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. TIMOTHY CRAIG
`
`Page 1 of 139
`
`CSL EXHIBIT 1012
`
`Page 1 of 139
`
`CSL EXHIBIT 1012
`
`
`
`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. TIMOTHY CRAIG
`
`Page 1 of 139
`
`CSL EXHIBIT 1012
`
`Page 1 of 139
`
`CSL EXHIBIT 1012
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page(s)
`INTRODUCTION ........................................................................................... 1
`I.
`II. QUALIFICATIONS ........................................................................................ 1
`III. MATERIALS CONSIDERED ........................................................................ 4
`IV. SUMMARY OF OPINIONS ........................................................................... 5
`V.
`BACKGROUND AND STATE OF THE ART .............................................. 7
`A.
`Introduction to HAE .............................................................................. 7
`B.
`The Literature Disclosed Low- and High-Concentration
`Subcutaneous C1-INH Therapies Prior to March 2013 ...................... 13
`1.
`Studies with Berinert® P ........................................................... 14
`2.
`Studies with Cinryze® ............................................................... 16
`VI. THE ’788 PATENT ....................................................................................... 25
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 27
`VIII. A POSA WOULD HAVE BEEN MOTIVATED TO ADMINISTER
`A HIGHER-CONCENTRATION SC FORMULATION OF C1-INH
`TO HAE PATIENTS ..................................................................................... 28
`IX. A POSA WOULD HAVE HAD A REASONABLE EXPECTATION
`OF SUCCESS IN TREATING HAE BY ADMINISTERING A
`HIGHER-CONCENTRATION SC FORMULATION ................................. 31
`X. ANY ALLEGED NEED FOR A SUBCUTANEOUS C1-INH
`THERAPY HAD BEEN MET BY MARCH 2013 ....................................... 36
`XI. A POSA WOULD NOT HAVE VIEWED THE LITERATURE AS
`CRITICIZING, DISCREDITING, OR DISCOURAGING HIGH-
`CONCENTRATION C1-INH FORMULATIONS ....................................... 43
`XII. CONCLUSION .............................................................................................. 49
`
`i
`
`
`
`Page 2 of 139
`
`
`
`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
`
`physician and clinician.
`
`2.
`
`I have been engaged at an hourly consulting rate of $750.00 per hour.
`
`My compensation is not contingent on the outcome of this proceeding.
`
`II. QUALIFICATIONS
`I am currently a Professor of Medicine and Pediatrics and a
`3.
`
`Distinguished Educator at Pennsylvania State University. I also serve as the Chief
`
`of the Allergy/Immunology Section, the Director of Allergy and Respiratory Clinical
`
`Research, Clinic Director of the alpha-1-deficiency Clinical Research Center, and
`
`Program Director of the Allergy/Immunology Fellowship. I am also currently a
`
`member of the Medical Advisory Board for the Hereditary Angioedema (HAE)
`
`Association of America.
`
`4.
`
`I graduated from New York College of Osteopathic Medicine in 1984
`
`with a Doctor of Osteopathic Medicine (DO) degree. I completed my residency in
`
`Internal Medicine in 1990 at San Diego Naval Hospital. I was certified by the
`
`American Board of Internal Medicine (ABIM) and the American Osteopathic Board
`
`of Internal Medicine (AOBIM) in 1990. I was recertified by both organizations in
`
`1
`
`Page 3 of 139
`
`
`
`2015. I also completed a Fellowship in Allergy/Immunology at Walter Reed Army
`
`Medical Center-GME in 1992.
`
`5.
`
`I have been providing clinical care for HAE patients for over 19 years
`
`and have been performing clinical research for at least 25 years. In addition, I train
`
`students, residents, and fellows on treatment of HAE. Our cohort is one of the largest
`
`in the USA and comprises over 165 patients who are referred from mainly the mid-
`
`Atlantic, but also from as far away as Wyoming and Alabama. Because of my
`
`expertise in treating HAE, I was chosen by the World Allergy Organization to
`
`develop Global Guidelines for management of patients with HAE. These guidelines
`
`were published in 2012. Ex. 1025 [Craig 2012].
`
`6.
`
`I have served as a leader in multiple organizations including Board of
`
`Directors for the AAAAI (American Academy of Allergy, Asthma & Immunology).
