!!!!!
`
`Exhibit 1002
`
`Declaration of George A. Digenis, Ph.D.
`(“Digenis Decl.”)
`
`
`
`
`Exhibit 1002
`
`Declaration of George A. Digenis, Ph.D.
`(“Digenis Decl.”)
`
`
`
`
`DECLARATION OF DR. GEORGE A. DIGENIS, PH. D.
`
`
`
`
`
`I, Dr. George A. Digenis, Ph. D., declare that:
`
`1.
`
`I am over 18 years of age. I have personal knowledge of the facts
`
`stated in this Declaration and could testify competently to them if asked to do so.
`
`Personal Background
`
`2.
`
`I am currently an Emeritus Professor at The University of Kentucky,
`
`College of Pharmacy, and have been since 2002.
`
`3.
`
`I received a B.S., in Pharmacy from the American University Beirut,
`
`in Beirut, Lebanon in 1959, and an M.S., in Pharmacy from the University of
`
`Wisconsin, Madison, Wisconsin, in 1962. I received a Ph. D. in Organic
`
`Pharmaceutical Chemistry from the University of Wisconsin, Madison, Wisconsin
`
`in 1964. In 1997 I received an Honorary Ph. D. in Pharmacy and Pharmaceutical
`
`Technology from the University of Athens, Athens, Greece.
`
`4.
`
`From 1964 to 1967 I worked as an Assistant Professor of
`
`Pharmaceutical Chemistry at the American University of Beirut. From 1967 to
`
`1970 I was an Assistant Professor of Materia Medica and Pharmaceutical
`
`Chemistry at the College of Pharmacy at the University of Kentucky.
`
`5.
`
`From 1970 to 1974 I was an Associate Professor of Materia Medica
`
`and Pharmaceutical Chemistry, at the College of Pharmacy at University of
`
`1
`
`
`
`
`
`
`
`Kentucky, and during this time I was also a Professor of Medicinal, Chemistry and
`
`Pharmacognosy, at the College of Pharmacy at the University of Kentucky.
`
`6.
`
`In 1975 I became an Associate Professor of Nuclear Medicine, at the
`
`College of Pharmacy, at the University of Kentucky. From 1975 to 1980 I was a
`
`Senior Scientist at the Sloan-Kettering Institute for Cancer Research.
`
`7.
`
`From 1974 to 2001 I was a Professor of Medicinal Chemistry and
`
`Pharmaceutics at the College of Pharmacy at the University of Kentucky. During
`
`this time I was also a Professor in the Department of Nuclear Medicine, at the
`
`College of Medicine at the University of Kentucky and a Professor of Toxicology
`
`at the University of Kentucky.
`
`8.
`
`I have authored over 200 referenced publications and 18 patents in
`
`the area of solid phase reactions, synthesis of radiolabeled compounds, drug
`
`metabolism, drug design and design of novel drug formulations. I have also been a
`
`pioneer in the rapid synthesis of drugs labeled with short-lived isotopes and am
`
`credited for being the first in applying gamma scintigraphy in the assessment of the
`
`in vivo performance of novel drug formulations.
`
`9.
`
`Furthermore, I have served as a major professor of forty-two Ph. D.
`
`graduates and twenty-two postdoctoral fellows. I am a Fellow of the American
`
`Association of Pharmaceutical Scientists (AAPS). I have served as a consultant to
`
`numerous major pharmaceutical companies and have served on the scientific Board
`
`2
`
`
`
`
`
`
`
`of Advisors of several companies. In addition, for many years I served as the
`
`Director of the Division of Medicinal Chemistry at the UK College of Pharmacy.
`
`10. My full CV is attached as Exhibit A.
`
`Background Discussion
`
`11.
`
`I have been retained by Petitioners to provide technical analysis of
`
`
`
`prior art references and prepare this declaration. If I am asked to provide live
`
`deposition testimony it will be at a rate of $400 an hour.
`
`12.
`
`In preparation for this declaration, I have reviewed U.S. Patent No.
