Docket No; SHR—l 184D S
`
`(PATENT)
`
`[N THE UNETED STATES PATENT AND TRADENIARK OFFICE
`
`in re application of: GALLAGHER, Cynthia, er al. Examiner: MTKNIS, Zachary J.
`
`Application No; 14/855,168
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`Group Art Unit: 8760
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`Filed: September 15, 2015
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`Confirmation No: 1675
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`For: C1 ~lNFi CQMPOSITIONS AND METHODS FOR THE PREVENTION AND
`'l'REATh/lENT OF DISORDERS ASSOCIATED Wl'l“H C1 ESTERASE INHIBITOR
`DEF [CHEN C ‘1’
`
`VIA EFS WEB FILING WWWJJSPTQGDV
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`DECLARATION OF DR. JENNIFER SCHRANZ UNDER 37 ERR.
`
`
`
`Dear Commissioner:
`
`17 Jennifer Schranz, hereby declare as follows:
`
`'1.
`
`1 am currently a Vice President of Clinical Development and the Global
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`Development Team Lead for Angioederna at Shires the assignee of the above~identifi ed patent
`
`application US 14/855,168 (the “present application”) as a result of Shire’s acquisition of
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`ViroPhanna, the original assignee of the application. Before Shire acquired ViroPharrna, I
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`served as ViroPharmaE Vice President of Clinical Research. Since March 201 1, i have overseen
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`the development of ClhmYZEE, including the ongoing effort for developing subcutaneous
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`formulation of Cl esterase inhibitor (Cl ~1NEE), the active ingredient in CINRYZEIg'.
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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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`spent over 20 years conducting clinical research and trials involving treatments for various
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`Page 1 0f 12
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`CSL EXHIBIT 1003
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`Page 1 of 12
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`CSL EXHIBIT 1003
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`: Gallagher, er a].
`In re
`ApplfNo: 14/855,168
`Filed
`: September 15, 2015
`Page
`: 2 of 12
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`Attomey’s Docket No; SHR—l 184US
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`diseases including hereditary angioedema (HAE). Before joining V iroPharnia, 1 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 (preclinical and
`
`clinical) for various diseases. M] experience and education, including publications in which I
`
`am an author are summarized in my curriculum Vitae, a mic and accurate copy of which is
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`provided with this declaration as Exhibit A.
`
`3.
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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 Virol’harnia Phase 2b Combination Study for Subcutaneous Administration of
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`Ciniyze® With Hyaluronidase (rHuPHZO), press release published 19 December
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`2012 (“ViroPharma Press Release”);
`
`6 Kreuz, W., Clinicaifi‘iialsgov NCTOO748202, published 4 September 2008: SC
`
`vs IV comparison study of Berinert P (“Kreuz”); and
`
`a
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`Jiang et al, Clinical Immunology 136323628, published 8 June 2010 (“.liang”).
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`4.
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`l have been asked to comment on, among other things, the development of
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`subcutaneous formulation for the treatment of hereditary an gioedema (HAE).
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`5.
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`HAE is a rare and potentially lifemthreatening genetic disorder characterized by
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`recurrent acute attacks of non—Whealing, nonupruritic edema affecting the cutaneous tissues or
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`mucous membranes. See, A Agostoniera/,1Allerng/m. Immunol. 2004; 114(3): 851—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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`[\2
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`: Gallagher, er a].
`In re
`ApplfNo:
`l4/8557l68
`Filed
`: September 15, 2015
`Page
`:
`'3 of 12
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`Attoniey’s Docket No; Sl-lR—l 184US
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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 signifi cant burden to the
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`parents.
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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 C l JINH.
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`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 mlNl-l 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 ClmmlH 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 (ag. 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:
`
`Lb)
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`: Gallagher, er an?~
`In re
`Applr'No‘: 14/851168
`Filed
`: September 15, 2015
`Page
`: 4 of 12
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`Attoniey’s Docket No; SHR—1184US
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` \-.‘.\\\
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`Big. 1: Female patient suffering from edema and requiring nasal intubation. See, K. Bork at al.
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`Am JM’edZOOéfl 19: 2672274.
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`
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`Fig“ 2: Progression of attack symptoms in male patient, See, Baneiji A, Ann/illergyAsthma
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`1112112141202 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. ClNRYZEIE
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`(Ci esterase inhibitor [HumanD is the only C i {ENE-ii replacement product approved for HA1?)
