Filed on behalf of: CSL Behring GmbH and CSL Behring LLC
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CSL BEHRING GMBH and CSL BEHRING LLC,
`Petitioners,
`
`SHIRE VIROPHARMA INC.,
`Patent Owner.
`
`US. Patent No. 10,080,788
`Case No. IPR2019-00459
`
`DECLARATION OF DR. GERHARD WINTER
`
`Page 1 of 106
`
`CSL EXHIBIT 1015
`
`Page 1 of 106
`
`CSL EXHIBIT 1015
`
`

`

`TABLE OF CONTENTS
`
`I.
`II.
`
`Page(s)
`INTRODUCTION ........................................................................................... 1
`QUALIFICATIONS ........................................................................................ 1
`A.
`Educational Background ....................................................................... 1
`B.
`Relevant Professional Experience ......................................................... 2
`1.
`Industrial experience ................................................................... 2
`2.
`Academic research ...................................................................... 4
`3.
`Patents ......................................................................................... 6
`4.
`Consulting work/other business interests ................................... 6
`III. MATERIALS CONSIDERED ........................................................................ 7
`IV.
`SUMMARY OF OPINIONS ........................................................................... 8
`V.
`BACKGROUND AND STATE OF THE ART .............................................. 9
`A.
`Introduction to Protein Formulation ...................................................... 9
`1.
`General approach to protein formulation .................................... 9
`2.
`General considerations regarding routes of administration ......19
`C1-INH ................................................................................................25
`1.
`Chemical and Physical Properties .............................................25
`2.
`The Literature Disclosed IV and SC Treatments for HAE,
`as Well as High Concentration C1-INH Formulations for
`IM Administration, and SC Administration of Both Low
`and High Concentration C1-INH Formulations .......................32
`Analysis of the Cited Art: the Schranz Poster ....................................41
`C.
`The ’788 Patent ..............................................................................................45
`i
`
`B.
`
`VI.
`
`Page 2 of 106
`
`

`

`VII. LEVEL OF ORDINARY SKILL IN THE ART ...........................................59
`VIII. A POSA WOULD HAVE BEEN MOTIVATED TO INCREASE
`THE CONCENTRATION OF THE SC C1-INH FORMULATIONS
`USED IN THE SCHRANZ POSTER ...........................................................60
`IX. A POSA WOULD HAVE HAD A REASONABLE EXPECTATION
`OF SUCCESS IN FORMULATING C1-INH FOR SC
`ADMINISTRATION AT A CONCENTRATION OF ABOUT
`500U/mL ........................................................................................................67
`CONCLUSION ..............................................................................................74
`
`X.
`
`
`ii
`
`
`
`Page 3 of 106
`
`

`

`I.
`
`INTRODUCTION
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
`1.
`
`Dunner, LLP, on behalf of CSL Behring GmbH and CSL Behring LLC (collectively
`
`“CSL”) to provide my opinions in this proceeding based on my qualifications as a
`
`pharmacist, formulation scientist, and expert in stability and physicochemical
`
`properties of therapeutic proteins as they relate to U.S. Patent No. 10,080,788 (“the
`
`’788 patent”).
`
`2.
`
`I have been engaged at my customary hourly consulting rate of $402,50
`
`per hour. My compensation is not contingent on the outcome of this proceeding.
`
`II. QUALIFICATIONS
`A copy of my curriculum vitae is provided as Appendix B.
`3.
`
`A. Educational Background
`I undertook a pharmacy study with a scholarship from
`4.
`
`the
`
`Studienstiftung des deutschen Volkes (the German National Academic Foundation)
`
`in 1977. In 1981, I obtained my second Staatsexamen in Pharmacy (a practical-
`
`based government licensing examination for pharmacists) from the University of
`
`Heidelberg.
`
`5.
`
`I then undertook compulsory pharmacy internships in a public
`
`pharmacy and in industry. In 1982, I received a license to practice Pharmacy from
`
`the Reg. Präsidium Stuttgart, the regulatory body that is responsible for licensing of
`
`1
`
`Page 4 of 106
`
`