`
`8,865,688 (“the ‘688 Patent”) along with the prior art references and portions from
`
`the file history of the ‘688 Patent set forth below:
`
`1) U.S. Patent No. 6,004,581 (“the ‘581 Patent”)
`
`2) Stephen Hanauer et al., Mesalamine Capsules for Treatment of
`
`Active Ulcerative Colitis: Results of A Controlled Trial, 88
`
`AMERICAN J. GASTROENTEROLOGY 1188 (1993) (“Hanauer”)
`
`3) J. N. C. Healey, Gastrointestinal Transit and Release of
`
`Mesalazine Tablets in Patients with Inflammatory Bowel Disease,
`
`25 SCAND J. GASTROENTEROLOGY 47 (Supp. 127 1990) (“Healey”)
`
`4) L. M. L. Stolk et al., Dissolution Profiles of Mesalazine
`
`Formulations
`
`in Vitro, 12 PHARMACEUTISCH WEEKBLAD
`
`SCIENTIFIC EDITION 200 (1990) (“Stolk”)
`
`3
`
`
`
`
`
`5) European Patent Application No. 0 671 168 A1 (“EP168”)
`
`6) PCT Publication No. WO 91/07949 (“PCT949”)
`
`7) S. S. Davis, The Design and Evaluation of Controlled Release
`
`Systems for the Gastrointestinal Tract, 2 J. CONTROLLED RELEASE
`
`27 (1985) (“Davis-1985”)
`
`8) S. S. Davis et al., Transit of Pharmaceutical Dosage Forms
`
`Through the Small Intestine, 27 GUT 886 (1986) (“Davis-1986”)
`
`9) U.S. Patent No. 6,551,620 (“the ‘620 Patent”)
`
`10) Salix Announces Statistically Significant Top-Line Results of a
`
`Unique Granulated Mesalamine Product Registration Study in
`
`Ulcerative
`
`Colitis
`
`(September
`
`2007),
`
`http://www.sec.gov/Archives/edgar/containers/fix021/1009356/000
`
`119312507195530/dex992.htm (“Sept. 2007 Press Release”)
`
`11) U.S. Patent Application Publication No. 2010/0035850 A1
`
`(“Meyeroff”)
`
`12) XIFAXAN Trials Initiated in C. difficile-Associated Diarrhea,
`
`Irritable Bowel Syndrome and Hepatic Encelophalopathy. New
`
`Article [online] EndoNurse, 12 January 2006 (“Endonurse”)
`
`13) European Patent Application No. 0 040 590 A2 (“EP ‘590”)
`
`14)
`
`‘688 Patent File History (“FH688”), Amendment 5/9/2014
`
`4
`
`
`
`
`
`
`
`15)
`
`16)
`
`17)
`
`18)
`
`19)
`
`‘688 Patent File History (“FH688”), Amendment 6/20/2014
`
`‘688 Patent File History (“FH688”), Amendment to the Claims
`
`‘688 Patent File History (“FH688”), Notice of Allowance
`
`‘688 Patent File History (“FH688”), Amendment 10/8/2013
`
`‘688 Patent File History (“FH688”), Amendment 4/24/2013
`
`20) European Patent Application No. 0 453 001 A1 (“EP001”)
`
`21) P.J. Watts et al., Encapsulation of 5-aminosalicylic Acid into
`
`Eudragit RS Microspheres and Modulation of Their Release
`
`Characteristics by Use of Surfactants, 16 J. CONTROLLED RELEASE
`
`311 (1991) (“Watts”)
`
`22) Marakhouski et al., “A Double- blind Dose-escalating Trial
`
`Comparing Novel Mesalazine Pellets with Mesalazine Tablets in
`
`Active Ulcerative Colitis,” Aliment Pharmacol. Ther. 21:133-140
`
`(2005) (“Marakhouski”)
`
`23) Brunner et al., “Gastrointestinal Transit and Release of 5-
`
`aminosalicylic Acid from 153Sm-labelled Mesalazine Pellets vs.
`
`Tablets in Male Healthy Volunteers,” Aliment. Pharmacol. Ther.
`
`17:1163-1169 (2003) (“Brunner”)
`24) Brouwers, J.R.B.J. “Advanced and controlled drug delivery
`systems in clinical disease management,” Pharmacy World &
`
`5
`
`
`
`
`
`
`
`
`
`Science: (1996) 18(5), 153-162 (“Brouwers”)
`
` Person of Ordinary Skill in the Art
`
`13.
`
`I understand that a patent claim is evaluated from the perspective of
`
`a “person of ordinary skill in the art,” which I understand is a hypothetical person
`
`considered to have the skill level and knowledge of a particular field related to an
`
`alleged invention claimed in a patent. I further understand that this hypothetical
`
`skilled artisan is presumed to have before him or her all of the relevant prior art. I
`
`understand that this “hypothetical person” can be more than one person or a team
`
`of people of different disciplines. The discussions in this declaration are intended
`
`to convey the state of the art and the knowledge of a person of ordinary skill in the
`
`art generally prior to the earliest priority date of the patent application that issued
`
`as the respective ‘688 patent.
