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`Confirmation No: 1675
`Filed: September 15, 2015
`For: C1-INH CONEPOSITIONS AND METHODS FOR THE PREVENTION AND
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`TREATIVLENT OF DISORDERS ASSOCIATED WITH C1 ESIERASE INHIBITOR
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`DEFICIENCY
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`spent over 20 years conducting clinical research and trials involving treatments for various
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re application of: GALLAGHER, Cynthia, et a]. Examiner: MIKNIS, Zachary I.
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`Application No: 14/855,168
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`Group Art Unit: 8760
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`VIA EFS WEB FILING — WWW.USPTO.GOV
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`Commissioner for Patents
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`PO. Box 1450
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`Alexandria, VA 22313-1450
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`DECLARATION OF DR. JENNIFER SCHRANZ UNDER 37 C.F.R. § 1.132
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`Dear Commissioner:
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`1, Jennifer Schranz, hereby declare as follows:
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`1.
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`1 am currently a Vice President of Clinical Development and the Global
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`Development Team Lead for Angioedema at Shire, the assignee of the above-identified patent
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`application US l4/855, 168 (the “present application”) as a result of Shire’s acquisition of
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`ViroPharma, the original assignee of the application. Before Shire acquired ViroPharma, I
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`served as ViroPharma’s Vice President of Clinical Research. Since March 2011, I have overseen
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`the development of CINRYZE®, including the ongoing effort for developing subcutaneous
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`formulation of C1 esterase inhibitor (Cl—INH), the active ingredient in CINRYZE®.
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`2.
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`I hold a doctorate of medicine degree from the University of Toronto and have
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`Docket No: SHR—l 184US
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`(PATENT)
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`CSL EXHIBIT 1002
`CSL v. Shire
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`Page 1 of 12
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`: Gallagher, er al.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`Attomey’s Docket No.: SHR—1184US
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`diseases including hereditary angioedema (HAE). Before joining ViroPharma, I held various
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`positions at other biotechnology and pharmaceutical companies, including Merck & Co., Inc,
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`GlaxoSmithKline, Vicuron Pharmaceuticals, Inc, Wyeth Pharmaceuticals, Inc, Pfizer Inc, and
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`Cempra, Inc, where I was involved in early and late stage clinical development (pre-clinical and
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`clinical) for various diseases. My experience and education, including publications in which I
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`am an author are summarized in my curriculum vitae, a true and accurate copy of which is
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`provided with this declaration as Exhibit A.
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`In preparation of this declaration, I have read and understand the specification and
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`pending claims of the present application and the following documents:
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`0 ViroPharma Phase 2b Combination Study for Subcutaneous Administration of
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`Cinryze® With Hyaluronidase (rHuPH20), press release published 19 December
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`2012 (“ViroPharma Press Release”);
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`0 Kreuz, W., ClinicalTrialsgov NCTOO748202, published 4 September 2008: SC
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`vs IV comparison study of Berinert P (“Kreuz”); and
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`Jiang et al., Clinical Immunology 136:323-328, published 8 June 2010 (“Jiang”).
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`4.
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`I have been asked to comment on, among other things, the development of
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`subcutaneous formulation for the treatment of hereditary angioedema (HAE).
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`5.
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`HAE is a rare and potentially life-threatening genetic disorder characterized by
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`recurrent acute attacks of non-whealing, non-pruritic edema affecting the cutaneous tissues or
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`mucous membranes. See, A. Agostoni er al, J. Allergy Clin. Immunol. 2004; 114(3): S51-131,
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`attached as Exhibit B. HAE symptoms include episodes of edema (swelling) in various body
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`parts including the hands, feet, face, abdomen, genitalia, and airway. See Figures 1 and 2 below.
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`Airway swelling is particularly dangerous and can lead to death by asphyxiation. In addition,
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`Attomey’s Docket No.: SHR—1184US
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`patients often have bouts of excruciating abdominal pain, nausea, and vomiting that are caused
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`by swelling in the intestinal wall.
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`6.
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`Thus, HAE is a debilitating disease that dramatically affects patients’ lives. The
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`uncertainty of attack onset combined with the severity of the symptoms results in many patients
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`suffering from anxiety and depression. Many patients also avoid normal daily activities, as well
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`as necessary medical and dental procedures out of fear of triggering an attack. Accordingly,
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`prevention of attacks is critical for both the mental and physical health of affected individuals,
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`often referred to as humanistic burden, and is an important part of treatment of HAE. As this is a
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`hereditary disorder, transfer of the genetic defect to children also brings significant burden to the
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`7.
