye disease
`
`that occurs when a protein called vascular endothelial growth factor (“VEGF”)
`
`impacts blood vessels in the back of the eye, causing vision loss.1
`
`15. Currently, the most common and effective clinical treatment for wet
`
`AMD is anti-VEGF therapy, which is periodic intravitreal injection of an anti-
`
`1 Exhibit 2277 (“Treatments for Wet AMD (Advanced Neovascular AMD),”
`
`National Eye Institute, https://www.nei.nih.gov/learn-about-eye-health/eye-
`
`conditions-and-diseases/age-related-macular-degeneration/treatments-wet-amd-
`
`advanced-neovascular-amd); Exhibit 2204 (Declaration of Andrew Calman, Ph.D.,
`
`¶¶ 43-45).
`
`Novartis Exhibit 2205.008
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`VEGF drug.2 There are several products in the anti-VEGF market for wet AMD,
`
`including Genentech’s Avastin (bevacizumab), Genentech’s Lucentis
`
`(ranibizumab), Regeneron’s Eylea (aflibercept), and Novartis’s Beovu
`
`(brolucizumab), among others, as discussed in the following sections.
`
`Figure 1: Wet AMD Anti-VEGF Market3
`
`Wet AMD is 57% of total aVEGF sales ($6 B),
`but is growing more slowly than total aVEGF
`market growth rate
`
`Sales Split by Indication for Bi nded
`aVEGF Sales (2018)
`
`Total wet AMO aVEGF SalH ($ M)
`
`-
`
`ytea • LUl:el11S
`
`
`
`- ----®-- •s•.4 --------
`
`3,299
`
`2 965
`
`3,033
`
`3 032
`
`~ annual growth rate
`from 2014-2018
`
`(~ .. ~
`
`US Ophthalmology
`
`2014
`
`201S
`
`:>016
`
`2017
`
`2018
`
`76'1(,
`
`70'1(,
`
`5"'1(, ~ 57!!.
`
`%Of
`aV!:GI'
`le$
`
`0
`
`RTI
`
`
`
`2 Exhibit 2258 (“Macular Degeneration Treatments,” American Macular
`
`Degeneration, https://www.macular.org/treatments).
`
`3 Exhibit 2172 (NOVITC(US)00718202-335 at 205).
`
`Novartis Exhibit 2205.009
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`i.
`
`Avastin
`
`16. Avastin (bevacizumab), manufactured by Genentech, is a VEGF
`
`inhibitor indicated for the treatment of metastatic colorectal cancer, glioblastoma,
`
`and several other types of cancer and is sold as a single-dose vial.4
`
`17. Avastin is sometimes used “off-label” in patients with wet AMD.5
`
`Avastin received its first FDA approval on February 26, 2004, for treatment for
`
`metastatic colorectal cancer.6
`
`4 Exhibit 2259 (“Highlights of Prescribing Information – Avastin,” Genentech,
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf.)
`
`5 Exhibit 2260 (“Comparison of Anti VEGF Treatments for Wet AMD,” American
`
`Academy of Ophthalmology, February 3, 2020, https://www.aao.org/eye-
`
`health/diseases/avastin-eylea-lucentis-difference); Exhibit 2261 (“Age-Related
`
`Macular Degeneration: Facts & Figures,” BrightFocus Foundation,
`
`https://www.brightfocus.org/macular/article/age-related-macular-facts-figures).
`
`6 Exhibit 2262 (“FDA Approves Avastin,” Drugs.com, February 2004,
`
`https://www.drugs.com/newdrugs/avastin-approved-metastatic-colorectal-cancer-
`
`21.html).
`
`Novartis Exhibit 2205.0010
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`ii.