`In view of the subject matter of the ‘688 Patent, a person of ordinary
`
`14.
`
`skill in the art as of the patent’s filing date would typically hold an advanced
`
`degree in the chemical or pharmaceutical fields (such as chemistry, polymer
`
`chemistry, pharmaceutics or pharmacokinetics), or a bachelor’s degree combined
`
`with several years of experience in these fields, or alternatively, an M.D. with
`
`several years specializing in the treatment of gastrointestinal disorders.
`
`15.
`
`As of the priority date of the ‘688 Patent, I have been a person of
`
`ordinary skill in the art as defined above.
`
`6
`
`
`
`
`
`V. Background
`
`A. The ‘688 Patent
`
`
`
`16.
`
`The ‘688 Patent is directed to methods for “maintaining the
`
`remission of ulcerative colitis” through a “granulated mesalamine formulation.”
`
`(Ex. 1001, ‘688 Patent col. 34:11-35:17). The ‘688 Patent acknowledges that, at
`
`the time it was filed, numerous prior art formulations containing mesalamine
`
`existed for treating ulcerative colitis. For instance, the patent identifies prior art
`
`formulations that are “related to delivery of the intact molecule to the colonic
`
`mucosa without breakdown during digestion.” (Ex. 1001, ‘688 Patent col. 1:60-
`
`63). This includes “oral mesalamine treatments [that] are based on 3 types of
`
`delivery systems” including “azo-bonded to release drug in the colon once the drug
`
`is exposed to colonic bacteria”, polymer-coated “delayed release tables” for
`
`“release of drug when the pH in the digestive tract reaches the desired value”, and
`
`“time-dependent release mechanisms”. (Ex. 1001, ‘688 Patent col. 1:61-2:3).
`
`17.
`
`The ‘688 Patent, however, claims
`
`the following problems
`
`purportedly existed with prior art mesalamine formulations for treating UC:
`
`“variation within formulations in the release of mesalamine, including premature
`
`release, the possibility of dose dumping, and sensitivity to conditions that increase
`
`gastric pH and cause premature release of mesalamine (e.g., ingestion of a meal).”
`
`(Ex. 1001, ‘688 Patent col. 2:3-8).
`
`7
`
`
`
`
`
`
`
`18.
`
`The ‘688 Patent, however, is not directed to a novel formulation of
`
`mesalamine. Rather, the claims are directed to a method of “maintaining the
`
`remission of ulcerative colitis” that comprises administration of “a granulated
`
`mesalamine formulation.” (Ex. 1001, ‘688 Patent col. 34:10-13). The ‘688 Patent
`
`expressly incorporates embodiments of granulated mesalamine formulations taught
`
`in prior patents (to which the ‘688 Patent does not claim priority.) (Ex. 1001, ‘688
`
`Patent col. 10:47-53).
`
`19.
`
`The ‘688 Patent purports to solve the alleged prior-art problems with
`
`the claimed methods for maintaining the remission of ulcerative colitis. (Ex. 1001,
`
`‘688 Patent col. 34:10-35:17). During prosecution, the Applicant identified his
`
`“discovery that the oral mesalamine formulation was equally effective when
`
`administered with or without food.” (Ex. 1017, FH688, Amendment 6/20/14 at 5-
`
`6). After a tortured prosecution history, including seven office action rejections
`
`and amendment to independent claim 1 on six separate occasions, the issued claims
`
`require that administration of the granulated mesalamine is “without food”. (Ex.
`
`1001, ‘688 Patent col. 34:15).
`
`B. Prosecution History of the ‘688 Patent
`
`20.
`
`The ‘688 Patent
`
`issued from U.S. Patent Application No.
`
`12/573,081, filed Oct. 9, 2009, which was purportedly related to U.S. Provisional
`
`Application Nos. 61/102,807 and 61/109,708, filed Oct. 3, 2008 and Oct. 30, 2008,
`
`8
`
`
`
`
`
`
`
`respectively. Accordingly, the priority date for the ‘688 Patent is not earlier than
`
`October 30, 2008.
`
`21.
`
`The ‘688 Patent underwent a tortured prosecution history before
`
`allowance. The claim that eventually issued as claim 1 (claim 14 during
`
`prosecution) was amended at least six times. Applicant submitted two additional
`
`office-action responses that included unsuccessful attempts to persuade the
`
`Examiner to allow the claim without amendment. (See Ex. 1018, FH688
`
`Amendments to the Claims).
`
`22.