`

`pharmacists and medical doctors, and for supervising any pharmaceutical
`
`practitioners in the state.
`
`6.
`
`In 1983, I returned to the University of Heidelberg to commence a
`
`Ph.D. in Pharmaceutical Technology and Biopharmaceutics under the supervision
`
`of Prof. Dr. Herbert Stricker. I received my Ph.D. (known as a Dr.rer.nat. in
`
`Germany) in 1987 summa cum laude. My thesis was entitled (translated from
`
`German) “The cutaneous absorption of drugs and its in vitro simulation” and
`
`concerned the development of an in vitro diffusion model to simulate the diffusion
`
`of drug substances from liquid and semisolid vehicles in to human skin.
`
`B. Relevant Professional Experience
`Industrial experience
`1.
`I joined Merck AG in Darmstadt, Germany as a Laboratory Head in
`
`7.
`
`1987. At Merck, I was involved in the development of solid dosage forms like
`
`tablets and coated tablets from lab scale to clinical supplies. In 1988, I moved to
`
`Boehringer Mannheim GmbH (which later became Roche Diagnostics GmbH) as a
`
`Laboratory Head. In 1993, I was promoted to Head of Formulations for liquid and
`
`parenteral dosage forms. From 1988 to 1999, the main task my team worked on was
`
`the formulation of parenteral drugs (i.e., drugs that are injected into the patient, either
`
`subcutaneously, intravenously or intramuscularly). Many of these drugs were
`
`protein based, for example cytokine proteins and enzyme proteins. Formulations we
`
`2
`
`Page 5 of 106
`
`

`

`developed under my leadership were liquid forms for intravenous (i.v.),
`
`intramuscular (i.m.), and subcutaneous (s.c.) application as well as freeze dried
`
`forms of the above-mentioned applications for reconstitution. In particular, I have
`
`adapted dosage forms and the pertaining formulations from i.v. use to s.c. use, the
`
`latter being introduced later into the market than the i.v form. I have worked on s.c.
`
`forms for proteins more extensively in the later phase of my employment at
`
`Boehringer Mannheim because s.c. application became more and more important
`
`due to its convenience in particular for patients who had to use it over long periods
`
`of time or lifelong.
`
`8.
`
`The responsibilities of my team comprised pre-formulation and other
`
`early stage tasks like delivery of formulations for pre-clinical and toxicological
`
`studies, formulation development and stability studies, development and production
`
`of clinical supplies in the pilot scale and lower production scale, process
`
`development, optimisation and validation, as well as scale up and transfer to
`
`production and editing regulatory documents for submission to the European
`
`Medicines Agency (the “EMA”) and the United States Food and Drug
`
`Administration (the “FDA”). Furthermore, drug delivery systems, novel injection
`
`devices, and alternative application pathways were researched by my group, together
`
`with leading groups in academia and business, such as the Massachusetts Institute
`
`of Technology and leading DDS companies like, e.g., ALZA and Alkermes. At that
`
`3
`
`Page 6 of 106
`
`

`

`time, the team was also involved in the development of antibody products.
`
`Typically, our task was to conduct pre-formulation and formulation studies, the early
`
`stages of which were in direct cooperation with the biotechnology research and
`
`development centre of Boehringer Mannheim in Penzberg, Germany. Here, I was
`
`the direct interface manager with respect to transfer from the bulk drug substance to
`
`the pharmaceutical formulation.
`
`9.
`
`In 1997, I was promoted to Deputy Area Head of the Formulation
`
`Department at Boehringer Mannheim and kept this position until I left Roche
`
`Diagnostics (as the company then became) in 1999. In this role I had, in addition to
`
`the previous responsibilities, responsibility for the pharmaceutical activities of the
`
`entire dosage form range (including solid dosage forms) including all clinical supply
`
`issues under my supervision. Since 1994, I was Stellv. Herstellungsleiter nach AMG
`
`(BRD), a formal function according to German drug laws responsible for the Good
`
`Manufacturing Practice (“GMP”) conforming production of drug products, in
`
`particular clinical supplies of parenteral products
`
`including
`
`their aseptic
`
`manufacture.
`
`Academic research
`2.
`In 1999, I left Roche Diagnostics and returned to academia, taking a
`
`10.
`
`position as Professor of Pharmaceutical Technology and Biopharmaceutics at the
`
`Ludwig Maximilian University of Munich. I was Director of the Department of
`
`4
`
`Page 7 of 106
`
`