`
`Lucentis
`
`18. Lucentis (ranibizumab), manufactured by Genentech, is a VEGF
`
`inhibitor indicated for the treatment of patients with wet AMD, macular edema
`
`following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and
`
`myopic choroidal neovascularization and is sold as a single-dose vial or a single-
`
`dose PFS.7
`
`19. Lucentis is made by Genentech in collaboration with Novartis.8 In
`
`June 2003, Genentech entered into an agreement with Novartis, under which
`
`Novartis licensed the exclusive right to develop and market Lucentis outside of
`
`North America for indications related to diseases of the eye.9 Novartis paid an
`
`upfront milestone payment and R&D related fees during the development of the
`
`7 Exhibit 2125 (“Highlights of Prescribing Information – Lucentis,” Genentech,
`
`https://www.gene.com/download/pdf/lucentis_prescribing.pdf).
`
`8 Exhibit 2264 (“Investor Update,” Roche, March 22, 2018,
`
`https://www.roche.com/investors/updates/inv-update-2018-03-22.htm).
`
`9 Exhibit 2265.007 (Genentech, Inc. 10-K for the year ended December 31, 2003,
`
`p. 6, https://www.sec.gov/Archives/edgar/data/318771/000031877104000002/dna-
`
`10k_2003.htm); Exhibit 2123 (NOVITC(CH)00007283-394).
`
`Novartis Exhibit 2205.0011
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`drug, and continues to pay royalties on net sales of Lucentis products outside of
`
`North America, which Genentech manufactures and supplies to Novartis.10
`
`20. Lucentis received FDA approval for treatment of wet AMD on June
`
`30, 2006.11 The FDA approved the Lucentis 0.5 mg PFS as a new method of
`
`administering the medicine on October 14, 2016.12 Genentech’s first sales of the
`
`Lucentis PFS began in January 2017.13 On March 21, 2018, the FDA approved the
`
`10 Exhibit 2265.007 (Genentech, Inc. 10-K for the year ended December 31, 2003,
`
`p. 6, https://www.sec.gov/Archives/edgar/data/318771/000031877104000002/dna-
`
`10k_2003.htm); Exhibit 2123 (NOVITC(CH)00007283-394).
`
`11 Exhibit 2266 (“FDA Approves Lucentis (ranibizumab) for the Treatment of Wet
`
`Age-Related Macular Degeneration,” Drugs.com, June 30, 2006,
`
`https://www.drugs.com/newdrugs/fda-approves-lucentis-ranibizumab-wet-age-
`
`related-macular-degeneration-327.html).
`
`12 Exhibit 2116 (“FDA Approves Genentech’s Lucentis (ranibizumab) Prefilled
`
`Syringe,” Drugs.com, October 14, 2016, https://www.drugs.com/newdrugs/fda-
`
`approves-genentech-s-lucentis-ranibizumab-prefilled-syringe-4444.html); Exhibit
`
`2166.009 (NOVITC(US)00389194-205 at 202).
`
`13 Exhibit 2099 (GENEITC_1207-0000030).
`
`Novartis Exhibit 2205.0012
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Lucentis 0.3 mg PFS.14 As of March 2018, PFS options were approved for all
`
`Lucentis indications.15
`
`iii.
`
`Eylea
`
`21. Eylea (aflibercept), manufactured by Regeneron, is a VEGF inhibitor
`
`indicated for treatment of patients with wet AMD, macular edema following retinal
`
`vein occlusion, diabetic macular edema, and diabetic retinopathy and is sold as a
`
`single-dose vial or a single-dose PFS.16
`
`14 Exhibit 2117 (“FDA Approves Lucentis (ranibizumab injection) 0.3 mg Prefilled
`
`Syringe for Diabetic Macular Edema and Diabetic Retinopathy,” Genentech,
`
`March 21, 2018, https://www.gene.com/media/press-releases/14708/2018-03-
`
`21/fda-approves-genentechs-lucentis-ranibiz).
`
`15 Exhibit 2267 (“FDA Approves Lucentis (ranibizumab injection) 0.3 mg Prefilled
`
`Syringe for Diabetic Macular Edema and Diabetic Retinopathy,” Roche, March 22,
`
`2018, https://www.roche.com/investors/updates/inv-update-2018-03-22.htm).