`
`Independent claims 1 and 16 (which recite substantively similar
`
`requirements) were both finally allowed upon Applicant’s amendment that the
`
`claimed methods for “maintaining the remission of ulcerative colitis” were
`
`“without food.” In support of this amendment, Applicant stated: “unlike other 5-
`
`mesalamine drugs available at the time of the invention, Applicant has
`
`demonstrated that the claimed methods are equally safe and effective when
`
`granulated mesalamine is administered to a subject without food.” (Ex. 1017,
`
`FH688, Amendment 6/20/14 at 5).
`
`23.
`
`Applicant further argued that, “[a]t the time of the invention, one of
`
`ordinary skill in the art would look to the teachings of the most similar formulation
`
`to determine if administration with food is required.” (Ex. 1017, FH688,
`
`Amendment 6/20/14 at 6). Applicant distinguished two FDA-approved oral
`
`9
`
`
`
`
`
`
`
`mesalamine formulations, Lialda® and Pentasa®. Applicant argued that Lialda,
`
`similar to the “pending claims [which] are directed to methods of administering a
`
`delayed and extended-release oral mesalamine formulation, Lialda®” is a “delayed
`
`and extended-release oral mesalamine tablet that was approved for inducing the
`
`remission of active, mild to moderate ulcerative colitis . . . .” (Id. at 6, emphasis in
`
`original). Citing prescribing information for Lialda®, Applicant argued that it is
`
`administered as “two to four 1.2 g tablets taken once daily with food.” (Id.,
`
`emphasis in original). With respect to Pentasa®, Applicant argued that it is “not a
`
`controlled and extended release formulation.” (Id.) Finally, Applicant pointed to
`
`two examples in the ‘688 Patent’s specification that purport to describe the results
`
`of a clinical trial showing that “there is no decrease in efficacy when granulated
`
`mesalamine is administered without food.” (Id. at 7).
`
`24.
`
`Upon allowing the application, the Examiner’s “Reasons for
`
`Allowance” stated:
`
`[t]he cited prior art is silent with respect to whether or not the mesalamine
`formulation is administered with or without food. One skilled in the art
`would reasonably expect the formulation to be administered with food, since
`similar mesalamine formulations are directed to be administered with food
`(see Lialda® information pamphlet, submitted by Applicants with response
`to filed 20 June 2014).
`(Ex. 1019, FH688, Notice of Allowance at 3).
`
`
`10
`
`
`
`
`
`
`
`25.
`
`The Examiner concluded that persons of skill in the art would have
`
`been motivated to administer mesalamine formulations with food:
`
`Additionally, one skilled in the art would be motivated to administer the
`mesalamine formulation with food, since 5-aminosalicylate compounds,
`including mesalamine, are known to have increased bioavailability when
`administered with food.
`(Ex. 1019, FH688, Notice of Allowance at 3).
`
`
`C. Background of the Prior Art
`
`1. Ulcerative Colitis
`
`26.
`
`Inflammatory bowel disease (“IBD”) refers
`
`to
`
`inflammatory
`
`conditions of the gastrointestinal tract, including ulcerative colitis (“UC”), Crohn’s
`
`disease (“CD”), as well as other conditions. CD can affect any portion of the
`
`gastrointestinal tract, from the mouth to the anus. By contrast, UC is limited to the
`
`colon, and often limited to the colonic mucosa (which is the most inner surface of
`
`the lumen of the colon.) The prevailing treatment for UC involves management of
`
`the symptoms. Management of UC symptoms includes two facets: inducing
`
`remission and maintaining remission. Inducement of remission controls an acute
`
`attack of UC, whereas maintenance of remission seeks to prevent relapses of acute
`
`attacks. (Ex. 1001, ‘688 Patent col. 1:54-59).
`
`2. Mesalamine (5-Aminosalicylic Acid)
`
`11
`
`
`
`
`
`
`
`27.
`
`Beginning in the 1950’s, sulfasalazine became the “the most widely
`
`prescribed medication for treatment of inflammatory bowel disease, specifically
`
`ulcerative colitis (UC).” (Ex. 1004, Hanauer at 1188). Sulfasalazine is composed
`
`of sulfapyridine and 5-aminosalicylic acid (also known as mesalamine or 5-ASA)
`
`that is linked by an azo bond. (Ex. 1004, Hanauer at 1188). In the 1970’s, it was
`
`discovered that 5-ASA was the therapeutically-active moiety of sulfasalazine. This
`
`led to the development of 5-ASA formulations for the treatment of IBD, UC and
`
`CD. (Ex. 1004, Hanauer at 1189).
`
`28.