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`HAE patients have a defect in the gene that encodes Cl-INH, which results in
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`inadequate or non-functioning Cl-INH. In the majority of cases, this defect is transmitted in an
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`autosomal dominant fashion; however in 25% of cases a spontaneous mutation occurs. Absent
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`the defect, Cl-INH functions as a constituent of human blood that regulates the complex
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`biochemical interactions of blood-based systems involved in disease fighting, inflammatory
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`response and coagulation. Because inadequate or defective Cl-INH does not adequately perform
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`this regulatory function, a biochemical imbalance can occur and produce unwanted peptides such
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`as bradykinin that induce the capillaries to release fluids into surrounding tissue, thereby causing
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`edema. Triggering events include stress, hormonal fluctuations (e. g. estrogen), toxins, injury,
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`inflammation, ischemia, viral infections, among others.
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`8.
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`The photos below show the debilitating effects of HAE attacks on patients who
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`suffer from the disorder, specifically upper airway or laryngeal edema:
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`Page 3 of 12
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`Filed
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`Attomey’s Docket No.: SHR—1184US
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`Fig. 1: Female patient suffering from edema and requiring nasal intubation. See, K. Bork er al.
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`Fig. 2: Progression of attack symptoms in male patient. See, Banerji A, Ann Allergy Asthma
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`Immunol 111 (2013) 329-336, Figure 2.
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`9.
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`At present, the treatment options for HAE prophylaxis are limited. CINRYZE®
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`(C1 esterase inhibitor [Human]) is the only Cl-INH replacement product approved for HAE
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`prophylaxis. CINRYZE® is human plasma derived Cl-INH, indicated for routine prophylaxis
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`against angioedema attacks in adolescent and adult patients. CINRYZE® is provided as 500 U of
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`lyophilisate per vial. Each vial is reconstituted in 5 mL of sterile water, to a concentration of 100
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`U/mL prior to administration. Two vials, or a total of 10 mL, are administered by intravenous
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`infusion every 3-4 days in order to achieve an appropriate threshold of functional Cl-INH
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`activity for routine prophylaxis against angioedema attacks in adolescent and adult patients.
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`Attomey’s Docket No.: SHR—1184US
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`10. While the current IV formulation of CINRYZE® provides an important and life-
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`saving treatment for HAE, a subcutaneous (SC) formulation of Cl-INH could represent a more
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`convenient and patient friendly option for many HAE patients and healthcare providers. For
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`example, SC formulation allows for self-administration by patients, especially those who do not
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`want to, or cannot, access an intravenous site. SC administration has the important advantage of
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`not requiring access to veins twice weekly or in some patients, maintaining a central venous
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`access port, when peripheral IV access is no longer possible. It also avoids significant
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`complications of central IV access, such as thromboembolism due to a foreign body, infections,
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`61C.
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`11.
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`However, typically it is difficult or impossible to formulate protein drugs like
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`CINRYZE® for SC administration. A successful SC formulation requires sufficiently high
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`protein concentration so that therapeutically effective dosages may be delivered in a small
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`volume into human patients safely. In other words, a successful SC formulation requires high
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`concentration, small volume, and acceptable viscosity and syringeability. Achieving this
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`combination of features has proven very difficult, particularly when dealing with large proteins,
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`due to physical and chemical instability at high protein concentrations. For example, physical
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`instability causes protein aggregation. Aggregated protein increases risk of immunogenicity and
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`may result in loss of potency. Chemical instability results in oxidation of the protein, particulate
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`formation, or product precipitation, which affects product homogeneity, safety, and efficacy.
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`The key to developing a formulation suitable for SC administration of Cl-INH is
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`to increase Cl-INH concentration in order to permit the administration of therapeutically
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`effective dosage (e.g., > 1000 IU) in as small a volume as feasible, typically, no more than 2-4
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`mL per injection site. In addition to the common challenges for SC formulation described above,
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`Cl-INH has certain characteristics that posed unique challenges in a high concentration SC
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`Page
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`Attomey’s Docket No.: SHR—1184US
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`13.
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`Cl-INH is a large protein, the largest member of serpin superfamily. Human C1-
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`INH is made up of 478 amino acids plus a 22-amino acid signal peptide. It has an apparent
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`molecular weight of about ~105 KDa. Cl-INH is highly glycosylated. In fact, Cl-INH is one of
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`the most highly glycosylated plasma proteins. More than 26% of the molecular weight of C1-
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`INH is carbohydrate. Cl-INH bears both N— and O-linked glycans. See Figure 3 below. Like
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`many highly glycosylated proteins, Cl-INH has high viscosity. Moreover, plasma-derived C1-
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`INH is particularly prone to aggregation due to the presence of certain co-eluates.
