UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`REGENERON PHARMACEUTICALS, INC.
`
`Petitioner,
`
`V.
`
`NOVARTIS PHARMA AG,
`NOV ARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`Patent Number: 9,220,631
`
`DECLARATION OF JAMES L. MULLINS. Ph.D.
`
`Regeneron Exhibit 1033.001
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`Introduction ...................................................................................................... I
`
`Qualifications and Compensation .................................................................... I
`
`III. Background ...................................................................................................... 3
`
`IV. Documents ....................................................................................................... 7
`
`A.
`
`B.
`
`C.
`
`Document 1. Bruno Reuter and Claudia Petersen. "Die
`Silikonisierung von Spritzen: Trends, Methoden,
`Analyseverfahren," TechnoPharm 2, Nr. 4 (2012): 238-244.
`("Reuter") .............................................................................................. 7
`1.
`Authentication ............................................................................. 7
`Public Accessibility .................................................................... 8
`2.
`Conclusion ................................................................................ 10
`3.
`
`Document 2. Arno Fries. "Drug Delivery of Sensitive
`Biopharmaceuticals with Prefilled Syringes." Drug Delivery
`Technology. Volume 9. Number 5 (May 2009): 22-27. ("Fries") ...... IO
`1.
`Authentication ........................................................................... 10
`Public Accessibility ................................................................. . 11
`2.
`Conclusion ................................................................................ 12
`3.
`
`Document 3. James A. Dixon, et al., "VEGF Trap-Eye for the
`Treatment of Neovascular Age-related Macular Degeneration."
`Expert Opinion on Investigational Drugs. Volume 18. Number
`10 (October 2009): 1573-1580. ("Dixon") .......................................... 13
`1.
`Authentication ........................................................................... 13
`Public Accessibility .................................................................. 14
`2.
`Conclusion ................................................................................ 15
`3.
`
`V.
`
`Declaration ..................................................................................................... 17
`
`1
`
`Regeneron Exhibit 1033.002
`
`

`

`I.
`
`Introduction
`
`I, James L. Mullins, hereby declare under penalty of perjury:
`
`1.
`
`In this declaration, I opine on the authenticity of certain documents
`
`referenced herein and explain when and how these documents were disseminated or
`
`otherwise made available to the extent that persons interested and ordinarily skilled
`
`in the subject matter or art, exercising reasonable diligence, could have located the
`
`document. I am being paid my usual hourly fee of $250/hour. My compensation in
`
`no way depends on the content of my testimony or the outcome of the proceeding.
`
`II. Qualifications and Compensation
`
`2.
`
`I am the Founder and Owner of the firm Prior Art Documentation
`
`Librarian Services, LLC at 106 Berrow, Williamsburg, VA 23188. Attached as
`
`Exhibit 1060 is a true and correct copy of my Curriculum Vitae describing my
`
`background and experience. Further information about my firm, Prior Art
`
`Documentation Librarian
`
`Services, LLC
`
`(P ADLS),
`
`1s
`
`available
`
`at
`
`www.priorartdoclib.com.
`
`3.
`
`I am presently Dean Emeritus of Libraries and Esther Ellis Norton
`
`Professor Emeritus, Purdue University, 2018 - present. I was previously employed
`
`as follows:
`
`(a) Dean of Libraries and Professor & Esther Ellis Norton Professor,
`
`Purdue University, West Lafayette, IN, 2004-2017;
`
`Regeneron Exhibit 1033.003
`
`

`

`(b) Assistant/ Associate Director
`
`for Administration, Massachusetts
`
`Institute of Technology (MIT), Cambridge, MA, 2000-2004;
`
`( c) University Librarian and Director, Falvey Memorial Library, Villanova
`
`University, Villanova, PA, 1996-2000;
`
`( d) Director of Library Services, Indiana University South Bend, South
`
`Bend, IN, 1978-1996. Part-time instructor, School of Library and Information
`
`Science, Indiana University, Bloomington, IN, 1979-1996;
`
`( e) Associate Law Librarian, and associated titles, Indiana University
`
`School of Law, Bloomington, IN, 1974-1978;
`
`(f)
`
`Catalog Librarian, Assistant Professor, Georgia Southern College (now
`
`University), Statesboro, GA, 1973-1974.
`
`4.
`
`Over the course of my career as a librarian, instructor of library science,
`
`author of scholarly publications, and presenter at national and international
`
`conferences, I have had experience with catalog records and online library
`
`management systems built around Machine-Readable Cataloging (MARC)
`
`standards.
`
`5.
`
`During more than forty-four years as an academic librarian and scholar,
`
`I have been an active researcher. In my years as a librarian, I have facilitated the
`
`research of faculty colleagues, either directly or through the provision of and access
`
`to the requisite print and/or digital materials and services at the universities I worked.
`
`2
`
`Regeneron Exhibit 1033.004
`
`

