UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2022-01102 - Patent No. 9,610,321
`Case No. IPR2022-01103 - Patent No. 9,616,097
`Case No. IPR2022-01104 - Patent No. 9,919,024
`Case No. IPR2022-01105 - Patent No. 9,925,231
`_____________________________
`
`DECLARATION OF GRAHAM BUCKTON, PH.D.
`
`MYLAN - EXHIBIT 1002
`
`

`

`TABLE OF CONTENTS
`
` Page
`QUALIFICATIONS............................................................................................... 1
`
`SCOPE OF WORK ............................................................................................... 4
`
`I.
`
`II.
`
`III.
`
`LEGAL PRINCIPLES ............................................................................................ 6
`
`IV. OVERVIEW OF THE CHALLENGED PATENTS ...................................................... 9
`
`Claims of the ’231 Patent .........................................................................14
`
`Claims of the ’097 Patent .........................................................................15
`
`Claims of the ’024 Patent .........................................................................18
`
`Claims of the ’321 Patent .........................................................................23
`
`Claim Comparison ....................................................................................27
`
`Prosecution Histories ................................................................................29
`
`1. The ’231 and ’024 patents ...................................................................31
`
`2. The ’097 Patent ...................................................................................31
`
`3. The ’321 Patent ...................................................................................37
`
`V.
`
`THE LEVEL OF ORDINARY SKILL IN THE ART .................................................. 40
`
`VI. CLAIM TERMS ................................................................................................. 41
`
`VII. THE STATE OF THE ART .................................................................................. 43
`
`VIII. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE
`CLAIMED FEATURES OF THE CHALLENGED PATENTS ...................................... 53
`
`Asserted Reference Summaries ................................................................53
`
`1. Shailubhai ............................................................................................53
`
`2. Remington ...........................................................................................55
`
`-i-
`
`

`

`3. Mihranyan ...........................................................................................56
`
`4. Aulton 56
`
`5. The 2009 Abstract ...............................................................................56
`
`6. Doelker ................................................................................................57
`
`7. Zimmer ................................................................................................58
`
`8. Camilleri ..............................................................................................59
`
`9. Currie 60
`
`Each Challenged Claim Was Obvious from the Prior Art .......................60
`
`1. The ’231 Patent ...................................................................................61
`
`2. The ’097 Patent .................................................................................117
`
`3. The ’024 Patent .................................................................................141
`
`4. The ’321 Patent .................................................................................175
`
`IX.
`
`X.
`
`SECONDARY CONSIDERATIONS ..................................................................... 198
`
`CONCLUDING STATEMENTS .......................................................................... 205
`
`XI. APPENDIX – LIST OF EXHIBITS ..................................................................... 206
`
`-ii-
`
`

`

`I, Graham Buckton, declare as follows:
`
`I. QUALIFICATIONS
`
` I am an Emeritus Professor of Pharmaceutics of the UCL School of
`
`Pharmacy of the University of London. I was employed at the School of Pharmacy
`
`of the University of London from 1988 to 2015, initially as Lecturer, then Senior
`
`Lecturer, Reader and Professor. I served as the Head of the Department of
`
`Pharmaceutics between January 2001 and April 2007. I served as Chair of the
`
`Master of Sciences in Pharmacy (MPharm) Exam Board between 2002 and 2012. I
`
`have been an MPharm (or Bachelors in Pharmacy, BPharm) Examiner at Queens
`
`University of Belfast, Cardiff University, University of Nottingham, Kings
`
`College, University of Colombo in Sri Lanka, Robert Gordon University, and the
`
`University of East Anglia. I received my Ph.D. in Pharmaceutics from Kings
`
`College London in 1985.
`
`In addition to my academic experience, I have extensive practical
`
`experience in formulation development. In 2000 I founded a contract services
`
`company called Pharmaterials Ltd. I sold the majority stake to a U.S. company,
`
`Pharmaceutics International Inc. (PII), in 2008 and the remaining stake in 2012, at
`
`which time I exited. I was Chief Executive Officer from 2000-2012. Pharmaterials
`
`carried out materials characterisation, salt selection, polymorph screening, pre-
`
`-1-
`
`