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`Fig. 3: Structural schematic of Cl-INH. N—linked glycans are represented at N, O-linked
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`glycans are represented at T or S.
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`14.
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`Thus, it was highly uncertain whether Cl-INH could be formulated at a high
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`concentration for SC injection. Indeed, for a long period of time prior to the present invention,
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`the consensus in the field was that it might not be feasible to develop high concentration with a
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`small volume SC formulation for Cl-INH. Leaders in the Cl-INH therapeutic field, ViroPharma
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`(the manufacture of CINRYZE®) and CSL Behring (the manufacturer of Berinert indicated for
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`acute HAE attack at 50 U/mL) appreciated the long-felt need by HAE patients for a more
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`convenient non-parenteral delivery of Cl-INH, ability for self-administration and thereby better
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`: Gallagher, er a1.
`In re
`Appl. No.: 14/855,168
`Filed
`: September 15, 2015
`Page
`: 7 of 12
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`Attomey’s Docket No.: SHR-1184US
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`control of their disease.1 Each of ViroPharma and CSL Behring initiated human clinical studies
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`of SC administration of C l-INH using low concentration formulations that had been developed
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`for IV injection. As explained below, those earlier human clinical trials were either
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`unsuccessful or did not continue to Phase 3.
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`15.
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`As Vice President of Clinical Research of ViroPharma, I was responsible for
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`ViroPharrna’s earlier human clinical studies of SC administration of CINRYZE® described in the
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`ViroPharma Press Release. In that study, subjects were subcutaneously infused with 20 mL of
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`liquid containing either 1000 U of Cinryze with 24,000 U of rHuPH20 or 2000 U of Cinryze
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`with 48,000 U recombinant human hyaluronidase (rHuPH20), a dispersing agent. Accordingly,
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`the final concentration of C 1-INH administered was 50 U/mL or 100 U/mL, respectively. See
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`ClinicalTrials.gov Identifier NCT01756157 which describes the same study in further detail:
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`Fig. 4: Table describing patient dosing regimen of SC Study NCT01756157 which involved SC
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`injection of Cinryze and rHuPH20.
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`16.
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`To enable subcutaneous delivery of such a large volume, we used Halozyme’s
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`proprietary drug delivery platform technology based on recombinant human hyaluronidase
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`' See the Background section of ViroPharma’s 2012 AAAAI poster (attached as Exhibit D).
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`enzyme (rHuPH20)2. Hyaluronidase is an enzyme which catalyzes the hydrolysis of hyaluronan,
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`a component of the human extracellular matrix. By degrading hyaluronan, hyaluronidase
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`increases tissue permeability. Hyaluronidase had been used to enhance absorption and
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`dispersion of therapeutics and enable the subcutaneous administration of much larger volumes
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`than can normally be administered subcutaneously. See Haller, M. F., “Converting Intravenous
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`Dosing to Subcutaneous Dosing with Recombinant Human Hyaluronidase,” Pharm. Tech,
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`published 02 October 2007, available at http://www.pharmtech.com/converting-intravenous-
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`dosing-subcutaneous-dosing-recombinant-human-hyaluronidase.
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`17.
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`However, this study was terminated due to safety concerns over emergence of,
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`and unexpected incidence and titer of, non-neutralizing anti-rHuPH20 antibodies after
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`administration of CINRYZE® in combination with rHuPH20 in a Phase 2 clinical study in HAE
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`subjects.
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`18.
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`CSL Behring’s study was designed to investigate the subcutaneous versus
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`intravenous administration of Berinert P in patients with mild or moderate HAE to evaluate the
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`possibility of an alternative administration mode in cases where IV access is not suitable. See,
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`Kreuz. According to published reports, CSL Behring’s study involved the SC administration of
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`a large volume of 50 U/mL Cl-INH formulation, Berinert. See Martinez-Saguer et al.,
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`TRANSFUSION, 54: 1552-1561 (2014) (providing more detail regarding the Kreuz study and
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`subsequent findings) (Exhibit C). As described in Martinez-Saguer, 20 mL of 50 U/mL Cl-INH
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`were administered to the patients. In order to administer such a large volume, 10 mL of
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`composition were administered in each of two different subcutaneous abdominal sites over 15
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`minutes using two medical infusion pumps for continuous, simultaneous administration. In my
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`experience, SC administration of such large volumes can be traumatic and labor intensive with
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`infusion pumps, particularly without the co-administration of a permeability enhancing agent
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`such as rHuPH20. In some cases, it may trigger an HAE attack. As far as I know, CSL
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`2 ViroPharma entered into a multi-million dollar license agreement with Halozyme for the purpose of this study.