`
`I also served on the Board of Directors for the American College of Allergy, Asthma
`
`& Immunology (ACAAI). I am a past president of the Pennsylvania Allergy
`
`Association, past Mid-Atlantic Governor for the Regional, State and Local Allergy,
`
`Asthma and Immunology Societies (RSLAAIS), and past board member of the Joint
`
`Council of Allergy, Asthma and Immunology (JCAAI) and ACAAI. I am also on
`
`the board of the HAE-Association and American Lung Association Mid Atlantic.
`
`2
`
`Page 4 of 139
`
`
`
`7.
`
`I have performed research with Biocryst, Shire, Dyax, ViroPharma
`
`(before it was purchased by Shire),1 CSL, Pharming, and Lev, all of which have
`
`brought HAE medications to the market. I was a major investigator in CSL’s
`
`IMPACT 2 and 3 trials and the open-label safety study, and also CSL’s COMPACT
`
`2 and 3 trials and the corresponding open label study. I have spoken for and
`
`consulted for CSL for over 10 years. In addition, CSL supports some of my CME
`
`and basic science activities through my University. I do not own stock in CSL, nor
`
`have I been given any financial support other than through the activities above.
`
`8.
`
`As noted above, I have worked on several projects for different
`
`pharmaceutical companies in the HAE space. This includes key studies that have
`
`led to the approval of Cinryze®, initially brought to the market by Lev, then
`
`purchased by ViroPharma, and now owned by Shire. I have also participated in
`
`clinical trials for Shire’s Kalbitor® and Lanadelumab, the latter of which recently
`
`has been purchased by Shire from Dyax. I was also on the data safety board for
`
`Biocryst to oversee safety for their phase 1b study of BCX7353. In addition, I have
`
`done clinical research for 20 years in other areas including asthma, COPD, Alpha-1
`
`deficiency, Primary Immunodeficiency and vaccines.
`
`9.
`
`I have received a number of awards and honors in recognition of my
`
`teaching and research, including distinguished Educator for my role in mentoring
`
`
`1 Shire purchased ViroPharma in 2013.
`
`3
`
`Page 5 of 139
`
`
`
`students in research, Alpha-Omega-Alpha membership for mentoring students in
`
`research, and multiple students I mentored have received awards for their research.
`
`10.
`
`I have been invited to speak at approximately 350 inviting presentations
`
`with at least 70 lectures on treating and diagnosing HAE, including at Johns Hopkins
`
`University, National Jewish Hospital, AAAAI, ACAAI, Egyptian Allergy
`
`Association, Mexican Allergy Association, Argentina Allergy and Immunology
`
`Association, Canadian Allergy and Immunology Association, and multiple other
`
`local, state and national allergy and immunology meetings and Universities.
`
`11.
`
`I have authored or coauthored approximately 290 peer-reviewed
`
`scientific articles, over 200 abstracts, multiple web-posted online articles, 4 book
`
`chapters, and 4 practice guidelines on HAE, including the World Allergy
`
`Organization Guidelines discussed above. My two most recent manuscripts on
`
`Hereditary Angioedema were published this year in the NEJM in 2018. I have also
`
`reviewed or edited hundreds of scientific manuscripts.
`
`12. A copy of my curriculum vitae is provided as Appendix B.
`
`III. MATERIALS CONSIDERED
`13.
`In preparing this declaration, I have relied on my extensive experience
`
`as an allergist-immunologist and specifically my experience treating patients with
`
`HAE. I have also considered the materials listed in Appendix A.
`
`4
`
`Page 6 of 139
`
`
`
`IV. SUMMARY OF OPINIONS
`I have been asked to provide an opinion on the state of the field in
`14.
`
`treating HAE, and specifically the use of C1-esterase inhibitors (C1-INH) for
`
`treating HAE, in March 2013, based on my experience as clinician in the HAE field.
`
`At the time, the use of intravenously-administered (iv) replacement C1-INH
`
`therapies for prophylaxis and acute treatment of HAE was well-established,
`
`including via self-infusion programs.
`
`15.
`
`In addition, the successful subcutaneous (sc) administration of C1-INH
`
`formulations, including both low- and high-concentration formulations, had also
`
`been demonstrated. It is my opinion that in light of this well-developed field, a
`
`person of ordinary skill in the art (“POSA”) in March 2013 would have been
`
`motivated to develop higher-concentration subcutaneous C1-INH formulations than
`
`those previously disclosed and would have had a reasonable expectation of success
`
`in treating HAE patients with such formulations.