`

`formulation, formulation development, assay development, clinical trials, and
`
`manufacturing.
`
`I served on the Committee on Safety of Medicines (CSM), which is
`
`the body in the United Kingdom that grants (and revokes) marketing authorizations
`
`(the equivalent of the FDA in the US), and I chaired its Chemistry, Pharmacy and
`
`Standards (CPS) sub-committee. I remain a member of CPS of the Commission on
`
`Human Medicines (a renamed version of CSM). I have been a member of the
`
`British Pharmacopoeia Commission and have been a member of working parties
`
`for the European and the United States Pharmacopoeias.
`
`I have consulted in the fields of physical form and formulation
`
`development for companies in Europe, USA, and India.
`
`My research has focused on investigating the behaviour of
`
`pharmaceutical materials. Applications of my research include studies of surface
`
`interactions, adaptation of physical properties of powders by crystallisation and
`
`physical manipulation such as milling, and the preparation of drug dosage forms
`
`including solid oral-dosage forms and inhalation dosage forms. I also organised the
`
`Royal Pharmaceutical Society of Great Britain (RPSGB) course on Tabletting
`
`Technology every year between 1989-2004, and invited industrial colleagues to
`
`assist with the teaching. I gave many lectures during the period as organiser and
`
`-2-
`
`

`

`continued giving many lectures on this course each year up to and including the
`
`2017 event.
`
` My research has been funded by such organisations as the
`
`Engineering and Physical Sciences Research Council, Pfizer, AstraZeneca, GSK,
`
`and Novartis, as well as other foundations and companies in industry.
`
`I served a 10-year term as Editor of the International Journal of
`
`Pharmaceutics and have been a member of the editorial boards of a number of
`
`journals, including Pharmaceutical Research, the American Association of
`
`Pharmaceutical Scientists (AAPS) Journal and AAPS Pharm SciTec.
`
`I have authored a book on Interfacial Phenomena in Drug Delivery
`
`and Targeting. I have also authored or co-authored over 180 peer-reviewed journal
`
`papers, many of which present original research related to solid dosage forms. In
`
`addition, I have authored or co-authored more than 100 abstracts and book
`
`reviews. I am listed as an inventor on six patents or patent applications.
`
`Additionally, I have lectured at over 130 conferences, seminars, and symposia
`
`around the world and have served as a testifying expert witness in 18 cases.
`
`I have received numerous awards and honours, specifically, the
`
`appointment in 2003 as the Science Chairman for the British Pharmaceutical
`
`Conference, the first recipient of the Academy of Pharmaceutical Sciences Medal
`
`in 2000, the 1998 Stig Sunner Award, the 1998 Foss Near Infrared European Users
`
`-3-
`
`

`

`Group Award, the 1993 British Pharmaceutical Conference Science Medal, and the
`
`1992 Pfizer Award for “excellence in published research.”
`
`For a more detailed listing of my credentials and publications, please
`
`see my curriculum vitae. EX1003.
`
`II. SCOPE OF WORK
`
`I understand a petition has been filed with the United States Patent
`
`and Trademark Office requesting Inter Partes Review of each of U.S. Patent Nos.
`
`9,616,097 (“’097 patent”; IPR2022-01103), 9,610,321 (“’321 patent”; IPR2022-
`
`01102), 9,919,024 (“’024 patent”; IPR2022-01104), and 9,925,231 (“’231 patent”;
`
`IPR2022-01105) (together, “the challenged patents”). I understand these petitions
`
`were filed on behalf of Mylan Pharmaceuticals Inc. (“Mylan”). I understand the
`
`challenged patents are currently assigned to Bausch Health Ireland Limited
`
`(“Bausch”). For simplicity, I shall use “Bausch” to refer to Bausch’s predecessors
`
`as well.
`
`Mylan retained me as a technical expert in all four proceedings to
`
`provide opinions regarding the challenged patents. Over the course of the past 10
`
`years I have served as an expert witness for Mylan in In re Sitagliptin Phosphate
`
`(’708 & ’921) Patent Litigation, 1:19-md-02902 (DDE) (sitagliptin phosphate);
`
`Mylan Technologies v. MonoSol Rx, IPR2017-00200 (film-based drug delivery);
`
`Janssen Products v. Lupin Ltd., 2:10-cv-05954 (DNJ) (darunavir tablets); Warner
`
`-4-
`
`