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`: Gallagher, er a1.
`In re
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`Appl. No. : 14/855,168
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`: September 15, 2015
`Filed
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`Attomey’s Docket No.: SHR—1184US
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`Behring’s earlier clinical subcutaneous study using low concentration high volume formulation
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`Berinert as described in Kreuz was not further developed.
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`19.
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`I am also familiar with the animal study described in Jiang, which sought to
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`assess whether reasonable levels of functional human Cl-INH could be achieved in swine
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`plasma following SC administration. In that study, again, a large volume of CINRYZE®(1OO
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`U/mL) was infused subcutaneously into pigs by continuous pump over a 60-minute period. See,
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`Jiang, p. 325, left column.
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`20.
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`Prior to the successful development of high concentration formulations by the
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`present inventors, the entire field had been focused on SC delivery of Cl-INH at a low
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`concentration (e. g., f 100 U/mL) in a large volume (e.g., 10-20 mL) due to the safety and
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`efficacy concerns over increasing Cl-INH concentrations in formulations. In other words, the
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`consensus in the field was that it was not an easy or obvious strategy to increase Cl-INH
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`concentration for SC injection purposes because of the various challenges described above.
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`21.
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`Indeed, it took years and millions of dollars in investment for Shire and
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`ViroPharma scientists to eventually develop a clinically acceptable, high concentration SC
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`formulation of Cl-INH that was safe and effective. Examples of such formulations were
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`described in the present application. One such high concentration SC formulation containing ~
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`500 U/mL Cl-INH is being tested in human clinical studies, which enables subcutaneous
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`delivery of 1000-2000 IU C1-INH in 2-4 mL.
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`22. We have now successfully completed a Phase I human clinical study and found
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`that the high concentration SC formulation is surprisingly safe, well-tolerated, stable, and has
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`unexpectedly good bioavailability.
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`23.
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`Despite concerns about increased Cl-INH aggregation at high protein
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`concentrations, there was no immunogenicity concerns, specifically no development of anti-C1-
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`: Gallagher, er a1.
`In re
`
`
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`Appl. No. : 14/855,168
`
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`: September 15, 2015
`Filed
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`Page
`: 10 of 12
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`Attomey’s Docket No.: SHR—1184US
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`INH antibodies in the Phase I healthy volunteers who received 2 subcutaneous doses of the new
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`high concentration formulation. The injection was unexpectedly well tolerated, with little or no
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`pain reported by the subjects, when I observed the injections. More surprisingly, the SC
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`injection of a high concentration formulation (e.g., 500 U/mL) achieved better bioavailability of
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`Cl-INH total antigen as compared to low concentration formulations. For example, SC injection
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`of 1000 U of Cl-INH at a concentration of 100 U/mL has achieved about 70% relative
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`bioavailability as compared to IV administration of Cl-INH at a concentration of 100 U/mL. By
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`contrast, the results reported by Martinez-Saguer showed that SC injection of Cl-INH at a low
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`concentration of 50 U/mL had about 40% bioavailability. See Martinez-Saguer at p. 1556. This
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`was unexpected because the increased viscosity of the high concentration formulation appeared
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`to have no negative impact on absorption and tissue distribution of Cl-INH.
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`24. We have now obtained FDA permission to advance to a phase III clinical trial
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`based on our successful Phase I study. Based on the totality of data, bioavailability data from
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`our phase I studies and prior human efficacy studies in HAE prevention, we have simulated a
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`twice-weekly efficacious dose regimen. See Figure 5 below. As shown below, injection of 1000
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`U or more Cl-INH at a high concentration (e. g., ~500 U/mL) twice a week would result in
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`maintaining functional Cl-INH blood levels above a threshold level (~04 U/mL or 40% of
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`functional C1 INH activity) to achieve therapeutic effects (see the red line in Figure 5 below).
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`: Gallagher, er al.
`In re
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`
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`Appl. No.: 14/855,168
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`
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`: September 15, 2015
`Filed
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`Page
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`Attomey’s Docket No.: SHR—l 184US
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`1:9
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`C:'1-<1HH{U}i":L)
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`Fig. 5: Predicted concentration of functional Cl-INH in adult HAE patients receiving twice
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`weekly subcutaneous injection of 500 U/mL Cl-INH formulation.
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`25.
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`Many have predicted that the successful development of this high concentration
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`small volume Cl-INH formulation would be a game-changer for HAE patients because this will
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`not only allow for a safer and potentially more effective treatment of HAE, but also permit self-
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`administration and give patients more control over their disease through routine prevention.
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