`

`I have kept current on the professional library science literature and served on the
`
`editorial board of the most prominent library journal, College and Research
`
`Libraries. This followed service as the chair of the Research Committee of the
`
`Association of College and Research Libraries (ACRL ), a division of the American
`
`Library Association (ALA). As an academic library administrator, I have had
`
`responsibility to ensure that students were educated to identify, locate, assess and
`
`integrate information garnered from library resources.
`
`III. Background
`
`6.
`
`Authentication. I understand that an item is considered authentic if
`
`there is sufficient evidence to support a finding that the item is what it is claimed to
`
`be. I am also informed that authenticity can be established based on the contents of
`
`the documents themselves, such as the appearance, content, substance, internal
`
`patterns, or other distinctive characteristics of the item, taken together with all of the
`
`circumstances.
`
`7.
`
`Public Accessibility. I understand that a given reference is publicly
`
`accessible upon a satisfactory showing that such a document has been disseminated
`
`or otherwise made available to the extent that persons interested and ordinarily
`
`skilled in the subject matter or art exercising reasonable diligence, can locate it. I
`
`have also been informed by counsel that materials available in a library constitute
`
`3
`
`Regeneron Exhibit 1033.005
`
`

`

`printed publications if they are cataloged and indexed according to general library
`
`practices that make the references available to members of the interested public.
`
`8.
`
`Materials considered. For purposes of this declaration I have reviewed
`
`the documents and appendices referenced herein. These materials are records created
`
`in the ordinary course of business by publishers, libraries, indexing services, and
`
`others. I am familiar with the process for creating many of these records, and I know
`
`these records are created by people with knowledge of the information in the record.
`
`Further, these records are created with the expectation that researchers and other
`
`members of the public will use them. All materials cited in this declaration and its
`
`appendices are of a type that professionals in my field would reasonably rely upon
`
`and refer to in forming their opinions.
`
`9.
`
`WorldCat. WorldCat is the world's largest public online catalog,
`
`maintained by the Online Computer Library Center, Inc., or OCLC, and built with
`
`the records created by the thousands of libraries that are members of OCLC.
`
`WorldCat is easily accessible on the internet to all who wish to search it; there are
`
`no restrictions to be a member of a particular community, etc.
`
`10. OP AC. Online public access catalog, or "OPAC," refers to a catalog of
`
`a library or a group of libraries. OPACs, generally, and both OPACs mentioned in
`
`this declaration, are easily accessible on the internet to all who wish to search them
`
`4
`
`Regeneron Exhibit 1033.006
`
`

`

`and there are no generally restrictions on who can search an OPAC and/or access its
`
`records.
`
`11. Periodical publications. A library typically creates a catalog record for
`
`a periodical publication when the library receives its first issue. When the institution
`
`receives subsequent issues/volumes of the periodical, the issues/volumes are
`
`generally checked in ( often using a date stamp), added to the institution's holding
`
`records, and made available very soon thereafter - normally within a few days of
`
`receipt or (at most) within a few weeks of receipt.
`
`12.
`
`Indexing. A common way of searching for a publication is to look for
`
`relevant information in an index of periodical and other publications. Having found
`
`relevant material, the researcher will then normally obtain it online, look for it in
`
`libraries, or purchase it from the publisher, a bookstore, a document delivery service,
`
`or other provider. Sometimes, the date of a document's public accessibility will
`
`involve both indexing and library date information. Date information for indexing
`
`entries is, however, often unavailable. This is especially true for online indices.
`
`Online indexing services commonly provide bibliographic information, abstracts,
`
`and full-text copies of the indexed publications, along with a list of the documents
`
`cited in the indexed publication. These services also often provide lists of
`
`publications that cite a given document. A citation of a document is evidence that
`
`5
`
`Regeneron Exhibit 1033.007
`
`