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`prophylaxis. CINRYZE? is human plasma derived CLINH, indicated for routine prophylaxis
`5‘3
`
`against angioederna attacks in adolescent and adult patients. CiNRYZl.
`
`is provided as 500 U of
`
`lyophilisate per Vial. Each Vial is reconstituted in 5 mL of sterile water, to a concentration of 100
`
`U/rnL prior to administration. Two vials, or a total of 10 mL, are adn'iinistered by intravenous
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`infusion every 3—4 days in order to achieve an appropriate threshold offunetional Cl—lNl—l
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`activity for routine prophylaxis against angioedema attacks in adoiescent and adult patients
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`: Gallagher, er crl.
`In re
`ApplN’o;
`l4/855,l68
`Filed
`: September 15, 2015
`Page
`: 5 of 12
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`Attomey’s Docket No; SHR—l 184US
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`IO.
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`While the current lV formulation of CINRYZE® provides an important and life-
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`saving treatment for HAE, a subcutaneous (SC) formulation of C lwflfli could represent a more
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`convenient and patient friendly option for many I-IAE 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 lV access, such as thromhoernbolisrn due to a foreign body, infections,
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`etc.
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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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`CINRYZEQ) for SC administration. A successful SC formulation requires sutticiently 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 ofimmunogenicity 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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`12.
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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—INi-l concentration in order to permit the administration of therapeutically
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`effective dosage tag, > lOOO III) in as small a volume as feasible, typically, no more than 3—4
`
`ml; per injection site. In addition to the common challenges for SC formulation described above,
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`Cl wlNlEl has certain characteristics that posed unique challenges in a hi gh concentration SC
`
`formulation.
`
`(J!
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`In re
`ApplfN’o;
`l4/8557l68
`Filed
`: September 15, 2015
`Page
`: 6 of 12
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`Attoniey’s Docket No; SHR—l 184US
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`l3.
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`Cl ~lNl’-l is a large protein, the largest member of serpin superfamily. Human Cl —
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`Hfli is made up of 478 amino acids plus a LIE—amino acid signal peptide. It has an apparent
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`molecular weight of about ~105 KDa. Cl-INH is highly glycosyla‘ted.
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`in fact, C l—INl-l is one of
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`the most highly glycosylated plasma proteins. More than 269/?) of the molecular weight of C l —
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`INH is carbohydrate C] ~lNH hears both N— and O~linked glycans. See. Figure 3 below. Like
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`many highly glycosylated proteins, ClulNl-l has high viscosity. Moreover, plasmauderived Cl—
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`mfi is particularly prone to aggregation due to the presence of certain co-eluates.
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`F55155 {LengthfiQS}
`
`
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`"fsttpniitifecentensgsf.era-Syst/derafl;no?pmreinfflapflfif55
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`Fig. 3: Structural schematic of (Tl-{NH N--linl<ed glycans are represented at N 0-—linked
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`glycans are represented at T or S.
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`l 4.
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`Thus; it was highly uneertai n whether Cl ~lNl’l could be formulated. at :1 hi gh
`
`concentration for SC inj ection, Indeed, for a long period of time prior to the present inventiorn
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`the consensus in the field was that it might not be feasible to develop high concentration with a
`
`small volume SC formulation for Cl—lNlEl. Leaders in the C l-lNlEl therapeutic field, ViroPhartna
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`(the manufacture of CH‘HKYZE‘E) and, CSL Behring (the manufacturer of Berinert indicated for
`
`acute HAE attack at 50 U/rnl.) appreciated the long~felt need by HAP, patients for a more
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`convenient non-parenteral delivery of Cl—lNiH) ability for self—adniinistrati on and thereby better
`6
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`: Gallagher, er a].
`In re
`ApplfN’og til/855368
`Filed
`: September 15, 2015
`Page
`: 7 of 12
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`Attoniey’s Docket No; SHR—l 184US
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`control of their disease,1 Each of ViroPharma and CSL Behring initiated human clinical studies
`
`of SC administration of CLINH 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 Virol’harina, l was responsible for
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`ViroPhanna’s earlier human clinical studies of SC administration ot‘ClNRYZE‘g) described in the
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`Virol9hanna Press Release.