`
`16.
`
`I also specifically considered Dr. Schranz’s unsupported assertions:
`
`that there had been a “long-felt need by HAE patients for a more convenient non-
`
`5
`
`Page 7 of 139
`
`
`
`parenteral[2] delivery of C1-INH”; that early clinical trials examining subcutaneous
`
`administration of C1-INH had been unsuccessful; that there had been safety and
`
`efficacy concerns over increasing C1-INH concentrations in formulations; and that
`
`there had been a consensus in the field that it would not be feasible to develop high-
`
`concentration formulations of C1-INH. Ex. 1003 [Schranz declaration], ¶¶ 14, 20,
`
`23. As explained below, Dr. Schranz’s unsupported assertions are incorrect and do
`
`not reflect the state of the art with respect to C1-INH therapies for treating HAE as
`
`of March 2013.
`
`17. First, to the extent there may have been a need in the field for a
`
`subcutaneously administered C1-INH-based treatment for HAE, that need had not
`
`been long-felt when assessed from the point in time at which C1-INH-based
`
`therapies first became accessible to the majority of HAE patients. Nor were the early
`
`studies of subcutaneously-administered C1-INH viewed by those in the field as
`
`
`2 I assume Dr. Schranz intended to say “non-intravenous” rather than “non-
`
`parenteral,” since subcutaneous administration is considered parenteral drug
`
`delivery (see Ex. 1006 [Gatlin, pp. 417-20], 29-32), and since intravenous self-
`
`administration of C1-INH had been approved by March 2013. Ex. 1010 [Cinryze®
`
`label, § 2], 1; Ex. 1031 [Berinert® label, § 2], 1.
`
`6
`
`Page 8 of 139
`
`
`
`failures. Rather, a POSA would have recognized that any alleged need for a
`
`subcutaneous C1-INH therapy had been satisfied by March 2013.
`
`18. Second, I was aware of no safety or efficacy concerns over
`
`administering high-concentration C1-INH formulations; nor was I aware of any
`
`consensus in the field that it would not be feasible to develop such high-
`
`concentration formulations. At the time, it was believed that C1-INH was a
`
`promising candidate for sc administration, and I was aware of nothing that would
`
`have discouraged those in the field from pursuing such treatments. Several studies
`
`had already demonstrated that sc administration was safe and raised plasma C1-INH
`
`levels to physiologically-relevant levels, prompting two major companies to
`
`separately investigate high-concentration C1-INH formulations. And one of those
`
`high-concentration formulations had already been shown by March 2013 to yield
`
`therapeutic levels of C1-INH in HAE patients. Thus, safety and efficacy
`
`considerations were not hindering the development of sc C1-INH therapies.
`
`V. BACKGROUND AND STATE OF THE ART
`Introduction to HAE
`A.
`19. HAE is a rare, autosomal dominantly-inherited disease affecting
`
`approximately one in 10,000 to 50,000 individuals. See, e.g., Ex. 1028 [Over, p.
`
`248], 10. Angioedema is defined as a vascular reaction of the deep dermis or
`
`subcutaneous/submucosal
`
`tissues with
`
`localized dilatation and
`
`increased
`
`7
`
`Page 9 of 139
`
`
`
`permeability of blood vessels resulting in tissue swelling. Ex. 1025 [Craig 2012, p.
`
`187], 6. HAE clinically manifests as recurrent episodic swelling of the subcutaneous
`
`tissues of the extremities, the mucosa of the bowel, and/or tissues of the face, mouth,
`
`upper airway, or the genital area. See, e.g., Ex. 1039 [Frank, p. S29], 1; Ex. 1028
`
`[Over, p. 248], 10; Ex. 1025 [Craig 2012, p. 187], 6. These attacks cause pain and
`
`disability during intestinal and subcutaneous episodes, and can be life-threatening
`
`when the upper airways are affected. Ex. 1028 [Over, p. 249], 11; Ex. 1025 [Craig
`
`2012, p. 188], 7.
`
`20. HAE is often grouped as an allergic disorder, but attacks are not due to
`
`histamine release, and patients typically do not have more allergic symptomatology
`
`than those in the general population. Ex. 1038 [Firszt & Frank, p. 383], 4.
`
`21. Because HAE is such a rare disease with a wide variability in disease
`
`expression, it is historically difficult to diagnose and treat. Ex. 1025 [Craig 2012, p.