`
`Indeed, prior to filing of the ‘688 Patent, it was well-known among
`
`persons of ordinary skill that aminosalicylic acid was therapeutically effective for
`
`treating UC. “The active compound aminosalicylic acid (in particular 5-ASA) or
`
`its derivatives have been used successfully for a relatively long time for the
`
`treatment of intestinal disorders, such as, for example, ulcerative colitis and
`
`Crohn’s disease.” (Ex. 1011, ‘620 Patent col. 1:15-18).
`
`29.
`
`Persons of ordinary skill also knew that aminosalicylic acid works
`
`by locally administering the drug at the sites of the lesions within the colon. (Ex.
`
`1011, ‘620 Patent col. 1:32-39 (“The action of aminosalicylic acid in the treatment
`
`of intestinal disorders, or in the prevention of their recurrence . . . takes place by
`
`means of the contact of the active compound directly at the site of the disorder in
`
`the intestine, the action of aminosalicylic acid, or a derivative thereof, being
`
`12
`
`
`
`
`
`
`
`directly related to its local concentration in the intestinal area to be treated.”); see
`
`also id. citing Ex. 1005, Healey at 47 (“[t]he effectiveness of mesalazine in the
`
`treatment of inflammatory bowel disease is attributed mainly to a topical action on
`
`the intestinal mucosa.” (emphasis added)).
`
`30.
`
`Oral administration of aminosalicylic acid, however, requires the
`
`drug to travel through the stomach and the small intestine before reaching the
`
`colon. Accordingly, the principal challenge to administering aminosalicylic acid
`
`for treatment of UC and other IBD conditions affecting the large intestine is that
`
`aminosalicylic acid will be readily absorbed in the small intestine. “A problem in
`
`the treatment with aminosalicylic acid is that the active compound is very easily
`
`absorbed and can be excreted via the kidney before its action can occur.” (Ex.
`
`1011, ‘620 Patent col. 1:45-48). (Ex. 1006, Stolk at 200 (“Plain mesalazine is
`
`totally absorbed in the upper part of the intestine.”); Ex. 1004, Hanuaer at 1189
`
`(“Oral administration of mesalamine is limited by absorption in the proximal small
`
`bowel, necessitating protected delivery systems for distribution to distal sites of
`
`enterocolonic inflammation.”)).
`
`31.
`
`For this reason, oral administration of 5-ASA has for a long time
`
`focused delayed and controlled/sustained release of mesalamine. (Ex. 1005,
`
`Healey at 47 (“Because mesalazine is readily absorbed from the small intestine,
`
`metabolized, and excreted in the urine, a delayed-release tablet preparation has
`
`13
`
`
`
`
`
`
`
`been developed to prevent release until the drug has reached the terminal ileum and
`
`colon.”; marketed as Claversal®); Ex. 1011, ‘620 Patent col. 1:49-51 (“[i]n the
`
`prior art, tablets and pellets are known which are coated with an enteric coating in
`
`order to thus prevent a premature release of the active compounds”; discussing
`
`numerous prior art references)). (Ex. 1006, Stolk at 200 (“pharmaceutical
`
`formulations [of mesalazine] have been designed, which can transport mesalazine
`
`undisturbed through stomach, duodenum and proximal jejunum and deliver high
`
`concentrations of mesalazine selectively at the inflammatory sites of the distal
`
`small intestine and colon”).
`
`32.
`
`In particular, the delayed/controlled release of mesalamine to the
`
`lower intestine has commonly been formulated as azo-bonded pro-drugs or non-
`
`linked agents. (Ex. 1009, Hanuaer at 1189). By the early 1990’s, non-linked
`
`agents used two mechanisms: (1) pH-dependent enteric coatings (such as acrylic-
`
`based resins) that dissolve above pH of approximately 7, after the drug has left the
`
`stomach, and (2) pH-independent slow-release
`
`that delivers “active drug
`
`continuously to the small and large bowel, independent of intestinal pH”). (Ex.
`
`1009, Hanuaer at 1189).
`
` 3. Enteric Coating
`
`33.
`
`Enteric coating was a well-known means to delay the release
`
`mesalamine prior to the filing of the ‘688 Patent. The stomach’s pH is generally
`
`14
`
`
`
`
`
`
`
`lower than the pH of the intestinal tract. (Ex. 1007, EP168 col. 1:27-33 (“it is
`
`recognized that the value of pH in the stomach is usually 1.8 to 4.5 in a healthy
`
`human and that the value of pH in the intestines is 6.5 to 7.5 and the pH does not
`
`essentially differ between the small intestine and the large intestine”).
`
`34.