`

`the document was publicly available and in use by researchers no later than the
`
`publication date of the citing document.
`
`13. Persons of ordinary skill in the art. I understand that a "person of
`
`ordinary skill in the art" ("POSITA") is a hypothetical person who is presumed to
`
`have been familiar with the relevant field and its literature at the time of the
`
`inventions. This hypothetical person is also a person of ordinary creativity, capable
`
`of understanding the scientific principles applicable to the pertinent field.
`
`14.
`
`I am told by counsel that a POSITA in this subject matter or art would
`
`either (a) have had at least an advanced degree (Dipl.Ing, M.S., or Ph.D.), with
`
`research experience in mechanical engineering, biomedical engineering, materials
`
`science, chemistry, or a related field or at least 2-3 years of professional experience
`
`in one or more of those fields and would have had experience with (i) the design of
`
`prefilled syringes; and (ii) sterilization of drug delivery devices, including those
`
`containing sterilization sensitive therapeutics, wherein such sterilization experience
`
`would include experience with microbiology; and with respect to certain claims in
`
`the challenged patent that deal with administering a drug, a POSIT A would be an
`
`ophthalmologist with some experience administering VEGF-antagonist drugs to
`
`patients via the intravitreal route.
`
`15.
`
`Such a person would have been engaged in academic research, learning
`
`through study and practice in the field and possibly through formal instruction the
`
`6
`
`Regeneron Exhibit 1033.008
`
`

`

`bibliographic resources relevant to his or her research. In and prior to 2012, such a
`
`person would have had access to a vast array of print resources in, for example,
`
`mechanical engineering, biomedical engineering, materials science, chemistry, or
`
`medicine, as well as to a set of online resources.
`
`IV. Documents
`
`A. Document 1. Bruno Reuter and Claudia Petersen. "Die Silikonisierung
`von Spritzen: Trends, Methoden, Analyseverfahren," TechnoPharm 2,
`Nr. 4 (2012): 238-244. ("Reuter")
`
`1. Authentication
`
`16. Appendix IA is a true and accurate copy from the issue of
`
`TechnoPharm, 2, Nnr.4 (2012) pages 238-244. Appendix IA includes a cover, with
`
`ownership stamp of Wurttembergische Landesbibliothek in Stuttgart, table of
`
`contents, and the Reuter article pages 238-244. This scan was provided to me at my
`
`request by the Wisconsin TechSearch (WTS),1 from the Wurttembergische
`
`Landesbibliothek in Stuttgart, Germany. I understand that is not the practice of
`
`German libraries to date stamp the receipt of an issue of a journal.
`
`17. Appendix IB is a true and accurate copy from the issue of
`
`TechnoPharm 2, Nr. 4 (2012) by Bruno Reuter and Claudia Petersen, downloaded
`
`by
`
`me
`
`from
`
`the
`
`TechnoPharm
`
`website:
`
`1 WTS (https://wts.wisc.edu/) is a service from the Libraries department at the University
`Wisconsin-Madison, which provides article delivery and certain librarian research services on
`request.
`
`7
`
`Regeneron Exhibit 1033.009
`
`

`

`https://www.ecv.de/download/download/Zeitschriften/TechnoPharm/volltext/tp-
`
`2012-04-0238-reuter-silikonisierung-web _ d.pdf.
`
`18. Appendix IA and Appendix IB are in a condition that appear in all
`
`respects to be authentic. The sequence from pages 238-244 is not missing
`
`intermediate pages, the text on each page appears to flow seamlessly from one page
`
`to the next, and there are no visible alterations to the document. Appendix IA was
`
`located and recovered from a library, the Wurttembergische Landesbibliothek.
`
`Appendix IB was downloaded from the TechnoPharm website, which is where a
`
`person looking for authentic copies would expect to find them. Therefore, I conclude
`
`that Appendix IA and Appendix IB are authentic copies of the Reuter article.
`
`2. Public Accessibility
`
`19. Appendix IC is a view of the WorldCat record for TechnoPharm
`
`making science work. W orldCat provides an international access point to locate
`
`TechnoPharm by title and by subject: Pharmazeutische Technologie. Listed among
`
`the eleven international libraries holding TechnoPharm is Wurttembergische
`
`Landesbibliothek in Stuttgart, Germany.
`
`20. Appendix ID is a letter from the Wurttembergische Landesbibliothek.
`
`In order to verify that the print version was processed and publicly accessible to a
`
`researcher at the Wurttembergische Landesbibliothek, counsel obtained a letter from
`
`8
`
`Regeneron Exhibit 1033.010
`
`