`
`188], 7; Ex. 1028 [Over, p. 249], 11.
`
`22.
`
`In about a third of patients, trauma or psychological stress triggered by,
`
`for example, infection, surgery, or dental work, can initiate an attack. Ex. 1038
`
`[Firszt & Frank, p. 384], 5; Ex. 1020 [Craig 2011, p. 1174], 11. Typically, attacks
`
`grow more severe within the first 24-36 hours after onset and then gradually subside
`
`over the next 48-72 hours. Ex. 1038 [Firszt & Frank, p. 384], 5; Ex. 1039 [Frank, p.
`
`S29], 1.
`
`8
`
`Page 10 of 139
`
`
`
`23. HAE is caused by mutations of the C1-INH gene. Ex. 1038 [Firszt &
`
`Frank, p. 384], 5; Ex. 1039 [Frank, p. S29], 2; Ex. 1025 [Craig 2012, p. 187], 6. C1-
`
`INH is a member of the serine protease inhibitor (serpin) superfamily and is a heavily
`
`glycosylated protein that has an apparent molecular weight of approximately 100-
`
`105kDa as determined by analytical centrifugation and SDS-PAGE. Ex. 1028
`
`[Over, p. 241], 3. When functioning normally, C1-INH inhibits plasma kallikrein,
`
`which prevents production of bradykinin, the primary mediator of swelling in HAE.
`
`Ex. 1028 [Over, p. 242], 4.
`
`24. HAE is classified into three types depending on the underlying cause
`
`and dysfunction in C1-INH: Type I is caused by a mutation that results in low levels
`
`(<30% of normal) of functional C1-INH protein; Type II is caused by a mutation in
`
`the active site of C1-INH that results in non-functional protein; and Type III, which
`
`is very rare, is not associated with any changes in the C1-INH protein. Ex. 1038
`
`[Firszt & Frank, p. 384], 5; Ex. 1025 [Craig 2012, p. 187], 6. By definition, one unit
`
`of C1-INH is equivalent to the concentration of C1-INH in one milliliter of normal
`
`human plasma. Ex. 1025 [Craig 2012, p. 189], 8.
`
`25. The link between HAE and C1-INH was first published in 1963.
`
`Ex. 1039 [Frank, p. S30], 2 (citing Donaldson & Evans Am. J. Med. 1963). Ten
`
`years later, investigators reported the first use of a partially-purified C1-INH
`
`concentrate for treating HAE patients. Ex. 1074 [Brackertz, p. 680], 2. Over the
`
`9
`
`Page 11 of 139
`
`
`
`course of the next several decades, C1-INH concentrates received approval for
`
`administration to HAE patients in approximately a half-dozen countries. However,
`
`C1-INH concentrates were not available to the vast majority of HAE patients until
`
`they were approved by the U.S. Food and Drug Administration (“FDA”) and the
`
`European Medicines Agency (“EMA”) in 2008. Ex. 1034 [Cinryze® approval
`
`letter], Ex. 1062 [CSL May 2010 press release].
`
`26. By March 2013, four C1-INH concentrates had been approved by either
`
`the FDA or EMA for treating HAE. Ex. 1025 [Craig 2012, pp. 189-90], 8-9. Three
`
`of the concentrates are purified from plasma: CSL’s Berinert® P, which is
`
`administered iv at a concentration of 50U/mL; Shire’s Cinryze®, which is
`
`administered iv at a concentration of 100U/mL; and Sanquin’s Cetor®, which is
`
`administered iv at a concentration of 100U/mL. Ex. 1025 [Craig 2012, p. 189], 8;
`
`see also Ex. 1031 [Berinert® label, § 2], 1; Ex. 1010 [Cinryze® label, § 2], 1;
`
`Ex. 1037 [Cinryze® FDA Briefing Document, pp. 2-3], 2-3. Cinryze® and Cetor®
`
`are both manufactured by Sanquin: Cetor® is distributed by Sanquin in limited
`
`markets, while Cinryze® is now distributed by Shire in all other markets.3 Ex. 1037
`
`
`3 Lev Pharmaceuticals, Inc. was organized in the United States to test and bring to
`
`market the Sanquin product. Lev was acquired by ViroPharma, which was then
`
`acquired by Shire.