`

`Pharmacy in 2003 and 2004, and again from 2015 to 2016, and have been a member
`
`of the Faculty Committee for Chemistry and Pharmacy since 2000.
`
`11. The research interests of my working group focus on protein
`
`formulations, parenteral dosage forms, and colloidal drug carriers. More precisely,
`
`we have worked (beside other topics) on the large scale freezing and thawing of
`
`antibodies, the development of novel field flow fractionation analytics for proteins,
`
`including antibodies and colloidal carriers, novel in-process monitoring tools for
`
`freeze drying, and alternative drying processes for protein products. We have
`
`studied collapse phenomena on diverse protein lyophilizates, and crystallisation and
`
`aggregation of antibodies and their relationship pertaining to drug stability studies.
`
`We have developed parenteral depot systems based on lipids for different protein
`
`drugs and are working on the effect of cyclodextrins to stabilize antibodies and other
`
`proteins. In addition, we developed local delivery systems for protein delivery to
`
`chronic wounds as well as liposomal formulations and microbubbles for tumour
`
`targeting and therapy. So far, I have supervised (or am still supervising) about 80
`
`Ph.D. students, more than 60 of them have already finished and defended their thesis,
`
`and another approximately 8 post docs. I am author or co-author of, at the moment,
`
`about 180 peer reviewed publications, and about 10 more are in the rebuttal or
`
`submission process. My Hirsch-index, at the moment, is 38, and the number of
`
`5
`
`Page 8 of 106
`
`

`

`citations about 4700. The bibliographic information can be found, inter alia, on
`
`PubMed, ResearchGate, Web of Science, and Google Scholar.
`
`12.
`
`I have also been a Visiting Professor at the MISR International
`
`University in Cairo, Egypt (2006) and at the University of Colorado Health Sciences
`
`Center in Denver, Colorado (2004 and 2007). I am also appointed as the Head
`
`Examiner for the Pharmaceutical Technology Specialist grade for Pharmacists in
`
`Bavaria.
`
`13.
`
`I am a member of inter alia
`
`the American Association of
`
`Pharmaceutical Scientists,
`
`the European Association of Pharmaceutical
`
`Biotechnology, and the German Pharmaceutical Society. I am also on the Editorial
`
`Boards of Journal of Pharmaceutical Sciences and the European Journal of
`
`Pharmaceutics and Biopharmaceutics, and a journal referee for a number of other
`
`leading scientific publications.
`
`Patents
`3.
`I am a co-inventor on approximately 50 patents/patent applications,
`
`14.
`
`with half of these arising from my time working in industry and half during my time
`
`in academia.
`
`Consulting work/other business interests
`4.
`In 2009, I co-founded Coriolis Pharma, which is a globally operating
`
`15.
`
`independent service provider for formulation research and development of
`
`6
`
`Page 9 of 106
`
`

`

`(bio)pharmaceutical drugs (proteins, peptides, monoclonal antibodies, RNA/DNA,
`
`etc.) and vaccines.1 I am part of Coriolis Pharma’s scientific advisory board and I
`
`am actively involved in some of their projects.
`
`16.
`
`In addition, I have provided scientific consultancy services in a variety
`
`of contexts, including in assisting patent attorneys and lawyers understand scientific
`
`issues.
`
`17. Since 2006, I have been one of the major organizers of a leading
`
`conference in the area or freeze drying of pharmaceuticals and biologics that took
`
`place since then 4 times in Garmisch-Partenkirchen, Germany and 3 times in
`
`Breckenridge, Co, USA. Each time about 150 attendees from all over the world
`
`came to hear the leading experts in the field present their new results.
`
`III. MATERIALS CONSIDERED
`In preparing this declaration, I have relied on my extensive experience
`18.
`
`in protein formulation sciences, and specifically my experience in developing
`
`formulations of protein drugs for parenteral administration through my time working
`
`in the pharmaceutical industry and my extensive industry collaborations and
`
`technical consulting roles. I have also considered the materials listed in Appendix
`
`A.
`
`
`1
`See ABOUT CORIOLIS PHARMA, http://www.coriolis-pharma.com/corporate-
`overview/about-coriolis-pharma/ (last visited Dec. 17, 2018).
`
`7
`
`Page 10 of 106
`
`