`
`Accordingly, a coating that is insoluble at the stomach’s pH range,
`
`but soluble at the intestinal tract’s pH range, can delay and control the release of
`
`mesalamine until it reaches the lower intestines. Indeed, this was well-known to
`
`persons of ordinary skill prior to filing of the ‘688 Patent. (Ex. 1008, PCT949 at
`
`1:10-18 (“In a medical context, it is particularly advantageous to be able to
`
`administer orally a medicament which is coated so that it passes through the
`
`stomach and is released only when the coated material reaches the small intestine.
`
`Such coatings are called ‘enteric’ coatings and are relatively easy to formulate
`
`taking advantage of the fact that the stomach contents are acid and the intestinal
`
`contents are neutral to slightly alkaline.”)).
`
`35.
`
`Enteric coatings, including methacrylic acid copolymer, among
`
`others, were known to persons of ordinary skill prior to filing the ‘688 Patent. (Ex.
`
`1005, Healey at 47). Methacrylic acid copolymer is soluble above pH 6.0.
`
`Accordingly, prior to filing the ‘688 Patent, persons of ordinary skill knew to apply
`
`enteric coatings of methacrylic acid copolymer to aminosalicylic acid formulations
`
`to delay its release so that it was insoluble in the stomach, but soluble within the
`
`15
`
`
`
`
`
`
`
`intestine. (Ex. 1005, Healey at 47 (discussing mesalazine tablets “coated with the
`
`enteric-coating polymer methacrylic acid copolymer, type A (Eudragit L). This pH
`
`sensitive polymer is resistant to gastric conditions but soluble above pH 6.0 in the
`
`intestine . . . . A relatively thick coating is applied to the tablets to delay any
`
`release of the drug until they reach the terminal ileum and proximal colon”); citing
`
`Ex. 1006, Stolk at 200 (“Asacol® tablets contain 400 mg mesalazine and the
`
`tablets are coated with an acrylic resign (Eudragit® S), which dissolves above pH
`
`7.0. Thus in vivo it should be transported intact until it reaches the ascending part
`
`of the colon where the intraluminal pH rises above 7 and mesalazine is liberated.”).
`
`36.
`
`Enteric coatings comprising methacrylic acid copolymer were sold
`
`before the filing of the ‘688 Patent under the brand names Eudragit S and Eudragit
`
`L, and were well-known among persons of skill in the art. (Ex. 1022, EP001 at
`
`3:17-18 (“Polymer types for forming pH-dependent membrane include . . .
`
`copolymers of methacrylic acid (Eudragit L, Eudragit S)”); Ex. 1005, Healey at 48
`
`(“enteric-coating polymer, methacrylic acid copolymer, type A (Eudragit L)”); Ex.
`
`1006, Stolk at 200 (mesalazine “tablets are coated with an acrylic resin (Eudragit®
`
`S)”); Ex. 1013, EP590 at 4:2-3 (“Suitable partly methyl esterified methacrylic acid
`
`polymers are sold under the names Eudragit L and Eudragit S.”); Ex. 1007, EP 168
`
`col. 6:3-13 (“poly(methacrylic acid, methyl methacrylate (Eudragit L and Endragit
`
`S [sic]) are preferably used as enteric polymer”)).
`
`16
`
`
`
`
`
`4. Polymer Matrix
`
`
`
`37.
`
`Polymer matrices were also a well-known means to sustain the
`
`release of mesaliamine, and treat IBD, long before the ‘688 Patent. For instance,
`
`in 1990, Watts disclosed an investigation regarding “the controlled delivery of
`
`drugs to the colon” that included the production of “Eudragit RS microspheres
`
`containing 5-aminosalicylic acid (5-ASA), an agent active against inflammatory
`
`bowel disease.” (Ex. 1023, Watts at 311). The Eudragit series of polymers “are a
`
`family of polymers based on acrylic and methacrylic acids suitable for use in
`
`orally-administered drug delivery systems.” (Ex. 1023, Watts at 311). Two grades
`
`of the Eudragit series, “Eudragit RL and RS, are insoluble in acqueous media but
`
`permeable and as such have been shown to be suitable for use in sustained-release
`
`microencapsulated dosage forms.” (Ex. 1023, Watts at 311). Watts explicitly
`
`disclosed a “drug polymer matrix” containing 5-ASA with Eudragit RS. (Ex.