`
`10
`
`Page 12 of 139
`
`
`
`[Cinryze® FDA Briefing Document, p. 3], 3. The fourth available concentrate
`
`(Pharming’s Ruconest®, which is administered iv at a concentration of 150U/mL) is
`
`prepared from recombinant protein expressed in rabbit milk. Ex. 1025 [Craig 2012,
`
`p. 190], 9; see also Ex. 1041 [Ruconest® EMA approval, p. 6], 6. In addition, self-
`
`administered iv protocols for these agents had also been approved prior to March
`
`2013. Ex. 1031 [Berinert® label], 2; Ex. 1010 [Cinryze® label], 2; see also Ex. 1009
`
`[Levi, p. 904], 12; Ex. 1032 [Longhurst 2007, p. 14], 6.
`
`27. Treatment with C1-INH concentrate eliminates the underlying cause of
`
`HAE Types 1 and 2 by replacing the deficient protein. Ex. 1025 [Craig 2012, p.
`
`189], 8. Restoring plasma C1-INH levels to approximately 40% of normal (i.e.,
`
`0.4U/mL) is considered sufficient to treat or prevent HAE attacks. Ex. 1009 [Levi,
`
`pp. 907-08], 15-16; Ex. 1083 [Späth, p. 157], 11. However, at least two other first-
`
`line treatments for HAE were also available in March 2013, including Shire’s
`
`bradykinin receptor antagonist, Firazyr®, and its kallikrein inhibitor, Kalbitor®.
`
`Ex. 1025 [Craig 2012, p. 190], 9; Ex. 1017 [Kalbitor® label]; Ex. 1018 [Firazyr®
`
`label]. Firazyr® and Kalbitor® are both administered subcutaneously. Id.
`
`11
`
`Page 13 of 139
`
`
`
`FDA
`Approval
`
`
`2008
`
`
`
`
`
`2009
`
`Table 1: FDA Approved Drugs for Treatment of HAE Attacks or prophylaxis
`against HAE Attacks as of March 2013
`Product
`Indication
`Active Agent Administration
`
`
`
`Plasma-
`purified C1-
`INH
`
`
`
`
`
`Plasma-
`purified C1-
`INH
`
`
`
`iv
`
`
`
`
`
`iv
`
`
`
`Cinryze®
`
`
`
`
`
`Berinert®
`
`“CINRYZE is a C1
`esterase inhibitor
`indicated for
`routine prophylaxis
`against angioedema
`attacks in
`adolescent and
`adult patients with
`Hereditary
`Angioedema
`(HAE).”
`“Berinert is a
`plasma-derived
`concentrate of C1
`Esterase Inhibitor
`(Human) indicated
`for the treatment of
`acute abdominal or
`facial attacks of
`hereditary
`angioedema (HAE)
`in adult and
`pediatric patients.
`The safety and
`efficacy of Berinert
`for prophylactic
`therapy have not
`been established.”
`
`12
`
`Page 14 of 139
`
`
`
`Product
`
`Indication
`
`Active Agent Administration
`
`
`
`Kallikrein
`inhibitor
`
`
`
`Bradykinin B2
`receptor
`antagonist
`
`
`
`Kalbitor®
`
`
`
`Firazyr®
`
`
`
`“KALBITOR®
`(ecallantide) is
`indicated for
`treatment of acute
`attacks of
`hereditary
`angioedema (HAE)
`in patients 12 years
`of age and older.”
`“FIRAZYR®
`(icatibant) is
`indicated for the
`treatment of acute
`attacks of
`hereditary
`angioedema (HAE)
`in adults 18 years of
`age and older.”
`
`
`
`sc
`
`
`
`sc
`
`FDA
`Approval
`
`
`2009
`
`
`
`2011
`
`B.
`
`The Literature Disclosed Low- and High-Concentration
`Subcutaneous C1-INH Therapies Prior to March 2013
`28. All of the currently-available C1-INH concentrates were initially
`
`approved for intravenous administration. Although self-administered intravenous
`
`protocols were later developed, subcutaneous administration offers obvious
`
`advantages over intravenous administration, including reduced risk of infection,
`
`improved patient convenience, and improved patient compliance. Ex. 1046
`
`[Longhurst 2010, pp. 3-5], 3-5. It is not surprising, therefore, that investigations into
`
`subcutaneously administered C1-INH concentrates followed closely on the heels of
`
`their FDA and EMA approvals. Indeed, such a progression from iv to sc is fairly
`
`13
`
`Page 15 of 139
`
`
`
`typical for therapeutic products. After therapeutic efficacy is established using iv
`
`administration, more convenient administration protocols are developed.
