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,
`
`v.
`
`
`
`SHIRE VIROPHARMA INC.,
`Patent Owner.
`
`__________________
`
`
`
`U.S. Patent No. 9,616,111
`
`__________________
`
`
`
`DECLARATION OF DR. TIMOTHY CRAIG
`
`
`
`
`
`
`
`
`
`CSL EXHIBIT 1012
`CSL v. Shire
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`Page 1 of 52
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`PRIVILEGED AND CONFIDENTIAL ATTORNEY-CLIENT COMMUNICATION
`
`TABLE OF CONTENTS
`
`Page(s)
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. QUALIFICATIONS ........................................................................................ 1
`
`III. MATERIALS CONSIDERED ........................................................................ 4
`
`IV. SUMMARY OF OPINIONS ........................................................................... 5
`
`V.
`
`BACKGROUND AND STATE OF THE ART .............................................. 7
`
`A.
`
`B.
`
`Introduction to HAE .............................................................................. 7
`
`The Literature Disclosed Low- and High-Concentration
`Subcutaneous C1-INH Therapies Prior to March 2013 ...................... 12
`Studies with Berinert® P ........................................................... 12
`Studies with Cinryze® ............................................................... 15
`
`1.
`
`2.
`
`VI. THE ’111 PATENT ....................................................................................... 22
`
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 24
`
`VIII. A POSA WOULD HAVE BEEN MOTIVATED TO ADMINISTER
`A HIGHER-CONCENTRATION SC FORMULATION OF C1-INH
`TO HAE PATIENTS ..................................................................................... 24
`
`IX. A POSA WOULD HAVE HAD A REASONABLE EXPECTATION
`OF SUCCESS IN TREATING HAE BY ADMINISTERING A
`HIGHER-CONCENTRATION SC FORMULATION ................................. 28
`
`X. ANY ALLEGED NEED FOR A SUBCUTANEOUS C1-INH
`THERAPY HAD BEEN MET BY MARCH 2013 ....................................... 31
`
`XI. A POSA WOULD NOT HAVE VIEWED THE LITERATURE AS
`CRITICIZING, DISCREDITING, OR DISCOURAGING HIGH-
`CONCENTRATION C1-INH FORMULATIONS ....................................... 38
`
`XII. CONCLUSION .............................................................................................. 43
`
`i
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`ii
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`ii
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`I.
`
`INTRODUCTION
`1.
`
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
`
`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
`3.
`I am currently a Professor of Medicine and Pediatrics and a
`
`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
`
`1
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`organizations in 2015. I also completed a Fellowship in Allergy/Immunology at
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`Walter Reed Army Medical Center-GME in 1992.
`
`5.
`
`I have been providing clinical care for HAE patients for over 18 years
`
`and have been performing clinical research for at least 15 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 150 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 as the
`
`Asthma Diagnosis and Treatment Interest Section Chair for the AAAAI (American
`
`Academy of Allergy, Asthma & Immunology). I also served as chair of the
`
`Occupational and Sports Committees for the AAAAI and 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.
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`2
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`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 activities through my University. I do not own stock in CSL, nor have I been
`
`given and 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
`
`research, including distinguished Educator for my role in mentoring students in
`
`1 Shire purchased ViroPharma in 2013.
`
`3
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`research, Alpha-Omega-Alpha membership for mentoring students in research, and
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`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 270 peer-reviewed
`
`scientific articles, over 200 abstracts, multiple web-posted online articles, 4 book
`
`chapters, and 3 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 February and
`
`March 2017. I have also reviewed or edited hundreds of scientific manuscripts.
`
`12. A copy of my curriculum vitae is provided as Exhibit 1016.
`
`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
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`IV. SUMMARY OF OPINIONS
`14.
`I have been asked to provide an opinion on the state of the field in
`
`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 assertions, which were not
`
`supported with any citations, that there had been a “long-felt need by HAE patients
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`5
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`for a more convenient non-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. 1002 [Schranz declaration, ¶¶ 14, 20, 23], 6, 9, 10. 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
`
`
`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, p. 405], 17), 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
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`as failures. Rather, a POSA would have recognized that any alleged need for a
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`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 develop 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
`A.
`Introduction to HAE
`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
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`permeability of blood vessels resulting in tissue swelling. Ex. 1025 [Craig 2012,
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`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. 195], 14. 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. 182], 1; 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
`
`8
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`subside over the next 48-72 hours. Ex. 1038 [Firszt & Frank, p. 384], 5; Ex. 1039
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`[Frank, p. S29], 1.