`
`16 Exhibit 2197 (“Highlights of Prescribing Information – Eylea,” Regeneron,
`
`https://www.regeneron.com/sites/default/files/EYLEA_FPI.pdf).
`
`Novartis Exhibit 2205.0013
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`22. Eylea received FDA approval in a vial presentation on November 18,
`
`2011, for treatment of wet AMD.17 The FDA approved an Eylea 2.0 mg PFS on
`
`August 13, 2019.18
`
`B. Market Transition from Vials to Prefilled Syringes
`
`23.
`
`Intravitreal injections of anti-VEGF medications play an increasingly
`
`important role in the treatment of several retinal vascular diseases.19 Initially, anti-
`
`17 Exhibit 2269 (“FDA Approves Eylea,” Drugs.com, November 18, 2011,
`
`https://www.drugs.com/newdrugs/fda-approves-eylea-wet-age-related-macular-
`
`degeneration-2955.html).
`
`18 Exhibit 2270 ( “FDA Approves Eylea® (aflibercept) Injection Prefilled
`
`Syringe,” Regeneron, August 13, 2019, https://investor.regeneron.com/news-
`
`releases/news-release-details/fda-approves-eylear-aflibercept-injection-prefilled-
`
`syringe).
`
`19 Exhibit 2018 (“Prefilled syringes for intravitreal drug delivery,” National Center
`
`for Biotechnology Information, April 23, 2019,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485318/); Exhibit 2204
`
`(Declaration of Andrew Calman, Ph.D., ¶ 81).
`
`Novartis Exhibit 2205.0014
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`VEGF medications came in vials that had to be drawn up by the physician into a
`
`syringe for administration.20
`
`24. A prefilled syringe, or PFS, is packaged in a single use, sealed sterile
`
`tray, which allows physicians to eliminate a number of steps in the preparation and
`
`administration of the anti-VEGF injection.21 The use of prefilled syringes offers
`
`certain advantages over vials including reduced injection time, possible reduced
`
`risk of endophthalmitis, reduction in intraocular air bubble and silicone oil
`
`droplets, and improved precision in the volume and dose of the intravitreal drug
`
`administered.22 Chris Simms, then the vice president of the U.S. Ophthalmics
`
`20 Exhibit 2018 (“Prefilled syringes for intravitreal drug delivery,” National Center
`
`for Biotechnology Information, April 23, 2019,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485318/).
`
`21 Exhibit 2018 (“Prefilled syringes for intravitreal drug delivery,” National Center
`
`for Biotechnology Information, April 23, 2019,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485318/); Exhibit 2204
`
`(Declaration of Andrew Calman, Ph.D., ¶ 88).
`
`22 Exhibit 2018 (“Prefilled syringes for intravitreal drug delivery,” National Center
`
`for Biotechnology Information, April 23, 2019,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485318/); Exhibit 2271
`
`Novartis Exhibit 2205.0015
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`franchise at Novartis, testified that the PFS is easier to use than the vial and
`
`requires fewer steps to prepare the drug for administration.23 Mr. Simms also
`
`stated that the prefilled syringe is preferable over the vial format for customers.24
`
`25. Since 2012, there have been three FDA approvals for PFS as a new
`
`method of administering anti-VEGF medicines: Genentech’s Lucentis 0.5 mg PFS
`
`in October 2016, Genentech’s Lucentis 0.3 mg PFS in March 2018, and
`
`Regeneron’s Eylea 2.0 mg PFS in August 2019.25
`
`(“Prefilled Syringe Delivery of Intravitreal Anti-VEGF Medications,”
`
`RetinalPhysician.com, March 1, 2019,
`
`https://www.retinalphysician.com/issues/2019/march-2019/prefilled-syringe-
`
`delivery-of-intravitreal-anti-ve); Exhibit 2204 (Declaration of Andrew Calman,
`
`Ph.D., ¶ 105 n. 68).