`

`IV. SUMMARY OF OPINIONS
`I have been asked to provide an opinion on the state of the art in
`19.
`
`formulating protein drugs, and specifically formulations for subcutaneous (“sc”)
`
`administration of protein drugs, as of March 2013. In March 2013, various
`
`techniques for formulating protein drugs were known and routinely used by those
`
`working in the field.
`
`20.
`
`I have also been asked to review information that was publicly available
`
`as of March 2013 regarding the C1 esterase inhibitor protein (termed “C1-INH”
`
`hereafter). I am aware of no reports dated prior to March 2013 that discussed any
`
`impediments to developing a concentrated C1-INH formulation for subcutaneous
`
`administration.
`
`21.
`
`It is my opinion that in March 2013, a person of ordinary skill in the art
`
`(“POSA”) would have been motivated to prepare a subcutaneous C1-INH
`
`formulation having as high a concentration as possible.
`
`22.
`
`It is also my opinion that in March 2013, a POSA would have had a
`
`reasonable expectation of success in formulating C1-INH at a concentration of about
`
`500U/mL for subcutaneous administration.
`
`23.
`
`I also considered the statements in Dr. Schranz’s declaration submitted
`
`during prosecution of the ’788 patent that it is difficult or impossible to formulate
`
`protein drugs like C1-INH for sc administration, and that certain features of C1-INH
`
`8
`
`Page 11 of 106
`
`

`

`would have made it difficult to develop a high concentration sc formulation of C1-
`
`INH. As an initial matter, I note that Dr. Schranz cited no evidence to support these
`
`allegations and additionally, these statements do not reflect the state of the art as of
`
`March 2013. Moreover, Dr. Schranz’s assertions are inconsistent with a POSA’s
`
`general understanding of protein formulation and protein chemistry in March 2013.
`
`V. BACKGROUND AND STATE OF THE ART
`Introduction to Protein Formulation
`A.
`1. General approach to protein formulation
`24. A formulation scientist (“FS”), when developing a new formulation of
`
`a therapeutic protein, would first meet with a project team, or at least the most
`
`important representatives of such a team regarding the formulation. These persons
`
`are typically the project manager, a clinician, a marketing person, an API production
`
`person, a person who has developed the molecule and knows its properties, a
`
`toxicologist, an analytics person, a registration specialist, and a pre-clinical expert.
`
`The FS would seek information from the team regarding any pre-formulation
`
`information on the protein to be formulated. Such information is often described as
`
`the physio-chemical and chemical information of the protein to be formulated and
`
`typically includes: molecular weight; structure (primary, secondary, and tertiary if
`
`known); isoelectric point; solubility (discussed below); syringeability (discussed
`
`below); short-term stability at different pH values; and sensitivity to light and
`
`oxidation. Ex. 1066 [Wang, pp. 2-3], 7-8; Ex. 1044 [Shire 2009, pp. 709, 712-13],
`
`9
`
`Page 12 of 106
`
`

`

`5, 8-9; Ex. 1060 [Sola, Table 1, p. 1225], 8-9. Information on any existing
`
`formulations of the therapeutic protein would also be taken into account.
`
`25. The FS would also discuss the desired product attributes (sometimes
`
`referred to as a “target product profile”) of the target formulation with the team.
`
`These attributes include: the preferred dosage form (e.g., freeze-dried or liquid); the
`
`desired concentration or concentration ranges; the dose and the pertaining volume
`
`of a single dose; the preferred primary packaging (e.g., vials or pre-filled syringes);
`
`the planned route of administration (e.g., iv, im, or sc injection); and the intended
`
`frequency of administration.
`
`26. Together, this information informs the formulation chemist of what he
`
`has (pre-formulation information) and where he needs to go (the target product
`
`profile). The task of the FS is to bridge the two and to carry out the formulation
`
`work as such.
`
`27. Solubility
`
`typically
`
`refers
`
`to
`
`the maximum quantity
`
`(e.g.,
`
`concentration) of a substance, such as a protein, that can be dissolved in another
`
`substance, a solvent (most often water), leading to a solution, without macroscopic
`
`phase separation. The solubility is an intrinsic property of the protein.
`
`Concentrating a protein formulation beyond that protein’s solubility threshold is
`
`challenging, but can be addressed, if needed, by changing one or more solution
`
`conditions, e.g., the pH or the use of certain buffers or the addition of excipients like,
`
`10
`
`Page 13 of 106
`
`