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`In that study. subjects were subcutaneously infused with 20 ml; of
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`liquid containing either lOOO U of Cinryze with 24,000 U of rHuPHZO or 2000 U of Cinryze
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`with 48,000 U recombinant human hyaluronidase (rl-luPl—lZO). a dispersing agent. Accordingly,
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`the final concentration of C LINE administered was 50 U/inL or 100 U/mL, respectively. See
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`ClinicalTrialsgov lden‘ti tier NCTOI 756] 57 which describes the same study in further detail:
`
`
`
`Regiment Sashes“? MB
`
`
`
`abuse in Sr‘euze 2..
`
`s 4 fines; £3 E» measles.
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` 3 Treatmentfie‘zsnenesx $3;
`
`
`
`
`. “.5-
`
`Fig. 4: Table describing patient dosing regimen of SC. Study N’C’I'Dl756157 which involved SC
`
`injection of Cinryze and rHuPHZO.
`
`16.
`
`To enable subcutaneous delivery of such a large volume, we used lilalozyme’s
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`proprietary drug delivery platform technology based on recombinant human hyaluronidase
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`1 See the Background section of ViroPharma’s 20 l 2 AAAAI poster (attached as Exhibit D).
`7
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`: Gallagher, er a].
`In re
`ApplfNo:
`l4z’8557l68
`Filed
`: September 15, 2015
`Page
`: 8 of 12
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`Attoniey’s Docket No; SIiR—l 184US
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`enzyme (rI—luPl—lZOf I-l’yaluronidase is an enzyme which catalyzes the hydrolysis ofhyaluronan,
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`a component of the human extracellular matrix. By degrading hyaluronan. hyaluronidase
`
`increases tissue permeability.
`
`l-Iyaluronidase had been used to enhance absorption and
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`dispersion of therapeutics and enable the subcutaneous administration of much larger volumes
`
`than can normally be administered subcutaneously. See Hallerfl M. F, “Converting Intravenous
`
`Dosing to Subcutaneous Dosing with Recombinant Human Hyaluronidase?” Pharm. Tech.)
`
`published 02 October 2007; available at http:/’/Www.pharmtech.com/converting-intravenous--
`
`dosing»subcutaneous-dosing~recombinant~huni an—hyaluroni dase.
`
`17.
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`l-Iowever, this study was terminated due to safety concerns over emergence ofi
`
`and unexpected incidence and titer of, non-neutralizing anti-rHuPHZt‘; antibodies after
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`administration of CINRVZE‘R’ in combination with rI-luPHZO in a Phase 2 clinical study in H AF.
`
`subj ects.
`
`l8.
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`CSL Behringls study was designed to investigate the subcutaneous versus
`
`intravenous adn'iii'iistrati on of Berinert P in patients with mild or moderate l-IAE to evaluate the
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`possibility of an alternative administration mode in cases where W access is not suitable. See,
`
`Kreuz. According to published reports, CSL Behring’s study involved the SC administration of
`
`a large volume of 50 U/rnL Cl—lNI'l formulation, Berinert. See h/l’artinez—Saguer et al,
`
`IRIINIS’FUS‘IOA'
`
`54215524561 (2014-) (providing more detail regarding the Kreuz study and
`
`subsequent findings) (Exhibit C.) As described in Martinez-Saguer., 20 ml“ of 50 LI/mL Cl ~INl-I
`
`were administered to the patients.
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`In order to administer such a large volume) 10 ml; of
`
`composition were administered in each of two different subcutaneous abdominal sites over 15
`
`minutes using two medical infusion pumps for continuous, simultaneous administration. In my
`
`experience, SC administration of such large volumes can be traumatic and labor intensive with
`
`infusion pumps, particularly Without the co—adrninistrati on of a permeability enhancing agent
`
`such as rHuPHZO. In some cases. it may trigger an HAE attack. As far as I know, CSL
`
`2 Vii‘oPharma entered into a multi—million dollar license agreement with Halozyme for the purpose of this study.
`8
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`: Gallagher, er a].
`In re
`ApplfNo.:
`l4/855,l68
`Filed
`: September 15, 2015
`Page
`: 9 of 12
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`Attomey’s Docket No; SllR—1184US
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`Behring’s earlier clinical subcutaneous study using low concentration high volume formulation
`
`Berinert as described in Kreuz was not further developed.
`
`19.
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`1 am also familiar with the animal study described in liang, which sought to
`
`assess whether reasonable levels of functional human Cl —INH could be achieved in swine
`
`plasma following SC administration.