`
`23 Exhibit 2272.011-.012 (Deposition of Christopher Simms, December 4, 2020,
`
`pp. 73-74).
`
`24 Exhibit 2272.010 (Deposition of Christopher Simms, December 4, 2020, p. 26).
`
`25 Exhibit 2015 (“FDA Approves Genentech’s Lucentis (ranibizumab) Prefilled
`
`Syringe,” Drugs.com, October 14, 2016, https://www.drugs.com/newdrugs/fda-
`
`approves-genentech-s-lucentis-ranibizumab-prefilled-syringe-4444.html); Exhibit
`
`2267 (“FDA Approves Lucentis (ranibizumab injection) 0.3 mg Prefilled Syringe
`
`Novartis Exhibit 2205.0016
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Figure 2: Benefits of Lucentis PFS26
`
`Lucentis PFS Approved in US - Oct 14th 2016
`
`"The Lucentis PFS allows
`physicians to eliminate several
`steps in the preparation and
`administration process,
`including disinfecting the vial,
`attaching a filter needle,
`drawing the medicine from the
`vial using the needle,
`removing the filter needle from
`the syringe and replacing with
`an injection needle. With the
`Lucentis PFS, physicians
`attach the injection needle to
`the syringe and adjust the
`dose prior to administration·
`
`Ophthamology Franchise
`
`
`
`for Diabetic Macular Edema and Diabetic Retinopathy,” Roche, March 22, 2018,
`
`https://www.roche.com/investors/updates/inv-update-2018-03-22.htm); Exhibit
`
`2270 (“FDA Approves Eylea® (aflibercept) Injection Prefilled Syringe,”
`
`Regeneron, August 13, 2019, https://investor.regeneron.com/news-releases/news-
`
`release-details/fda-approves-eylear-aflibercept-injection-prefilled-syringe).
`
`26 Exhibit 2166.009 (NOVITC(US)00389194-205 at 202).
`
`Novartis Exhibit 2205.0017
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`V. THE ʼ631 PATENT
`
`26. The ʼ631 Patent, titled “Syringe,” issued on December 29, 2015.27
`
`The application for the ʼ631 Patent was filed on January 25, 2013. The abstract of
`
`the patent reads as follows:
`
`The present invention relates to a syringe, particularly to a small
`
`volume syringe such as a syringe suitable for ophthalmic injections.
`
`27.
`
`I understand that Mr. Karl R. Leinsing, expert witness for Novartis
`
`regarding syringe design, has opined that the ʼ631 Patent is directed to the
`
`invention of a terminally-sterilized small-volume PFS for intravitreal injection of a
`
`VEGF antagonist, which includes low levels of silicone oil while maintaining low
`
`injection forces.28 The ʼ631 Patent also enabled terminal sterilization of a PFS
`
`suitable for intravitreal injection through improvements to prior art syringe
`
`designs.29
`
`28. The ʼ631 Patent has a single independent claim and twenty-five
`
`dependent claims. Independent claim 1 reads as follows:30
`
`27 Exhibit 1001.001 (U.S. Patent No. 9,220,631, p. 1).
`
`28 Exhibit 2001 (Declaration of Karl R. Leinsing, PE, ¶ 23).
`
`29 Exhibit 2001 (Declaration of Karl R. Leinsing, PE, ¶ 26).
`
`30 Exhibit 1001 at 19:2-13 (U.S. Patent No. 9,220,631, c. 19:2-13).
`
`Novartis Exhibit 2205.0018
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`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,
`
`(b)
`
`the syringe barrel comprises from about 1 μg to 100 ug 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.
`
`29.
`
`In describing the background art and the need that the invention
`
`addressed, the ʼ631 Patent provides the following:31
`
`Many medicaments are delivered to a patient in a syringe from which
`
`the user can dispense the medicament. If medicament is delivered to a
`
`patient in a syringe it is often to enable the patient, or a caregiver, to inject
`
`the medicament. It is important for patient safety and medicament integrity
`
`that the syringe and the contents of that syringe are sufficiently sterile to
`
`31 Exhibit 1001 at 1:11-43 (U.S. Patent No. 9,220,631, c. 1:11-43).