`
`Studies with Berinert® P
`1.
`In September 2008, the Johann Wolfgang Goethe University Hospitals
`
`29.
`
`in Germany (“Goethe”) sponsored a clinical trial, called the PASSION study, to
`
`compare subcutaneous versus intravenous administration of Berinert® P in HAE
`
`patients. Ex. 1023 [PASSION study clinicaltrials.gov, p. 1], 1. The goal of the study
`
`was to investigate the safety and efficacy of a second administration mode in cases
`
`where iv access is not suitable. Id. The PASSION study was an investigator-
`
`initiated trial, meaning that although CSL, the manufacturer of Berinert® P,
`
`supported the study, CSL did not have any control over the study. The study design,
`
`patient selection, dose, dosing regimen, and other trial parameters were determined
`
`by the investigators at Goethe. Because the clinical trial protocol indicated that
`
`patients would receive sc or iv infusions of Berinert® P, a POSA would have
`
`understood that the investigators were administering the product at its approved
`
`concentration of 50U/mL. And, in fact, later publications discussing the PASSION
`
`study confirmed that was the case. Ex. 1048 [Martinez-Saguer 2014, p. 1553], 6
`
`(reporting that patients in the PASSION study were administered 1000U in 20mL).
`
`30. Early results from the PASSION study were reported at the 2011
`
`AAAAI annual meeting that was held in San Francisco, CA from March 18-22,
`
`14
`
`Page 16 of 139
`
`
`
`2011. Ex. 1047 [Martinez-Saguer abstract, p. AB104], 3. The meeting abstract
`
`reports that 24 patients suffering from moderate HAE received either iv or sc
`
`treatment with 1000U of Berinert® P. Id. The authors reported less than 50%
`
`bioavailability compared to iv when Berinert® P was administered sc, and that sc
`
`administration was well-tolerated with no serious adverse events. Id. The authors
`
`concluded that sc administration of C1-INH “leads to potentially clinically relevant
`
`C1-INH plasma levels in patients with moderate HAE and warrant[s] further
`
`studies.” Id. Thus, the PASSION study was a successful proof-of-concept for the
`
`feasibility of sc administration of C1-INH.
`
`31. CSL then initiated its own international phase I/II trial in May 2012,
`
`called the COMPACT study, to evaluate the pharmacokinetics, pharmacodynamics,
`
`and safety of a volume-reduced, subcutaneous formulation of C1-INH concentrate.
`
`Ex. 1026 [CSL May 2012 press release, p. 1], 1. The study was designed to examine
`
`twice-weekly sc injections of two different doses of a volume-reduced formulation
`
`of Berinert® in adult patients with HAE Type I or II. Id.; see also Ex. 1071 [CSL
`
`R&D slides], 34. It was stated in the press release that “each participant will be
`
`assigned to receive a single subcutaneous injection of the volume-reduced
`
`formulation of C1-INH twice a week for four weeks.” Ex. 1026 [CSL May 2012
`
`press release, p. 1], 1. Although no information was released about the precise
`
`volume or concentration of the C1-INH formulation that would be administered in
`
`15
`
`Page 17 of 139
`
`
`
`the COMPACT study, a POSA would have understood that typical sc injections have
`
`volumes on the order of a few milliliters. Ex. 1006 [Gatlin, p. 417], 29. Larger
`
`injection volumes, such as the 20mL infusions administered in the PASSION study,
`
`had known drawbacks, including increased patient pain and discomfort (Ex. 1006
`
`[Gatlin, p. 405], 17), and also a tendency to leak back out of the site of injection.
`
`Thus, a POSA would have assumed that the “volume-reduced” formulations
`
`disclosed as being tested in the COMPACT study as a single subcutaneous injection
`
`were lower-volume formulations than those used in the PASSION study. A POSA
`
`also would have understood that in order to achieve therapeutically-effective doses
`
`in such reduced volume formulations and as a single subcutaneous injection, the sc
`
`injections would have to be formulated at higher concentrations. Thus, a POSA
`
`would have assumed that the COMPACT study was investigating C1-INH
`
`formulations having much increased concentrations compared to Berinert®.