`

`Birgit Hacker, Head of Journals Department, Wurttembergische Landesbibliothek.
`
`This letter dated July 25, 2018 states:
`
`I hereby confirm, that the printed issue of the journal
`
`TechnoPharm : making science work / APV,
`
`Arbeitsgemeinschaft fur Pharmazeutische
`
`V erfahrenstechnik e. V.
`
`Aulendorf: ECV, Edito-Cantor-Verlag fur Medizin und
`
`N aturwissenschaften
`
`Volume 2.2012, no. 4
`
`has been received in our library in the month of August
`
`2012.
`
`Since the 14th of August, it has always been open to the
`
`public.
`
`It is part of a bound volume and is lendable with the shelf
`
`number Za 15974-2.2012,4-6.
`
`21. Appendix IE is the OPAC (public catalog) record of Wurttembergische
`
`Landesbibliothek for TechnoPharm. Below the middle of the record on the left-hand
`
`side, under Band [Volume] are
`
`the holdings of the Wurttembergische
`
`Landesbibliothek. Among the holdings is: 2. 2012 (2012), Heft. [Issue] 4-6.
`
`22. After verifying by a search on the internet that Birgit Hacker is with the
`
`Wurttembergische Landesbibliothek and from my years of experience in academic
`
`libraries, I can state that this letter is consistent with ones sent to verify the receipt
`
`and availability of library materials. I see no reason to suspect that this is not an
`
`9
`
`Regeneron Exhibit 1033.011
`
`

`

`authentic and reliable statement on the receipt and availability of Techno Pharm. 2,
`
`nr. 4 (2012) and its availability as of August 14, 2012.
`
`3. Conclusion
`
`23.
`
`I conclude, based on finding Document 1, the Reuter article, in a library
`
`and on finding library catalog records and an online record for the Reuter article.
`
`Appendices ID and IE indicate it was locatable by a researcher in August 2012.
`
`Document 1, the Reuter article, would have been available to an interested person
`
`no later than August 14, 2012.
`
`B. Document 2. Arno Fries. "Drug Delivery of Sensitive
`Biopharmaceuticals with Prefilled Syringes." Drug Delivery Technology.
`Volume 9. Number 5 (May 2009): 22-27. ("Fries")
`
`1. Authentication
`
`24. Appendix 2A is a true and accurate copy from the issue of Drug
`
`Delivery Technology, volume 9, number 5, May 2009, pages 22 - 27. Appendix 2A
`
`includes cover, with ownership and date stamp of National Library of Medicine
`
`(NLM) May 18, 2009 (upper left hand comer of cover); the front material relating
`
`to the publication of the journal, Drug Delivery Technology and the Fries article
`
`pages 22-27. This scan was provided to me at my request by the Wisconsin
`
`TechSearch (WTS) from the National Library of Medicine (NLM).
`
`25. Appendix 2B is a download from the proprietary website of Drug
`
`Development & Delivery (formerly "Drug Delivery Technology" through 2010):
`
`10
`
`Regeneron Exhibit 1033.012
`
`

`

`http://drug-dev.com/wp-content/uploads/2018/05/May-2009 .pdf.
`
`It provided me
`
`access to the digital copy of the Fries article.
`
`26. Appendices 2A and 2B are in a condition that creates no suspicion
`
`about their authenticity. Specifically, the cover, the front material, the table of
`
`contents, and the sequence from page 22-27 is not missing intermediate pages, the
`
`text on each page appears to flow seamlessly from one page to the next, and there
`
`are no visible alterations to the document. Appendix 2B was found within the
`
`custody of a library - National Library of Medicine - a place where, if authentic, it
`
`would likely be found. Appendix 2B was located and downloaded by me from the
`
`proprietary website of the journal, where, if authentic, it would be found. Therefore,
`
`with the documentation provided above, I conclude that Document 2, the Fries
`
`article, is authentic.
`
`2. Public Accessibility
`
`27. Appendix 2A has the check-in date ( on label on upper left hand corner
`
`of the cover) by the National Library of Medicine of May 18, 2009. Based on my
`
`knowledge and experience of academic libraries, I understand that it would take at
`
`most a week for such a periodical to be accessible on the library's shelf, the Fries
`
`article would have been publicly accessible no later than May 25, 2009.
`
`28. Appendix 2C is a download from W orldCat that indicates that Drug
`
`Delivery Technology, as of September 21, 2018, is held by 59 libraries among these
`
`11
`
`Regeneron Exhibit 1033.013
`
`