`
`Novartis Exhibit 2205.0019
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`avoid infection, or other, risks for patients. Sterilisation can be achieved by
`
`terminal sterilisation in which the assembled product, typically already in its
`
`associated packaging, is sterilised using heat or a sterilising gas.
`
`For small volume syringes, for example those for injections into the
`
`eye in which it is intended that about 0.1 ml or less of liquid is to be injected
`
`the sterilisation can pose difficulties that are not necessarily associated with
`
`larger syringes. Changes in pressure, internal or external to the syringe,
`
`can cause parts of the syringe to move unpredictably, which may alter
`
`sealing characteristics and potentially compromise sterility. Incorrect
`
`handling of the syringe can also pose risks to product sterility.
`
`Furthermore, certain therapeutics such as biologic molecules are
`
`particularly sensitive to sterilisation, be it cold gas sterilisation, thermal
`
`sterilisation, or irradiation. Thus, a careful balancing act is required to
`
`ensure that while a suitable level of sterilisation is carried out, the syringe
`
`remains suitably sealed, such that the therapeutic is not compromised. Of
`
`course, the syringe must also remain easy to use, in that the force required
`
`to depress the plunger to administer the medicament must not be too high.
`
`There is therefore a need for a new syringe construct which provides
`
`a robust seal for its content, but which maintains ease of use.
`
`Novartis Exhibit 2205.0020
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`30.
`
`In generally describing the invention, the ʼ631 Patent states:32
`
`The present invention provides a pre-filled syringe, the syringe
`
`comprising a body, a stopper and a plunger, the body comprising an outlet
`
`at an outlet end and the stopper being arranged within the body such that a
`
`front surface of the stopper and the body define a variable volume chamber
`
`from which a fluid can be expelled though the outlet, the plunger comprising
`
`a plunger contact surface at a first end and a rod extending between the
`
`plunger contact surface and a rear portion, the plunger contact surface
`
`arranged to contact the stopper, such that the plunger can be used to force
`
`the stopper towards the outlet end of the body, reducing the volume of the
`
`variable volume chamber, characterised in that the fluid comprises an
`
`ophthalmic solution. In one embodiment, the ophthalmic solution comprises
`
`a VEGF-antagonist.
`
`In one embodiment, the syringe is suitable for ophthalmic injections,
`
`more particularly intravitreal injections, and as such has a suitably small
`
`volume. The syringe may also be silicone oil free, or substantially silicone
`
`oil free, or may comprise a low level of silicone oil as lubricant. In one
`
`32 Exhibit 1001 at 1:47-68 (U.S. Patent No. 9,220,631, c. 1:47-68).
`
`Novartis Exhibit 2205.0021
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`embodiment, despite the low silicone oil level, the stopper break loose and
`
`slide force is less than 20N.
`
`VI. LEGAL PRINCIPLES
`
`31.
`
`I am not an attorney and I will offer no opinions on the law. I have,
`
`however, been instructed by Counsel regarding the following legal principles
`
`related to my opinions. Based on these instructions, I have developed and applied
`
`the following understandings in arriving at the opinions and conclusions in this
`
`Declaration. The legal principles I have employed are set out below.
`
`32.
`
`I understand the determination of whether or not an invention is
`
`obvious is a legal conclusion based on underlying factual inquiries including
`
`objective indicia of non-obviousness. Objective indicia of non-obviousness are
`
`sometimes referred to as “secondary considerations of non-obviousness.” I
`
`understand that it is not permissible to use hindsight in determining whether or not
`
`a patent was obvious as of the relevant date, and that a judge will consider the
`
`existence of secondary considerations of non-obviousness, in order to mitigate the
`
`possible impact of hindsight in an obviousness analysis. Two examples of
`
`secondary considerations of non-obviousness include: 1) the commercial success
`
`of products incorporating the claimed technology and 2) licensing.