`
`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
`
`9
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`later, investigators reported the first use of a partially-purified C1-INH concentrate
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`for treating HAE patients. Ex. 1074 [Brackertz, p. 680], 2. Over the 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, there were four C1-INH concentrates available for
`
`treating HAE. Ex. 1025 [Craig 2012, pp. 189-190], 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,
`
`10
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`while Cinryze® is now distributed by Shire in all other markets.3 Ex. 1037
`
`[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. 11], 3.
`
`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. 905, 907], 13, 15; Ex. 1083 [Späth, pp. 147-48], 1-2. However, at least two
`
`other first-line treatments for HAE were also available in March 2013, including
`
`Shire’s bradykinin receptor antagonist, Icatibant®, and its kallikrein inhibitor,
`
`
`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.
`
`11
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`Kalbitor®. Ex. 1025 [Craig 2012, p. 190], 9. Icatibant® and Kalbitor® are both
`
`administered subcutaneously. Id.
`
`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 typical for therapeutic products.
`
`Studies with Berinert® P
`1.
`In September 2008,
`the Johann Wolfgang Goethe University
`
`29.
`
`Hospitals 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
`
`12
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`Berinert® P, supported the study, CSL did not have any control over the study. The
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`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-March
`
`22, 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.
`
`13
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`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 in adult patients with HAE Type I or II. Id. 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.” Id. Although no information was released about the precise
`
`volume or concentration of the C1-INH formulation that would be administered in
`
`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, higher-concentration
`
`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
`
`14
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`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.
`
`2.
`Studies with Cinryze®
`In 2009, investigators reported early results of a study comparing iv
`
`32.
`
`and sc administration of Cinryze®4 in pigs. Ex. 1069 [Jiang abstract, p. 46], 47.
`
`The 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.
`
`
`4 According to Shire, Cinryze® is a plasma-purified human C1-INH protein
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`manufactured by a combination of filtration and chromatographic procedures,
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`followed by a series of viral reduction steps. Ex. 1010 [Cinryze label, § 11], 1.
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`15
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`33. A full report of the pig study was published in 2010. Ex. 1005 [Jiang
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`2010]. Figure 4 of that publication compares plasma levels of human C1-INH
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`after sc and iv infusion in six of the pigs. Ex. 1005 [Jiang 2010, p. 327], 12. The
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`authors observed that the blood levels of human C1-INH after sc infusion in pigs
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`“compared favorably with the levels obtained after IV infusion.” Id. The authors
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`noted that sc infusion of human C1-INH “appeared safe and led to sustained blood
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`levels in this pig model, which has similar drug distribution and skin physiology to
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`humans.” Ex. 1005 [Jiang 2010, p. 328], 13. As a result, the authors concluded
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`that sc infusion “is a viable possibility for administering human C1 inhibitor to
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`patients with HAE on prophylactic therapy with no need for intravenous
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`administration. This approach warrants further study.” Id.
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`34.
`
`It is my understanding that the 2010 publication of the study
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`comparing iv and sc administration of Cinryze® in pigs was cited by the USPTO
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`Examiner during prosecution of the ’111 patent, and that Shire filed a declaration
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`by one of the co-authors of that publication, Dr. Michael M. Frank, in response to
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`the Examiner’s rejection. Ex. 1003 [Frank declaration], 1-2. In his declaration,
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`Dr. Frank explained that the Cinryze® used in the pig study was prepared according
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`to the prescribing instructions. Ex. 1003 [Frank declaration, ¶ 4], 2. Specifically,
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`the lyophilized Cinryze® product was reconstituted with sterile water to achieve a
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`concentration of 100U/mL, which was then administered to the animals in volumes
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`16
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`ranging from 8mL to 11.5mL, for total doses ranging from 800U to 1150U. Id.
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`(¶ 5).
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`35.
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`In 2010, ViroPharma announced that it had completed enrollment of a
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`Phase 2 study evaluating sc delivery of Cinryze®. Ex. 1063 [ViroPharma Oct 2010
`
`press release, p. 1], 1. Patients in that trial received Cinryze® via iv infusion twice-
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`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. And
`
`in 2012, ViroPharma presented a poster (“ViroPharma’s poster”) at the annual
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`AAAAI meeting that was held in Orlando, FL from March 2 to March 6, 2012,
`
`comparing pharmacokinetic data from clinical studies on the subcutaneous
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`administration of Cinryze® either alone but reconstituted at a higher concentration
`
`than normally used for iv administration, or in a combination with a recombinant
`
`human hyaluronidase (rHuPH20).5 Ex. 1004 [ViroPharma’s poster], Abstract
`
`(Methods), Figure 1, Methods. 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
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`degradation of hyaluronan, thereby enhancing the dispersion and delivery of
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`subcutaneously-administered drugs.