`

`e.g., arginine, or the use of certain storage conditions (e.g., temperature). These
`
`factors have immediate effects on protein solubility.
`
`28. Unlike many other molecules, proteins can aggregate over time and
`
`such aggregates can grow so large that they appear as visible particles and the
`
`solubility of the protein is thereby reduced—the protein is not soluble any more at
`
`the concentration it was before. However, larger proteins tend to have more surface
`
`area shielded from the surrounding solution and are less likely than smaller proteins
`
`at the same molar concentration to unfold and form aggregates that precipitate out
`
`of solution. Often aggregation leads to turbidity, haze, and colloidal particles in
`
`which the protein is not fully precipitated but kept in solution in a colloidal form.
`
`But the solution containing protein aggregates has a compromised quality and,
`
`therefore, formulation scientists are motivated to suppress such aggregation to retain
`
`high solubility. For that reason, we add stabilizing excipients. Such excipients do
`
`not increase solubility (which is an intrinsic property of the protein); rather, the
`
`excipients reduce aggregation and may keep the solution stable for longer periods of
`
`time while keeping the protein at its former solubility. Both lyophilization and
`
`spray-drying can also halt protein aggregation during long-term storage, allowing
`
`easy and fast reconstitution before the formulation is administered to a patient.
`
`Changes to the protein molecule itself may also affect solubility. For example,
`
`11
`
`Page 14 of 106
`
`

`

`glycosylation had been shown to increase the solubility of many proteins, including
`
`Shire’s alpha-galactosidase A product, Replagal®. Ex. 1060 [Sola, p. 1237], 21.
`
`29. The above means of increasing protein solubility and means of reducing
`
`or preventing protein aggregation were all known in the literature as of March 2013.
`
`30. The term syringeability refers to the force or time (at a constant force)
`
`required to push a formulation through a needle of a set diameter. Syringeability is
`
`lower for more viscous formulations. This can lead to difficult or painful drug
`
`administration, which may be mitigated or avoided by reducing the formulation’s
`
`viscosity or by using a needle with a wider diameter.
`
`31.
`
`Just as an increased molar concentration of protein can increase the
`
`likelihood of protein aggregations and increase aggregation, so too can an increased
`
`molar concentration of protein increase a solution’s viscosity. As shown in
`
`Drawings 2 and 3, below, globular proteins, which have a roughly spherical shape,
`
`exhibit qualitatively similar concentration-viscosity curves:
`
`
`
`12
`
`Page 15 of 106
`
`

`

`
`
`
`
`DRAWING 2. Viscosity of different forms of the
`globular protein hemoglobin (MW ~ 64 kDa) as a
`function of protein concentration at 25°C and
`approximately neutral pH. Adapted from Ex. 1049
`[Monkos 1994, Figure 1], 4.
`
`13
`
`Page 16 of 106
`
`

`

`
`
`
`
`
`
`
`
`DRAWING 3. Viscosity of the globular protein
`ovalbumin (MW ~ 45 kDa) as a function of protein
`concentration at 25°C (black circles) and 20 °C (blue
`squares). Adapted from Ex. 1052 [Monkos 2000, Figure
`1], 7.
`32. Formulations of globular proteins such as hemoglobin and ovalbumin
`
`typically exhibit viscosities of low absolute values that rise only slowly up to protein
`
`concentrations of 200-250 mg/mL. For instance, BSA (another globular protein),
`
`which has a molecular weight of 66.5 kDa, exhibits the following viscosity-
`
`concentration profiles at various pH values:
`
`14
`
`Page 17 of 106
`
`

`

`
`
`DRAWING 4. Viscosity of the globular protein bovine
`serum albumin (BSA) (MW ~ 66.5 kDa) as a function of
`protein concentration at pH 4.0 (diamond), pH 5.0
`(triangle), pH 6.0 (exes) and pH 7.0 (circles). Reproduced
`from Ex. 1067 [Yadav, Figure 5], 11.
`
`33. As can be seen, BSA exhibits a viscosity under 5Pa⋅s at concentrations
`
`up to 200 mg/mL and at pH values between 4.0 and 7.0. Other globular proteins
`
`were also known to exhibit similar behavior as a function of typical formulation
`
`variables such as solution pH. Ex. 1061 [’432 patent, 2:46-52], 9.
`
`34.
`
`In contrast to globular proteins, monoclonal antibodies are non-
`
`globular, Y-shaped proteins with a much more extended molecular structure. Unlike
`
`globular proteins, some monoclonal antibodies are more likely to be highly viscous
`
`at lower protein concentrations (e.g., below 150 mg/mL), while others show only
`
`15
`
`Page 18 of 106
`
`