`

`is the National Library of Medicine. The WorldCat record indicates it would have
`
`been accessible by title, Drug Delivery Technology, and by subjects: Drug delivery
`
`systems - periodicals; Drug delivery systems; and Biological transport.
`
`29. Appendix 2D is a download from the National Library of Medicine
`
`OPAC (online catalog). The NLM OPAC record indicates that Drug Delivery
`
`Technology began publication in 2001 and ceased with volume 10, no. 9 (Nov. -
`
`Dec. 2010). The available volumes held by NLM are shown as v.2 (2002) - 10
`
`(2010), inclusive of volume 9, number 5, the issue in which the Fries article was
`
`published.
`
`30. Appendix 2E is an article by D. Brett Ludwig, et al., titled "Flow
`
`cytometry: A Promising Technique for the Study of Silicone Oil-induced Particulate
`
`Formation in Protein Formulations," published in Analytical Biochemistry, volume
`
`410 (2011 ): 191-199. On page 199, in References, is number 11, the Fries article.
`
`3. Conclusion
`
`31.
`
`I conclude, based on finding Document 2 in a library and on finding
`
`library catalog records, indicating it was locatable and accessible to the public, that
`
`Document 2, the Fries article, is an authentic document and that Appendix 2A and
`
`Appendix 2B are authentic copies of Document 2 and that Appendix 2C and
`
`Appendix 2D are accurate reflections of the acquisition and cataloging of Document
`
`2 and its accessibility to a researcher. Further evidence of its public accessibility is
`
`12
`
`Regeneron Exhibit 1033.014
`
`

`

`it being listed as a reference in an article (Appendix 2E) published in 2011. It is,
`
`therefore, my conclusion that Document 2, the Fries article, is an authentic document
`
`and was publicly accessible no later than May 25, 2009.
`
`C. Document 3. James A. Dixon, et al., "VEGF Trap-Eye for the Treatment
`ofNeovascular Age-related Macular Degeneration." Expert Opinion on
`Investigational Drugs. Volume 18. Number 10 (October 2009): 1573-
`1580. ("Dixon")
`
`1. Authentication
`
`32. Appendix 3A is a true and accurate copy, requested by me from the
`
`Wisconsin TechSearch (WTS), of the article by James A. Dixon, et al., titled "VEGF
`
`Trap-Eye for the Treatment of Neovascular Age-related Macular Degeneration"
`
`published in Expert Opinion on Investigational Drugs, volume 18, no. 10 (October
`
`2009) pages 1573-1580.
`
`33. Appendix 3A includes cover of the October 2009 issue with National
`
`Library of Medicine (NLM) label ( upper left hand comer of cover), indicating the
`
`issue was checked in by the NLM staff on October 20, 2009; table of contents;
`
`publication information, and the Dixon article, pages 1573-1580.
`
`34. Appendix 3B is a download from the Taylor and Francis website, that
`
`provides the bibliographic description of the Dixon article and also indicates it was
`
`published online 20 August 2009. Appendix 3B was downloaded by me on
`
`September
`
`21,
`
`2018
`
`at
`
`the
`
`Taylor
`
`and
`
`Francis
`
`website:
`
`https://www.tandfonline.com/doi/abs/10.1517 /13543780903201684.
`
`13
`
`Regeneron Exhibit 1033.015
`
`

`

`35. Appendix 3A is in a condition that creates no suspicion about its
`
`authenticity. Specifically, the cover, the front material, the table of contents, and the
`
`sequence from page 1573 to 1580 is not missing intermediate pages, the text on each
`
`page appears to flow seamlessly from one page to the next, and there are no visible
`
`alterations to the document. Appendix 3A was found within the custody of a library
`
`- the National Library of Medicine - a place where, if authentic, it would likely be
`
`found.
`
`36. Appendix 3B documents that the Dixon article was published online by
`
`Taylor and Francis in its publication Expert Opinion on Investigational Drugs on
`
`August 20, 2009.
`
`3 7. With the evidence identified above, I have determined that Document
`
`3, the Dixon article, is an authentic document.
`
`2. Public Accessibility
`
`38. Appendix 3C is the view of the WorldCat record for the journal Expert
`
`Opinion on Investigational Drugs. It illustrates the availability to the public of the
`
`journal. One-hundred eighty-one libraries worldwide hold Expert Opinion on
`
`Investigational Drugs (in all formats and editions) as of September 2018, among
`
`these it shows the National Library of Medicine as owning the journal. The ability
`
`to locate this record is by title and by subject: Drugs - Periodicals - Design; and
`
`Drugs.
`
`14
`
`Regeneron Exhibit 1033.016
`
`