`
`Studies with Cinryze®
`2.
`In 2009, investigators reported early results of a study comparing iv and
`
`32.
`
`sc administration of Cinryze®4 in pigs. Ex. 1069 [Jiang abstract, p. 46], 47. The
`
`
`4 According to Shire, Cinryze® is a plasma-purified human C1-INH protein
`
`manufactured by a combination of filtration and chromatographic procedures,
`
`followed by a series of viral reduction steps. Ex. 1010 [Cinryze label, § 11], 1.
`
`16
`
`Page 18 of 139
`
`
`
`report was presented at the 6th C1 Inhibitor Deficiency Workshop held in Budapest,
`
`Hungary from May 22-24, 2009. The pigs were administered 50U/kg, which was
`
`chosen to be in excess of the 20-30U/kg effective in man, and the animals received
`
`3 infusions at 3-day intervals. Id. This dosing regimen would have been expected
`
`to result in therapeutic plasma C1-INH levels above 40% of normal. The
`
`investigators observed sustained plasma C1-INH levels after sc infusion, and no
`
`evidence of adverse events. Id. The investigators concluded that sc infusion of C1-
`
`INH “appears safe and leads to sustained blood levels in this animal model.” Id.
`
`33. A full report of the pig study was published in 2010. Ex. 1005 [Jiang
`
`2010, pp. 323-28], 8-13. Figure 4 of that publication compares plasma levels of
`
`human C1-INH after sc and iv infusion in six of the pigs. Ex. 1005 [Jiang 2010, p.
`
`327], 12. The authors observed that the blood levels of human C1-INH after sc
`
`infusion in pigs “compared favorably with the levels obtained after IV infusion.” Id.
`
`The authors noted that sc infusion of human C1-INH “appeared safe and led to
`
`sustained blood levels in this pig model, which has similar drug distribution and skin
`
`physiology to humans.” Ex. 1005 [Jiang 2010, p. 328], 13. As a result, the authors
`
`concluded that sc infusion “is a viable possibility for administering human C1
`
`inhibitor to patients with HAE on prophylactic therapy with no need for intravenous
`
`administration. This approach warrants further study.” Id.
`
`17
`
`Page 19 of 139
`
`
`
`34.
`
`It is my understanding that the 2010 publication of the study comparing
`
`iv and sc administration of Cinryze® in pigs was cited by the USPTO Examiner
`
`during prosecution of the ’788 patent, and that Shire filed a declaration by one of the
`
`co-authors of that publication, Dr. Michael M. Frank, in response to the Examiner’s
`
`rejection. Ex. 1016 [Frank declaration]. In his declaration, Dr. Frank explained that
`
`the Cinryze® used in the pig study was prepared according to the prescribing
`
`instructions. Ex. 1016 [Frank declaration], ¶ 4. Specifically, the lyophilized
`
`Cinryze® product was reconstituted with sterile water to achieve a concentration of
`
`100U/mL, which was then administered to the animals in volumes ranging from
`
`8mL to 11.5mL, for total doses ranging from 800U to 1150U. Id. at ¶ 5.
`
`35.
`
`In 2010, ViroPharma announced that it had completed enrollment of a
`
`Phase 2 study evaluating sc delivery of Cinryze®. Ex. 1063 [ViroPharma Oct. 2010
`
`press release, p. 1], 1. Patients in the ViroPharma trial received Cinryze® via iv
`
`infusion twice-weekly for two weeks and then, following a 14-day washout period,
`
`either 1000U or 2000U of Cinryze® via sc administration twice weekly for two
`
`weeks. Id.
`
`36. And in 2012, ViroPharma presented a poster (“ViroPharma’s poster”)
`
`at the annual AAAAI meeting that was held in Orlando, FL from March 2 to March
`
`6, 2012, comparing pharmacokinetic data from clinical studies on the subcutaneous
`
`administration of Cinryze® either alone but reconstituted at a higher concentration
`
`18
`
`Page 20 of 139
`
`
`
`than normally used for iv administration, or in a combination with a recombinant
`
`human hyaluronidase (rHuPH20).5 Ex. 1004 [ViroPharma’s poster], Abstract,
`
`Figure 1, Methods. Because Cinryze® was (and still is) only approved as an iv
`
`formulation, a skilled artisan would have understood that ViroPharma administered
`
`the iv version of Cinryze® subcutaneously in this study. Indeed, researchers often
`
`subcutaneously administer approved iv formulations when testing the feasibility of
`
`sc administration. Ex. 1048 [Martinez-Saguer 2014, p. 1553], 6.