`

`low to moderate increase in viscosities at 150 mg/ml. See, e.g., Ex. 1019 [Connolly,
`
`Figure 2], 6; Ex. 1044 [Shire 2009, p. 709], 5. This can be seen in Drawing 5, below:
`
`
`
`DRAWING 5. Viscosity versus concentration for an IgG1
`monoclonal antibody with (triangle) and without (circle)
`viscosity-decreasing excipients.
` Reproduced
`from
`Ex. 1044 [Shire 2009, Figure 1], 5.
`
`35. Many formulation approaches (i.e., changes to solution conditions)
`
`may be implemented to decrease the viscosity of a protein formulation. For example,
`
`a formulator may decrease viscosity through choice or adjustment of pH or of
`
`commonly accepted types and concentration ranges of buffers or excipients.
`
`Ex. 1044 [Shire 2009, Figure 1], 5; Ex. 1019 [Connolly, Figure 2], 6; Ex. 1067
`
`[Yadev, Figures 3, 5, 7], 10-11, 14. For instance, U.S. Patent No. 6,875,432 shows
`
`that adjusting pH within accepted ranges for pharmaceutical products can decrease
`
`16
`
`Page 19 of 106
`
`

`

`the viscosity of a concentrated protein composition. Ex. 1061 [’432 patent, 2:49-
`
`52], 9.
`
`36. As noted above, by March 2013 numerous studies had established that
`
`glycosylation can increase protein solubility and stability. Ex. 1060 [Sola, pp. 1225,
`
`1231], 9, 15. These studies showed that glycosylation can prevent both chemical
`
`instabilities (e.g., proteolytic degradation, oxidation, etc.) and physical instabilities
`
`(e.g., adsorption, aggregation, precipitation, etc.), and can further increase
`
`conformational stability from pH denaturation, chemical denaturation, and thermal
`
`denaturation. Id., at 13-21; see generally Ex. 1081 [Latypov]. Glycosylation can
`
`also result in greater kinetic stability and improved long-term storage of a protein
`
`formulation. Ex. 1060 [Sola, p. 1236], 20.
`
`37. All proteins experience physical and chemical instability when
`
`removed from their natural environment. The goal of a formulation scientist is to
`
`ensure sufficient solubility and stability of a protein pharmaceutical while
`
`maintaining therapeutic efficacy. Ex. 1066 [Wang, pp. 2-3], 7-8. By March 2013,
`
`well-developed techniques existed for stabilizing protein formulations and reducing
`
`undesirable properties. See, e.g., Ex. 1066 [Wang, Tables 1, 3], 13, 19-22; Ex. 1019
`
`[Connolly, p. 74], 6; Ex. 1044 [Shire 2009, pp. 708-13], 4-9; Ex. 1067 [Yadav,
`
`pp. 1974-75, 1982], 6-7, 14; Ex. 1060 [Sola, Table 1, p. 1223-38], 8-22.
`
`17
`
`Page 20 of 106
`
`

`

`38.
`
`In optimizing a protein formulation, a skilled formulator would know
`
`to do one or more of the following: adjust the pH and buffer, add or adjust
`
`excipients, and add or adjust surfactants. The identity and concentration of buffer
`
`generally has little impact on a protein’s therapeutic efficacy.
`
`39. Although in an ideal world, the skilled formulator would want the pH
`
`of the protein formulation to be as close as possible to that of blood (between pH
`
`7.35 and 7.45), a pH range from 4 to 8 is generally considered acceptable. If the
`
`skilled formulator were to start from scratch, then he might look at pHs across that
`
`entire range. But if there are formulations in which the protein is known to be stable,
`
`then the skilled formulator is likely to start at a range of pHs that are ± 1.5 pH units
`
`of the pH of the known, stable protein formulation, staying overall in the range of
`
`pH 4-8. When considering this range, the skilled formulator would include the
`
`buffer of the known formulation and select a small number of alternative buffers
`
`(e.g., two or three) that have sufficient buffering capacity at the pH to be tested. The
`
`skilled formulator would then select buffer solutions at regular intervals (most likely
`
`at fixed 0.5 pH or 1 pH unit intervals) to test the entire pH range under consideration.
`
`40. For each of the protein formulations made, the skilled formulator would
`
`test these for viscosity and stability over time using standard techniques and
`
`methodologies (see below). The skilled formulator would then consider whether
`
`additional materials should be added to the formulation. As noted above, the
`
`18
`
`Page 21 of 106
`
`