`

`39. Appendix 3D is a download from the National Library of Medicine
`
`OPAC ( online catalog). The NLM OPAC record indicates that Expert Opinion on
`
`Investigational Drugs began publication in 1994 in London by Ashley Publications
`
`Ltd. The OPAC record indicates that the National Library of Medicine started
`
`receiving the journal with Vol. 3, no. 2, (Feb. 1994)- and has continued to subscribe
`
`to the present. In the availability portion of the OP AC record it indicates volumes
`
`held by NLM are shown as v.3: no.2 (1994)-v.3: no. 4 (1994), v.3: no. 6 (1994) -
`
`v.22: no. 4 (2013), inclusive of volume 18, number 10, October 2009, the issue in
`
`which the Dixon article was published.
`
`40. Appendix 3E is an article by Dong Hyun Jo, et al., titled "How to
`
`Overcome Retinal Neuropathy: The Fight Against Angiogenesis-related Blindness,"
`
`published in Archives of Pharmacal Research, volume 33, number 10. (2010) pages
`
`1557-1565. On page 1563, in References, is alphabetical order, is the citation to the
`
`Dixon article.
`
`3. Conclusion
`
`41.
`
`I conclude, based on finding Document 3 in a library and on finding
`
`library catalog records, indicating it was locatable and accessible to the public, that
`
`Document 3, the Dixon article, is an authentic document and that Appendix 3A and
`
`Appendix 3B are authentic copies of Document 3 and that Appendix 3C and
`
`Appendix 3D are accurate reflections of the acquisition and cataloging of Document
`
`15
`
`Regeneron Exhibit 1033.017
`
`

`

`3 and its accessibility to a researcher. Further evidence of its public accessibility is
`
`it being listed as a reference in an article (Appendix 3E) published in 20 IO. It is,
`
`therefore, my conclusion that Document 3, the Dixon article, is an authentic
`
`document and was publicly accessible no later than end of October 2009 in print and
`
`online no later than August 20, 2009.
`
`16
`
`Regeneron Exhibit 1033.018
`
`

`

`

`

`Appendix lA
`Appendix 1A
`
`Regeneron Exhibit 1033.020
`Regeneron Exhibit 1033.020
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`Appendix 1B
`Appendix 1B
`
`Regeneron Exhibit 1033.030
`Regeneron Exhibit 1033.030
`
`