`

`Chilcott Laboratories Ireland v. Impax Laboratories, 2:08-cv-06304 (DNJ)
`
`(modified release formulations); Eisai Co. v. Glenmark Pharms., Ltd., 13-1279-
`
`LPS (DDE) (rufinamide polymorphs); Actavis Group PTC EHF v. ICOS Corp,
`
`[2016] EWHC 1955 (Pat) (tadalafil formulation); Noven Pharms. Inc., v. Mylan
`
`Techs. Inc., 1:15-CV-194 (NDWV) (methylphenidate transdermal patch). I do not
`
`have any current or past affiliation with Bausch.
`
`I have been specifically asked to provide my expert opinions on the
`
`validity of claims 1-12 of the ’097 patent, claims 1-16 of the ’321 patent, claims 1-
`
`16 of the ’024 patent, and claims 1-12 of the ’231 patent (together, “the challenged
`
`claims”). In connection with my analyses, I have reviewed each of the challenged
`
`patents and their prosecution histories. I have also reviewed and considered various
`
`other documents in arriving at my opinions and may cite to them in this
`
`declaration. For convenience, I list additional documents that I considered in
`
`arriving at my opinions in Section XI.
`
`In preparing my declaration, I have also reviewed the declaration of
`
`Dr. Uwe Christians, M.D., Ph.D., who has opined on various clinical aspects of the
`
`claimed formulations, including the obviousness of the claimed dosage amounts, as
`
`well as their use in the treatment of medical conditions such as chronic
`
`constipation, irritable bowel syndrome (“IBS”), and related symptoms. See
`
`-5-
`
`

`

`EX1004. I include some quotations from Dr. Christians’s analysis in my own
`
`analysis of the claims.
`
`I understand this declaration will be submitted in all four IPR
`
`proceedings. In citing EX1001, which is different across the four cases, I have
`
`noted which case includes the material I am citing (e.g., EX1001 (’231 Patent),
`
`claim 1). If a citation is the same across the four cases, I have not added a case-
`
`specific designation (e.g., EX1006 (Remington), 889-91).
`
`Mylan is compensating me £500 per hour for my services. No part of
`
`my compensation depends opinions or on the outcome of this proceeding.
`
`III. LEGAL PRINCIPLES
`
`I have been advised that the burden in this proceeding is on the
`
`petitioner (Mylan) to demonstrate the unpatentability of the challenged claims.
`
`I have been advised that a claimed invention is not patentable under
`
`35 U.S.C. §102 (anticipation) if every element of the claim is disclosed, either
`
`expressly or inherently, as arranged in the claim in a single prior-art reference.
`
`I have also been advised that a claimed invention is not patentable
`
`under 35 U.S.C. §103 (obviousness) if the differences between the claimed
`
`invention and the prior art are such that the subject matter as a whole would have
`
`been obvious at the time the claimed invention was made to the person of ordinary
`
`skill in the art (“POSA”) to which the subject matter pertains.
`
`-6-
`
`