`
`1023, Watts at 312, 317). Watts concluded, “[w]e have demonstrated that 5-ASA
`
`can be successfully encapsulated into Eudragit RS to produce microspheres for
`
`potential sustained-release oral drug-delivery applications.” (Ex. 1023, Watts at
`
`316-17). Importantly, the ‘620 Patent (which long preceded the ‘688 Patent)
`
`identifies Eudragit RS as a non-gel forming polymer, i.e., one that is “insoluble in
`
`the intestinal tract and permeable to intestinal fluids.” (Ex. 1011, ‘620 Patent at
`
`17
`
`col. 3:47-55).
`
`
`
`
`
`
`
`38.
`
`Similarly, EP477 disclosed combining mesalamine in a non gel-
`
`forming polymer matrix comprising Eudragit RS. (Ex. 1015, EP477 at 8:1-14
`
`(disclosing “[e]ncapsulation of 5-amino-salicylic acid in EUDRAGIT®RS” in a
`
`polymer matrix, including through stirring); EP477 at 2:14-17 (disclosing “[t]he
`
`products [of encapsulation] may also be ‘homogeneous microspheres’, wherein the
`
`bioactive substance [5-ASA] is dispersed in the polymer [Eudragit RS].”).
`
`39. Watts further explained that the motivation for investigating
`
`controlled delivery of 5-ASA was the same as that of the ‘688 Patent: “[s]ince 5-
`
`ASA largely is absorbed from the upper intestine, selective delivery into the colon
`
`is required for it to be therapeutically effective.” (Ex. 1023, Watts at 312).
`
`5. Combinations of Enteric Coatings and Polymer Matrices
`
`40.
`
`Delayed and controlled dosage formulations for treating IBD was
`
`not a quiet art before the ‘688 Patent. On the contrary, long before, persons of skill
`
`in the art had been actively investigating alternative dosage formulations to
`
`adequately delay/control/sustain release of mesalamine for the treatment of IBD.
`
`(Ex. 1023, Watts at 312 (“colon-specific delivery of 5-ASA is currently receiving
`
`considerable research interest [as of 1990]”, listing numerous existing approaches);
`
`see Ex. 1004, Hanauer at 1189).
`
`41.
`
`Indeed, existing drugs before the ‘620 Patent (which long preceded
`
`the ‘688 Patent) employed variations of soluble enteric coatings as well as
`
`18
`
`
`
`
`
`
`
`permeable polymers: Asacol® (enteric coating of Eudragit S), Claversal® (enteric
`
`coating of Eudragit L), Pentasa® (semi-permeable polymer coating). (Ex. 1006,
`
`Stolk at 200; Ex. 1005, Healey at 47; see also Ex. 1023, Watts at 312 (citing other
`
`approaches)).
`
`Persons of skill also experimented with combinations of enteric coatings and
`
`insoluble permeable polymers. For instance, Salofalk® comprised an outer-coating
`
`of semi-permeable ethylcellulose, and an inner enteric coating of Eudragit L. (Ex.
`
`1006, Stolk at 200). EP001 disclosed a pharmaceutical composition for “targeted
`
`controlled release . . . within the intestine” comprising “two membranes, one of
`
`pH-dependent solubility and the other insoluble but permeable to the intestinal
`
`fluids.” (Ex. 1022, EP001 at 1). EP590 disclosed pharmaceutical formulations for
`
`treatment of IBD comprising a coating of both “acrylic polymer soluble only above
`
`pH 5.5” and a “water insoluble [sic] polymer” such as Eudragit RS/RL. (Ex. 1015,
`
`EP590 at 3:11-20). Persons of ordinary skill also combined 5-ASA in a polymer
`
`matrix surrounded by an enteric coating. Marakhouski disclosed pellets “coated
`
`with Eudragit-L” that contained 5-ASA “located in the core embedded in a matrix
`
`polymer responsible for prolonged release of the drug.” (Ex. 1024, Marakhouski at
`
`135). Brunner (published in 2003—5 years before earliest priority date of the ‘688
`
`Patent) disclosed pellets provided by Dr Falk Pharma GmbH, the patent owner of
`
`the ‘688 Patent. (Ex. 1025, Brunner at 1164). The pellets contained 500 mg of
`
`19
`
`
`
`
`
`
`
`mesalamine, “coated with Eudragit L” and “with an additional polymer in the
`
`pellet core providing prolonged release after removal of the Eudragit L coating.”
`
`(Id.).
`
`42.
`
`
`
`A. Without Food
`
`43.
`
`The term “without food” should be construed to mean “without a
`
`meal”. The claim language recites, a method of “administering to the subject a
`
`granulated mesalamine formulation . . . without food”. (Ex. 1001, ‘688 Patent col.
`
`34:10-15).
`
`44.