`

`

`

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`Anwendungen
`pharmazeutischen
`eingesetzt zum Beispiel als Hilfsstoffe
`in der Pharmaproduktion (Schmier(cid:173)
`mittel) und als inerte pharmazeuti(cid:173)
`sche Grundmasse (z.B. Weichkapsel(cid:173)
`wande) [5]. Fiir die Silikonisierung
`werden in der Regel Trimethylsi(cid:173)
`loxy-endgeblockte Polydimethylsilo(cid:173)
`xane (PDMS, Dimethicone) in ver(cid:173)
`schiedenen Viskositaten eingesetzt
`(Abb. I).
`Das am haufigsten genutzte Sili(cid:173)
`konol zur Silikonisierung van Pri(cid:173)
`marpackmitteln ist das DOW COR(cid:173)
`NING1" 360 Medical Fluid mit einer
`Viskositat van I 000 cSt.
`Die Herstellung van PDMS erfolgt
`iiber die Reduktion van Quarzsand
`zu metallischem Silizium. Im nach(cid:173)
`sten Schritt wird das Silizium <lurch
`eine Milller-Rochow-Synthese mit
`Methylchlorid zu Methylchlorsilanen
`weiterverarbeitet. Hierbei entsteht
`ein Gemisch unterschiedlicher Sila(cid:173)
`ne, bei dem Dimethyldichlorsilan
`(CH3h SiCl2 mit 75 % - 90 % iiber(cid:173)
`wiegt. Nach einer destillativen Ab(cid:173)
`trennung wird das Dimethyldichlorsi
`Ian <lurch Hydrolyse oder Methano(cid:173)
`lyse zu Silanolen umgesetzt, die zu
`niedermolekularen Ketten und Zy(cid:173)
`klen kondensieren. In einer sauer
`(kationisch) oder alkalisch (anio(cid:173)
`nisch) katalysierten Polymerisation
`werden Polydimethylsiloxane mit
`Hydroxy-Funktionen erzeugt, die ab(cid:173)
`schlieBend <lurch Zugabe van Tri(cid:173)
`methylchlorsilan
`Trimethylsiloxy(cid:173)
`Endgruppen erhalten. Aus den ent(cid:173)
`stehenden polydispersen Polymeren
`werden die kurzkettigen Molekille
`<lurch Verdampfen entfernt, um ein(cid:173)
`satzfahiges PDMS zu erhalten.
`Pragend fur das PDMS-Molekill ist
`die Si-O-Bindung. Sie ist mit einer
`Bindungsenergie van 108 kcal/mo)
`deutlich stabiler als beispielsweise
`die C-O-Bindung (83 kcal/mol) oder
`die
`C-C-Bindung
`(85 kcal/mol).
`PDMS ist dementsprechend unemp(cid:173)
`findlich gegeniiber thermischen Be(cid:173)
`lastungen, UV-Strahlung oder Oxy(cid:173)
`dationsmitteln. Erst oberhalb van
`130 °C kommt es zu Reaktionen wie
`Oxidation, Polymerisierung oder De(cid:173)
`polymerisierung. Fiir das Molekill ist
`
`Abh. 2: Riiumliche Da1'.~tellang Polydimethyl(cid:173)
`siloxan.
`
`dariiber hinaus ein flacher Bindungs(cid:173)
`winkel typisch (Si-O-Si 130 °C), der
`eine geringe Rotationsenergie zur
`Falge hat und es besonders flexibel
`macht (Abb. 2). Eine hohe Bindungs(cid:173)
`lange (1,63A Si-O im Vergleich zu
`1,43A fur C-O) macht das Molekill
`vergleichsweise gasdurchlassig [ 6].
`Das spiralformige (und daher gut
`komprimierbare) Molekill
`ist van
`CH3-Gruppen umhilllt, welche das
`chemische und mechanische Verhal(cid:173)
`ten van PDMS bestimmen. Die Me(cid:173)
`thylgruppen der Molekille
`ent(cid:173)
`wickeln nur sehr geringe Wechsel(cid:173)
`wirkungen untereinander. Dies sorgt
`selbst bei hohen Molekulargewichten
`fur eine niedrige Viskositat, die das
`Verteilen van PDMS auf Oberflachen
`erleichtert und die Substanz zu ei(cid:173)
`nem
`sehr effektiven Gleitmittel
`macht. Zudem ist PDMS weitgehend
`inert, Reaktionen mit Glas, Metallen,
`Kunststoffen oder Korpergeweben
`finden nur in sehr geringem Umfang
`statt. Die CH3-Gruppen machen
`PDMS stark hydrophob. Es ist daher
`in \Vasser unloslich, in nichtpolaren
`Losungsmitteln dagegen loslich [6].
`
`Silikonisierte Spritzen
`
`Wie schon dargestellt, funktioniert
`das System ,,Spritze" nur, wenn die
`Glaskorper- und Kolbenstopfensili(cid:173)
`konisierung homogen und richtig
`aufeinander abgestimmt sind. Bei
`Hohlnadelspritzen ist auBerdem eine
`Silikonisierung derselben unerlass(cid:173)
`lich, um ein Kleben der Haut an der
`Nadel zu vermeiden und damit eine
`schmerzarme Injektion zu ermogli(cid:173)
`chen. Fiir die Innensilikonisierung
`des Glaskorpers wird bei der sage-
`
`der USP [2] erlaubt hingegen die Ver(cid:173)
`wendung van Silikonolen mit einer
`Viskositat van 20 bis 30000 centisto(cid:173)
`kes. Steigende Qualitatsanforderun(cid:173)
`gen und neue biotechnologisch her(cid:173)
`gestellte Medikamente zeigen aber
`auch die Grenzen der Silikonisie(cid:173)
`rungstechnik auf. Eine inhomogene
`Silikonisierung, wie sie var allem bei
`einfachen Beschichtungstechniken
`und langeren Spritzenkorpern auf(cid:173)
`treten kann, fiihrt eventuell zu me(cid:173)
`chanischen Problemen. Beispielhaft
`seien hier eine unvollstandige Entlee·
`rung der Spritze in einem Autoinjek(cid:173)
`tor oder hohe Gleitkrafte genannt.
`Silikonoltropfen sind in abgefull(cid:173)
`ten Spritzen immer zu beobachten.
`Die Anzahl an Silikonoltropfen in Lo(cid:173)
`sung nimmt mit steigender Silikonol(cid:173)
`menge zu. Visuell erkennbare Trap·
`fen konnen als kosmetischer Pehler
`betrachtet werden. Fiir Silikonolpar(cid:173)
`tikel im subvisuellen Bereich wird
`diskutiert, ob sie ein Ausloser fur
`die Aggregation van Proteinen sein
`konnen [4].
`Var diesem Hintergrund zeigt sich
`daher ein deutlicher Trend zu opti(cid:173)
`mierten oder alternativen Beschich(cid:173)
`tungstechniken. Beispiele hierfur
`sind eine moglichst gleichmiillige Be(cid:173)
`schichtung mit reduzierter Silikonol(cid:173)
`menge oder eine Minimierung der
`freien Silikonolmenge <lurch das so(cid:173)
`genannte Einbrennverfaliren. In die(cid:173)
`sem Kontext sind zuverlassige Ana(cid:173)
`lysetechnologien unabdingbar, mit
`denen die Qualitat der Beschichtung
`qualitativ und quantitativ iiberpriift
`werden kann. Dariiber hinaus befin(cid:173)
`den sich auch alternative Beschich(cid:173)
`tungsverfahren in der Entwicklung.
`
`Silikonole und
`ihre Eigenschaften
`
`Silikonole werden schon seit einem
`halben Jal1rhundert in zahlreichen
`
`TechnoPharm 2, Nr. 4, 238-244 (2012)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`Petersen und Reuter• Silikonisierung
`
`239
`
`Regeneron Exhibit 1033.032
`
`