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`17
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`36.
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`In the Prior 200 Study, 26 HAE patients received twice-weekly
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`1000U or 2000U doses of Cinryze® alone administered subcutaneously on days 1,
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`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), Figure 1, Methods,
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`Figures 2, 5, 6. In the Current 204 Study, 12 patients from the Prior 200 Study
`
`received twice-weekly 1000U or 2000U doses of Cinryze® in combination with
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`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. Although the poster did not specify which type of HAE the patients
`
`had, given the rarity of Type 3 HAE, a POSA would have understood that the
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`patients examined in the Prior 200 and Current 204 studies described in the poster
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`had HAE Type I or Type II.
`
`18
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`37. Tables 3 and 4, and Figures 2-6 of ViroPharma’s poster compared
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`pharmacokinetic data across the Prior 200 and Current 204 Studies for the 12
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`subjects who participated in both investigations. Id. at Abstract.
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`38. Table 3 demonstrated that Cinryze® has adequate bioavailability when
`
`administered subcutaneously.
`
`
`39. And as shown in Figure 2, sc administration of 2000U of Cinryze®
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`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).
`
`19
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`40. Figure 2 also demonstrates that after an initial ramp-up period, the
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`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.
`
`41. 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 these studies, plasma C1-INH levels would have been
`
`maintained above 0.4U/mL for at least 50% of the time between the fourth and
`
`fifth administrations.
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`20
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`42. Based on this data, the authors concluded that sc administration of
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`Cinryze® with hyaluronidase “resulted in physiologically relevant and sustained C1
`
`INH functional concentrations >0.4 U/mL.” Id. at Conclusion. The same
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`conclusion can also be drawn for the sc administration of Cinryze® alone at a
`
`concentration of 333U/mL and a dose of 2000U. Id. at Figure 2.
`
`43.
`
`In June 2012, ViroPharma began recruiting for a Phase 2 study to
`
`evaluate the safety, tolerability, and efficacy of two doses of Cinryze® in
`
`combination with hyaluronidase (rHuPH20) administered by subcutaneous
`
`injection to prevent HAE attacks. Ex. 1035 [Cinryze® sc clinicaltrials.gov, p. 1], 1.
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`Two months later, ViroPharma announced that FDA had placed a temporary hold
`
`on the clinical trial due to potential safety concerns with the rHuPH20. Ex. 1070
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`21
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`[ViroPharma Aug 2012 press release, p. 1], 1. By December 2012, however,
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`ViroPharma had resumed
`
`the Phase 2 study.
`
` Ex. 1022 [Cinryze® sc
`
`clinicaltrials.gov Dec 2012 update, p. 2], 2; Ex. 1027 [ViroPharma Dec 2012 press
`
`release, p. 1], 1. As discussed below, the results of that study were later published
`
`in 2016.
`
`VI. THE ’111 PATENT
`44.
`I understand that U.S. Patent No. 9,616,111 (“the ’111 patent”)
`
`contains 18 claims directed to methods of treating HAE by subcutaneously
`
`administering a composition comprising a C1-INH protein. Ex. 1000 [’111 patent,
`
`cols. 13-14], 13. Each of the claims requires (1) that the C1-INH sequence has at
`
`least 95% identity to residues 23 to 500 of SEQ ID NO:1,6 (2) that the dose of C1-
`
`
`6 SEQ ID NO:1 is the sequence of the human C1-INH protein. Ex. 1011 [Bock, p.
`
`4293, Figure 1a], 7-8. Amino acids 1-22 comprise a signal sequence that is present
`
`in the initial translated protein, but is later cleaved to form the mature protein. As
`
`discussed above, Cinryze®
`
`is a plasma-purified human C1-INH product
`
`manufactured by a combination of filtration and chromatographic procedures,
`
`followed by a series of viral reduction steps. Supra n. 4. Because these
`
`manufacturing steps do not impact the amino acid sequence of the protein,
`
`Cinryze® is 100% identical to residues 23 to 500 of SEQ ID NO:1.
`
`22
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`INH is at least about 1000U, (3) that the concentration of C1-INH in the
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`composition is at least about 400U/mL (dependent claim 2 specifies 500U/mL),
`
`and (4) that the treatment increases t