`

`literature in March 2013 provides a broad range of excipients and additives that may
`
`act as stabilizers and reduce protein aggregation and protein formulation viscosity.
`
`Ex. 1066 [Wang, Table 3, p. 20], 19-22, 25; Ex. 1019 [Connolly, Figure 2], 6;
`
`Ex. 1067 [Yadav, Figures 3, 5, 7], 10-11, 14. The formulation examples and
`
`guidance provided by this literature would allow formulators to select or optimize
`
`protein formulation conditions as a matter of routine experimentation.
`
`2. General considerations regarding routes of administration
`41. Protein drugs are typically administered parenterally rather than orally
`
`to avoid chemical degradation by digestive system proteases (Ex. 1060 [Sola,
`
`p. 1229], 13), and because protein drugs have poor intracellular transport in the gut.
`
`Intravenous, intramuscular, and subcutaneous administrations are the most common
`
`modes of parenteral administration. Ex. 1006 [Gatlin pp. 417-18], 29-30.
`
`42. Typical formulation volumes for im and sc are on the order of a few
`
`milliliters, often necessitating higher protein concentrations to achieve a given dose
`
`than iv administration, which is more tolerant of higher volumes and thus allows for
`
`formulations with low per-dose protein concentrations. Ex. 1006 [Gatlin, pp. 417-
`
`18], 29-30; see also Ex. 1019 [Connolly, p. 69], 1; Ex. 1044 [Shire 2009, p. 709], 5.
`
`One skilled in the art would know that im and sc formulations share comparable
`
`requirements regarding protein aggregation, protein stability, viscosity, pH, tonicity,
`
`sterility, and particulate matter. As a result, a POSA would reasonably expect that a
`
`19
`
`Page 22 of 106
`
`

`

`stable im formulation could also serve as a successful sc formulation. For example,
`
`the formulation for Subcuvia® may be used for both sc and im administration. Chart
`
`1 below offers a subset of marketed protein drugs as of 2013.
`
`Chart 1. “LYO” denotes a lyophilized product; “LIQ”
`denotes a liquid product; “Mab” denotes monoclonal
`antibody.
`
`Drug name
`
`MW
`(kDa)
`
`Protein type,
`liquid v. lyo
`
`pH, buffer* Protein
`conc.
`
`Synagis
`(Palivizumab)1
`
`Herceptin
`(Trastuzumab)2
`Herceptin SC3
`
`148 MAb, LYO
`
`145.5 MAb, LYO
`
`Not listed,
`47mM
`Histidine
`6
`
`145.5 MAb, LIQ
`
`~ 6
`
`Vivaglobin4
`
`Not
`listed
`
`Immunoglobulins
`from plasma,
`LIQ
`
`6.4-7.2
`
`Humira
`(Adalimumab)5
`
`148 MAb, LIQ
`
`Xolair
`(Omalizumab)6
`
`Procrit (Epoetin
`alpha)7
`
`Neupogen
`(Filgrastim)8
`
`149 MAb, LYO
`
`30.4 Glycoprotein,
`LIQ
`
`18.8 G-CSF, LIQ
`
`Enbrel
`(Etanercept)9
`
`~150 TNFR-Fc fusion,
`LIQ
`
`Enbrel
`(Etanercept)9
`
`~150 TNFR-Fc fusion,
`LYO
`
`5.2,
`sodium
`phosphate
`/ citrate
`Not listed,
`histidine
`
`Not listed,
`sodium
`citrate
`4, sodium
`acetate
`
`6.1-6.5,
`sodium
`phosphate
`7.1-7.7,
`not listed
`
`20
`
`100
`mg/mL
`
`21
`mg/mL
`140
`mg/mL
`
`160
`mg/mL
`
`50
`mg/mL
`
`125
`mg/mL
`
`< 0.4
`mg/mL
`
`0.3
`mg/mL
`
`50
`mg/mL
`
`25
`mg/mL
`
`Trehalose,
`histidine, PS20
`Trehalose,
`histidine, PS20,
`methionine,
`vorhyaluronidase
`alfa
`
`Glycine, NaCl
`
`6.16mg/mL
`NaCl, 1.2%
`mannitol, 0.1%
`PS80
`Sucrose, PS20
`
`NaCl, sodium
`phosphate,
`Albumin
`Sorbitol, PS80
`
`1 % sucrose,
`100mM NaCl,
`25mM Arg-HCl
`Mannitol,
`sucrose,
`tromethamine
`
`Other excipients SC, IM,
`or IV
`delivery
`IM
`(0.5 to 1
`mL)
`IV
`
`3mM glycine, 5.6
`% mannitol
`
`Approval
`yr US
`
`1998
`
`1998
`
`2013**
`
`2006
`
`2002,
`2011
`
`2003,
`2015
`
`2008
`
`1991
`
`1998
`
`1998
`
`SC (5mL
`per site)
`
`SC
`(max vol
`= 15mL
`per site)
`SC (0.4
`to 0.8
`mL)
`
`SC (1.2
`mL)
`
`SC (1
`mL), IV
`
`SC
`(<1.5mL),
`IV
`SC
`(<1mL)
`
`SC
`(<1mL)
`
`Page 23 of 106
`
`