`

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`

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`

`Appendix lC
`Appendix 1C
`
`Regeneron Exhibit 1033.039
`Regeneron Exhibit 1033.039
`
`

`

`

`

`

`

`Appendix 1D
`Appendix 1D
`
`Regeneron Exhibit 1033.042
`Regeneron Exhibit 1033.042
`
`

`

`

`

`Appendix lE
`Appendix 1E
`
`Regeneron Exhibit 1033.044
`Regeneron Exhibit 1033.044
`
`

`

`

`

`Online-Katalog der Wtirttembergischen Landesbibliothek
`
`https:/ /w lb.ibs-bw.de/aDISWeb/app;jsessionid=89171 D4D554 l EB2 ..
`
`Katalogangaben
`
`6 (2016), Heft 6
`6 (2016), Heft 5
`6 (2016), Heft 4
`6 (2016), Heft 3
`6 (2016), Heft 2
`6 (2016), Heft 1
`
`Regeneron Exhibit 1033.046
`
`

`

`Appendix 2A
`Appendix 2A
`
`Regeneron Exhibit 1033.047
`Regeneron Exhibit 1033.047
`
`

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`

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`

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`

`

`

`

`Appendix 2B
`Appendix 2B
`
`Regeneron Exhibit 1033.055
`Regeneron Exhibit 1033.055
`
`

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`

`

`

`

`

`

`

`

`

`

`

`

`

`

`Appendix 2C
`Appendix 2C
`
`Regeneron Exhibit 1033.064
`Regeneron Exhibit 1033.064
`
`

`

`

`

`

`

`9/21/2018
`
`Drug delivery technology. (Journal, magazine, 2001) [WorldCat.org]
`
`User lists with this item (1)
`
`CUH2A geriodicals (83 items)
`by MTuftsCUH2A
`
`±.: Linked Data
`
`https://www.worldcat.org/title/drug-delivery-technology/oclc/48060225?referer=br&ht=edition
`
`3/3
`
`Regeneron Exhibit 1033.067
`
`

`

`Appendix 2D
`Appendix 2D
`
`Regeneron Exhibit 1033.068
`Regeneron Exhibit 1033.068
`
`

`

`

`

`9/20/2018
`
`Summary View
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