`

`I understand that a determination of obviousness requires inquiries
`
`into: (i) the scope and content of the art when the claimed invention was made; (ii)
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the claimed invention was made; and, to the extent
`
`any exist, (iv) secondary considerations indicating non-obviousness.
`
`I understand that hindsight must not be used when comparing the
`
`prior art to the claimed invention for obviousness. Thus, a conclusion of
`
`obviousness must be firmly based on the knowledge and skill of the POSA at the
`
`time the claimed invention was made, without the use of post-filing knowledge.
`
`I understand that for a claimed invention to be considered obvious,
`
`there must be some rational underpinning for combining cited references as
`
`proposed.
`
`I further understand that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the claimed invention. Obviousness may be shown by
`
`demonstrating that the POSA would have considered it obvious to combine the
`
`teachings of more than one element disclosed by prior art. I understand that the
`
`following examples are approaches and rationales that may be considered in
`
`determining whether a piece of prior art could have been combined with other prior
`
`art or with other information within a POSA’s knowledge:
`
`-7-
`
`

`

`(a)
`
`combining prior-art elements according to known methods to yield
`
`predictable results;
`
`(b)
`
`substituting one known element for another to obtain predictable
`
`results;
`
`(c)
`
`using a known technique to improve similar devices (methods, or
`
`products) in the same way;
`
`(d)
`
`applying a known technique to a known device (method, or product)
`
`that was ready for improvement to yield predictable results;
`
`(e)
`
`applying a technique or approach that would have been “obvious to
`
`try” (i.e., choosing something from a finite number of identified,
`
`predictable solutions, with a reasonable expectation of success);
`
`(f)
`
`applying variations based on known work in one field of endeavour
`
`for use in either the same field or a different one, based on design
`
`incentives or other market forces, if the variations would have been
`
`predictable to one of ordinary skill in the art; or
`
`(g)
`
`acting upon some teaching, suggestion, or motivation in the prior art
`
`to modify the prior-art reference or to combine prior-art reference
`
`teachings thereby arriving at the claimed invention.
`
`I have been instructed that secondary considerations, when in
`
`evidence, may include: (i) commercial success of a product due to the merits of the
`
`-8-
`
`

`

`claimed invention; (ii) a long-felt, but unsatisfied need for the claimed invention;
`
`(iii) failure of others to find the solution provided by the claimed invention;
`
`(iv) deliberate copying of the claimed invention by others; (v) unexpected results
`
`achieved by the claimed invention; (vi) praise of the claimed invention by others
`
`skilled in the art; (vii) lack of independent simultaneous invention within a
`
`comparatively short span of time; and (viii) teaching away from the claimed
`
`invention in the prior art. I am informed that secondary considerations are relevant
`
`where there is a nexus between the evidence and the claimed invention.
`
`I am informed that Bausch bears the burden to establish any
`
`secondary considerations indicating non-obviousness. I am further informed that
`
`for anticipation secondary considerations are not relevant and that for obviousness
`
`they must be clearly linked to a claimed feature or features not already known in
`
`the prior art.
`
`IV. OVERVIEW OF THE CHALLENGED PATENTS
`
`All four of the challenged patents are entitled “Formulations of
`
`Guanylate Cyclase C Agonists and Methods of Use.” EX1001, Title. I understand
`
`the challenged patents also share a claimed priority date of September 15, 2011.
`
`Id., [60]; see Section IV.F, below (discussing priority dates in more detail).
`
`The challenged patents are generally directed to an oral-dosage
`
`formulation consisting of a known peptide, an “inert low moisture carrier,” and a
`
`-9-
`
`

`

`lubricant, and methods of treatment using the same. EX1001, cover [54], [57]. The
`
`claimed composition should have a “chromatographic purity of no less than 91%
`
`after storage for at least three months.” Id., claim 1.
`
`I note that while the challenged claims recite a chromatographic purity
`
`of 91% after three months of storage, the disclosures never suggest this degree of
`
`purity is critical. Nor does the specification provide any data supporting this claim
`
`limitation. Instead, the specification provides stability data for a formulation
`
`consisting of the recited peptide, Avicel PH102 (an inert carrier that Bausch
`
`distinguished in earlier prosecution as not a low-moisture carrier), and magnesium
`
`stearate. EX1001, Examples 11 & 12; see also EX1022 (’097 File History), 0382-
`
`86.
`
`I note that the challenged patents also acknowledge several known
`
`aspects concerning the recited formulation. For example, the challenged patents
`
`acknowledge that the GCC-agonist peptides of interest, including SEQ ID NO:1
`
`(referred to as “SP-304” and “plecanatide”) were already known and disclosed in
`
`-10-
`
`