`
`In that study, again, a large volume of ClNRYZl5®(100
`
`U/mL) was infused subcutaneously into pigs by continuous pump over a 60~minute period. See,
`
`.l’iang, p. 325, left column.
`
`2.0.
`
`Prior to the successful development of high concentration formulations by the
`
`present inventors, the entire field had been focused on SC deliveiy of Cl—INH at a low
`
`concentration (e. g, 5; 100 U/rnL) in a large volume (cg, 10—20 nit.) due to the safety and
`
`efficacy concerns over increasing C luINH concentrations in formulations. In other words, the
`
`consensus in the ii old was that it, was not an easy or obvious strategy to increase Cl-INH
`
`concentration for SC injection purposes because of the various challenges described above.
`
`21.
`
`Indeed, it took years and millions of dollars in investment for Shire and
`
`ViroPharrna scientists to eventually develop a. clinically acceptable, high concentration SC
`
`formulation of Cl-INl-l that was safe and effective. Examples of such formulations were
`
`described in the present application. One such high concentration SC formulation containing ~
`
`500 U/mL ClwlNl-l is being tested in human clinical studies, which enables subcutaneous
`
`delivery of 1000—2000 1U Cl-INH in Emil mL.
`
`22.
`
`We have now successfully completed a Phase 1 human clinical study and found
`
`that the high concentration SC formulation is surpri singly safe, wellmtolerated, stable, and has
`
`unexpectedly good bioavailahility.
`
`23.
`
`Despite concerns about increased C 1-INH aggregation at high protein
`
`concentrations, there was no irnmunogenicity concerns, specifically no development of anti—Cl-
`
`9
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`

`: Gallagher, er ct]~
`In re
`Appli'No‘:
`l4z’8557l68
`Filed
`: September 15, 2015
`Page
`: 10 of l2
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`Attoniey’s Docket No; SHR—l 184US
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`lNH antibodies in the Phase I healthy volunteers who received 2 subcutaneous doses of the new
`
`hi gh concentration formulation The injection was unexpectedly well tolerated with little or no
`
`pain reported by the subjects, when I observed the injections. More surprisingly, the SC
`
`injection of a hi gh concentration formulation (tag, 500 U/mL) achieved better bioavailability of
`
`Cl~INI-I total antigen as compared to low concentration formulations. For example, SC injection
`
`of l 000 U of C l—INH at a concentration of 100 U/mL has achieved about 7 0% relative
`
`bioavailability as compared to IV administration of Cl-II‘HI at a concentration of 100 U/mL. By
`
`contrast”, the results reported by h/‘Eartinez—Saguer showed that SC injection of ClwlNH at a low
`
`concentration of 50 U/mL had about 40% bioavailability. See Martineanaguer at p. l556. This
`
`was unexpected because the increased Viscosity of the high concentration fornntlation appeared
`
`to have no negative impact on absorption and tissue distribution of C luINH.
`
`24.
`
`We have now obtained FDA permission to advance to a phage III clinical trial
`
`based on our successful Phase I study. Based on the totality of data, bioavailability data from
`
`our phase I studies and prior human efficacy studies in Hall: prevention we have simulated a
`
`twice—weekly efficacious dose regimen. See Figure 5 below As shown below; injection of 1000
`
`U or more Cl—INH at a hi gh concentration toga, ~-‘SOO U/mLT) twice a week would result in
`
`maintaining functional Cl —INH blood levels above a threshold level (~04 U/mL or 409/?» of
`
`functional Cl ENE-l activity) to achieve therapeutic effects (see the red line in Figure 5 below).
`
`l0
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`

`: Gallagher, er an?~
`In re
`Appli'No‘:
`l4/8557l68
`Filed
`: September 15, 2015
`Page
`:
`ll of l2
`
`Attomey’s Docket No; SHR—l 184E}S
`
`‘4,
`
`:114ththJImL
`
`Fig. 5: Predicted concentration of functional Cl ~lNE-l in adult HALE patients receiving twice
`
`weekly subcutaneous injection of 500 U/mL ClnINH formulation.
`
`25.
`
`Many have predicted that the successful development of this high concentration
`
`small volume Cl wlNl—i formulation would be a game-changer for HAE patients because this will
`
`not only allow for a safer and potentially more effective treatment ofHAE, but also permit self—
`
`administration and give patients more control over their disease through routine prevention
`
`ii
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`Page 11 0f 12
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`Page 11 of 12
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`Page 12 0f 12
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`Page 12 of 12
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