`

`Actimmmune
`(Interferon
`gamma-1b)10
`Intron A
`(interferon
`alpha-2b)11
`Subcuvia12
`
`~ 33
`
`19.3
`
`>100
`
`Not listed,
`Interferon
`sodium
`gamma dimer,
`succinate
`LIQ
`Interferon, LYO Not listed,
`sodium
`phosphate
`Not listed
`
`Subgam13
`
`>100
`
`Not listed
`
`0.2
`mg/mL
`
`Mannitol, PS20, SC
`(<1mL)
`
`< 0.2
`mg/mL
`
`NaCl, EDTA, m-
`cresol, PS80
`
`160
`mg/mL
`
`Glycine, NaCl
`
`160
`mg/mL
`
`Glycine, sodium
`acetate, NaCl,
`PS80
`
`Immunoglobulin
`mixture (IgG1,
`IgG2, IgG3,
`IgG4), LIQ
`Immunoglobulin
`mixture (IgG1,
`IgG2, IgG3,
`IgG4), LIQ
`Immunoglobulin
`mixture (IgG1,
`IgG2, IgG3,
`IgG4), LIQ
`Immunoglobulin
`mixture (IgG1,
`IgG2, IgG3,
`IgG4), LIQ
`Zinc, m-cresol,
`3.6
`Human insulin,
`glycerol
`mg/mL
`LIQ
`*for LYO products, pH and buffer type/concentration is post reconstitution
`
`Hizentra14
`
`>100
`
`Gammanorm15
`
`>100
`
`4.6 - 5.2
`
`200
`mg/mL
`
`Proline, PS80
`
`Not listed
`
`165
`mg/mL
`
`NaCl, sodium
`acetate, PS80
`
`Humulin R16,17
`
`6
`
`7 - 7.8
`
`1990
`
`1995
`
`2003
`
`2004
`
`2010
`
`SC (1
`mL), IV,
`IM
`SC (10
`mL/hr),
`IM
`
`SC (10
`mL/hr),
`IM
`
`SC (15
`mL/hr)
`
`SC (10
`mL/hr)
`
`2008
`
`SC
`
`1982
`
`** the product is administered with an enzyme that reduces the pain upon injecting a higher volume
`
`by SC; the product was approved in 3Q2013, but publications and a patent were available prior to
`that which enabled the marketed product
`1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/palimed102302LB.pdf.
`2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf.
`3A http://www.medsafe.govt.nz/consumers/cmi/h/herceptinsc.pdf.
`
`3B https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0032-1321831.
`
`3C https://www.google.com/patents/US20110044977.
`
`4 https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProdu
`
`cts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM070360.pdf.
`
`5 https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125057s0276lbl.pdf.
`
`21
`
`Page 24 of 106
`
`

`

`6 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pdf.
`
`7 https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/103234s5196PI.pdf.
`
`8 https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/filgamg040298lb.pdf.
`
`9 https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103795s5548lbl.pdf.
`
`10 https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103836s5182lbl.pdf.
`
`11 https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103132s5191lbl.pdf.
`
`12 https://www.medicines.org.uk/emc/medicine/30223.
`
`13 https://www.