`
`The specification supports this construction. The specification
`
`suggests that “without food” means “without a high-fat meal.” The specification
`
`discloses examples that allegedly studied the “effect of food intake on 5-ASA
`
`absorption.” (Ex. 1001, ‘688 Patent col. 16:53-55). Example 1 describes a study
`
`of the pharmacokinetics of 5-ASA and its metabolite (N—Ac-5-ASA) under
`
`“fasting conditions.” (Ex. 1001, ‘688 Patent col. 14:10-15). Subjects received
`
`granulated mesalamine either following an “overnight fast or a high-fat meal”.
`
`(Ex. 1001, ‘688 Patent col. 14:61-63).
`
` Similarly, Example 4 describes
`
`administration of granulated mesalamine to subjects either “following an overnight
`
`fast or a high-fat meal”. (Ex. 1001, ‘688 Patent col. 16:54-55). Bell Atlantic
`
`Network Services, Inc. v. Convad Communications, Inc., 262 F.3d 1258, 1271 (Fed
`
`20
`
`
`
`
`
`
`
`Cir. 2001) (“when a patentee uses a claim term throughout the entire patent
`
`specification, in a manner consistent with only a single meaning, he has defined
`
`that term by implication”) (citations omitted)). A person of ordinary skill at the
`
`time of the ‘688 Patent filing would understand “fasting conditions” to yield an
`
`empty stomach.
`
`45.
`
`The prosecution history also supports this construction. During
`
`prosecution, the Applicant repeatedly distinguished a “meal” with the claimed
`
`requirement of administering granulated mesalamine “without food”. For instance,
`
`after amending the claim to require that granulated mesalamine is taken “with or
`
`without food,” the Applicant distinguished over the prior art (including other 5-
`
`ASA prodrugs) on the ground that his invention can be “administered without
`
`regard to meals (i.e., with or without food)”. (Ex. 1016, FH688, Amendment
`
`5/9/14 at 7). The Applicant also distinguished over other 5-ASA prodrugs by
`
`equating “with food” with “at the same time as the subject has a meal”. (Ex. 1017,
`
`FH688, Amendment 6/20/14 at 6-7). Subsequently, after amending the claim to
`
`require administration of granulated mesalamine “without food,” the Applicant
`
`distinguished the invention from a prior art formulation (Lialda®) on the ground
`
`that Lialda® was prescribed to be taken “with food” or “with a meal”. (Ex. 1017,
`
`FH688, Amendment 6/20/14 at 6).
`
`46.
`
`Accordingly, a person ordinary skill would understand from both the
`
`21
`
`
`
`
`
`
`
`‘688 Patent’s specification and prosecution history that, in the course of amending
`
`the challenged claims to require mesalamine administration “without food”, the
`
`Applicant clearly and unmistakably disclaimed embodiments of “without food”
`
`that did not comprise, or amount to, a “meal”.
`
`47.
`
`Thus, in light of the foregoing statements during prosecution,
`
`Applicant unequivocally disavowed embodiments of “without food” that comprise
`
`less than “without a meal”. See Biogen Idec, Inc. v. GlaxoSmithKline LLC, 713
`
`F.3d 1090, 1095 (Fed. Cir. 2013) (“when the patentee unequivocally and
`
`unambiguously disavows a certain meaning to obtain a patent, the doctrine of
`
`prosecution history disclaimer narrows the meaning of the claim consistent with
`
`the scope of the claim surrendered”). The fact that Applicant may have
`
`surrendered more than was necessary for allowance is besides the point; the
`
`statements nevertheless “shed light on what the applicant meant by its various
`
`terms.” Uship Intellectual Props., LLC v. United States, 714 F.3d 1311, 1316
`
`(Fed. Cir. 2013).
`
`B. Granulated Mesalamine Formulation
`
`48.
`
`The term “granulated mesalamine formulation” should be construed
`
`to mean a mesalamine formulation with a pH dependent enteric coating around a
`
`polymer matrix core.
`
`49.
`
`During prosecution, Applicant repeatedly distinguished the claimed
`
`22
`
`
`
`
`
`
`
`“granulated mesalamine formulation” over the prior art on the ground that it
`
`contained a pH dependent enteric coating around a polymer matrix core. For
`
`instance, Applicant specifically distinguished the claims over a cited prior art
`
`reference, NetDoctor. NetDoctor taught a prior art mesalamine formulation called
`
`Asacol. Applicant pointed out to the Examiner that “the chemical makeup of both
`
`formulations [the claimed formulation and Asacol], and consequently, as is
`
`evidenced by Applicants’ specificatio
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