`
`33.
`
` I have been asked to evaluate the commercial success of the Lucentis
`
`PFS, a product incorporating the ʼ631 Patent. I understand that commercial
`
`Novartis Exhibit 2205.0022
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`success may be established by looking to the patented products of a patentee or
`
`licensee, as well as infringing products. Further, I understand that commercial
`
`success is relevant regardless of whether it takes place within the United States.
`
`Finally, I understand that independently, licenses granted under a patent, including
`
`those resulting from settlement of litigation, can also support a finding of non-
`
`obviousness.
`
`34.
`
`In evaluating the commercial success of a patented product for the
`
`purposes of considering non-obviousness, I understand that courts often look to a
`
`standard of “significant sales in a relevant market.” While there may not be a strict
`
`quantitative test to determine what constitutes “significant sales in a relevant
`
`market,” I understand that commercial success should be shown in a market
`
`context rather than simply a recounting of a company’s sales.
`
`35.
`
`I also understand courts have indicated that, in order to demonstrate
`
`commercial success, the patentee must show a factually sufficient connection, or
`
`nexus, between the patented invention and the product’s commercial success. In
`
`demonstrating nexus, the patentee is not necessarily required to demonstrate that
`
`its claimed inventions are “solely responsible” for commercial success of its
`
`products. Additionally, I understand that nexus is presumed to exist if the
`
`commercially successful product is coextensive with the invention disclosed and
`
`claimed in the patent.
`
`Novartis Exhibit 2205.0023
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`VII. SECONDARY CONSIDERATIONS SUPPORTING THE NON-
`
`OBVIOUSNESS OF THE ʼ631 PATENT
`
`A. Commercial Success
`
`36. As discussed above, I understand that commercial success may be
`
`established by looking to the patented products of a patentee or licensee, as well as
`
`infringing products. I also understand that Regeneron’s expert witness, Mr. Horst
`
`Koller, concludes that “the evidence does not show a nexus between the alleged
`
`commercial success of Lucentis PFS and the claims in the ʼ631 Patent.”33 I
`
`disagree with Mr. Koller’s conclusion for the reasons that follow.
`
`37.
`
`I understand that the first product sold in the U.S. that practices the
`
`ʼ631 Patent was the Lucentis PFS, sold by Genentech, a licensee to the ʼ631
`
`33 Exhibit 1003.197 (Declaration of Horst Koller, April 16, 2021, p. 192).
`
`Novartis Exhibit 2205.0024
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Patent.34 The FDA approved the Lucentis PFS on October 14, 2016,35 while
`
`Genentech’s first sales of the Lucentis PFS began in January 2017.36
`
`38. As seen in the following figure, by early 2018, Novartis recognized
`
`that Lucentis PFS “
`
`” in total Lucentis
`
`sales twelve months after launch.37
`
`34 Exhibit 2201 (Supplemental Declaration of Karl Leinsing, PE, ¶¶ 117 n. 14,
`
`167); Exhibit 2204 (Declaration of Andrew Calman, Ph.D., ¶¶ 51-54).
`
`35 Exhibit 2015 (“FDA Approves Genentech’s Lucentis (ranibizumab) Prefilled
`
`Syringe,” Drugs.com, October 14, 2016, https://www.drugs.com/newdrugs/fda-
`
`approves-genentech-s-lucentis-ranibizumab-prefilled-syringe-4444.html).
`
`36 Exhibit 2099 (GENEITC_1207-0000030).
`
`37 Exhibit 2170 (NOVITC(US)00507243).
`
`Novartis Exhibit 2205.0025
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Figure 3: Lucentis Sales Impact from PFS Launch38
`
`39. This positive impact on sales is even more apparent when Lucentis’
`
`longer sales trends are considered. Lucentis vial sales had generally increased
`
`from 2010 through 2014,39 apart from a decrease in 2012 “due to the entry of a
`
`co
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