`
`37. ViroPharma’s poster described two clinical studies: a “Prior 200
`
`Study” and a “Current 204 Study.” Figure 1 depicted a graphical representation of
`
`the two clinical studies:
`
`
`5 Hyaluronidase enzymes increase tissue permeability by catalyzing the reversible
`
`degradation of hyaluronan, thereby enhancing the dispersion and delivery of
`
`subcutaneously-administered drugs.
`
`19
`
`Page 21 of 139
`
`
`
`
`
`38.
`
`In the Prior 200 Study, 26 HAE patients received iv Cinryze® and then
`
`underwent a “14 day wash-out period” before receiving twice-weekly 1000U or
`
`2000U doses of Cinryze® alone administered subcutaneously on days 1, 4, 8, and 11
`
`in 2 or 4 injections of 1.5mL each at a concentration of 333U/mL (i.e., 1000U in
`
`3mL or 2000U in 6mL). Id. at Abstract, Methods, Figures 1, 2, 5, and 6. After
`
`undergoing a “9 month interval” 12 patients from the Prior 200 Study participated
`
`in the Current 204 study and received twice-weekly 1000U or 2000U doses of
`
`Cinryze® in combination with rHuPH20 administered subcutaneously on days 1, 4,
`
`8, and 11 in a single injection of 10 or 20mL at a concentration of 100U/mL (1,000U
`
`in 10mL or 2,000U in 20mL). Id. A “washout period” is a period of time during a
`
`clinical study when a participant is taken off of a study drug or other medication in
`
`order to eliminate the effects of the treatment. The reported average half-life of
`
`20
`
`Page 22 of 139
`
`
`
`Cinryze® is 56 hours. Ex. 1010 [Cinryze® label, § 12.3], 1. Thus, the 14-day
`
`washout periods applied during ViroPharma’s study would have eliminated the
`
`effects of the previous iv doses upon the study participants. A POSA, therefore,
`
`would have understood the sc dosing regimens of the Prior 200 and Current 204
`
`studies as not involving an initial iv C1-INH step.6
`
`39. Tables 3 and 4, and Figures 2-6 of ViroPharma’s poster compared
`
`pharmacokinetic data across the Prior 200 and Current 204 Studies for the 12
`
`subjects who participated in both investigations. Id. at Abstract.
`
`40. Table 3 demonstrated that Cinryze® has adequate bioavailability when
`
`administered subcutaneously.
`
`
`6 Moreover, a POSA would have understood from the PASSION study that
`
`successful sc administration of C1-INH need not be preceded by an iv dose, since
`
`the results of that study “suggest[ed] that s.c. administration of C1-INH leads to
`
`potentially clinically relevant C1-INH plasma levels in patients” who had not
`
`received an initial iv dose of C1-INH. Ex. 1047 [Martinez-Saguer abstract, p.
`
`AB104], 3; see also Ex. 1048 [Martinez Saguer 2014, p. 1552], 5.
`
`21
`
`Page 23 of 139
`
`
`
`
`
`41. And as shown in Figure 2, sc administration of 2000U of Cinryze®
`
`alone via four 1.5mL injections in the Prior 200 Study (purple line) or in combination
`
`with hyaluronidase via one 20mL injection in the Current 204 Study (blue line)
`
`achieved therapeutic mean plasma C1-INH concentrations above 0.4U/mL. In
`
`contrast, sc administration of 1000U doses of Cinryze® either alone or in
`
`combination yielded lower plasma C1-INH concentrations that fluctuated between
`
`0.2-0.3U/mL (red and green lines).
`
`22
`
`Page 24 of 139
`
`
`
`
`
`42. Figure 2 also demonstrates that after an initial ramp-up period, the
`
`therapeutic (>0.4U/mL) C1-INH plasma levels that were achieved with the 2000U
`
`doses were maintained between each of the sc administrations for the entire two-
`
`week duration of the study.
`
`43. Figure 4 likewise confirmed that when outlier data points are excluded,
`
`the therapeutic plasma levels were maintained for 50% of the time in the 72-hour
`
`period after the last administration. Thus, had there been a fifth administration on
`
`day 14 in
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