`

`the prior art. EX1001 (’231 Patent)1, 3:59-65, 21:62-22:4, 26:58-64, 25:58-66,
`
`27:18-23. They also acknowledge that methods for preparing GCC-agonist cyclic
`
`peptides were known in the art. Id., 27:26-28:40, 29:7-10, 29:7-30:62.
`
`The challenged patents assert that the “invention is also based in part
`
`upon the discovery that a divalent cation (e.g., Ca2+) and/or an amino acid (e.g.,
`
`leucine or arginine) stabilise the GCC agonist peptides…provid[ing] stability
`
`against degradation both during the manufacturing process and storage of the
`
`formulation” EX1001 (’231 Patent), 7:34-41. However, neither a divalent cation
`
`nor a stabilising amino acid is present in the claimed formulation sufficient for
`
`providing this described stabilisation.2 Moreover, the stabilising nature of such
`
`1 All four challenged patents possess substantially the same specification
`
`disclosures. I have provided direct citations to the ’231 Patent as a representative
`
`disclosure for each of the challenged patents.
`
`2 I note that the claimed formulations contain magnesium stearate, which
`
`includes a divalent cation (Mg2+). However, magnesium stearate is used as a
`
`lubricant, and not to provide the described stabilisation role. See EX1022 (’097
`
`File History), 4477 (asserting claims of the ’097 parent patent exclude a divalent
`
`cation).
`
`-11-
`
`

`

`excipients was already known and disclosed elsewhere. See, e.g., EX1012
`
`(Fretzen3), Examples 22 (providing storage stability data for the formulations in
`
`Examples 1-15 and 17, many of which comprise a GCC agonist, a divalent cation,
`
`and a stabilising amino acid) & 54 (similar, for formulations of Examples 27-53). I
`
`also understand that Bausch distinguished formulations comprising these
`
`additional excipients during prosecution of a parent application. See EX1022 (’097
`
`File History), 5086-87.
`
`I understand that Dr. Christians also notes that:
`
`The peptide of interest, plecanatide, was known before the challenged
`patents—a fact that the patents themselves admit. EX1001 (’231
`Patent), 3:59-65, 21:62-22:4, 25:58-66, 27:18-23; see also id., 27:26-
`28:40, 29:7-10, 29:7-30:62 (noting methods of preparing this peptide
`were also known). The challenged patents also acknowledge that the
`mechanism of action of guanylate cyclase-c (“GCC”) peptides and
`biology involved in conditions such as chronic constipation and IBS
`were known. Id., 2:40-42. Notably, the challenged patents do not
`
`3 A. Fretzen et al., Stable Solid Formulation of a GC-C Receptor Agonist
`
`Polypeptide Suitable for Oral Administration, WO 2010/019266, published
`
`February 18, 2010 (“Fretzen,” EX1012).
`
`-12-
`
`

`

`purport to elucidate any additional information regarding the “precise
`causes of IBS and inflammatory bowel diseases.” Id., 2:44-45.
`
`EX1004 (Christians Declaration), ¶25.
`
`Dr. Christians also notes that:
`
`The challenged patents further assert that the “invention is also based
`in part on the discovery that very low doses of the GCC agonist peptides
`described herein are effective for the treatment of diseases and
`disorders in humans.” EX1001 (’231 patent), 7:30-33. I note, however,
`that two of the four patents (the ’231 and ’024 Patents) do not recite
`dosage amounts and two of the four patents (the ’231 and ’097 Patents)
`do not recite the treatment of a particular disease or disorder.
`Nevertheless, the challenged patents assert that the “dosage range found
`to be effective was not predicted based on animal studies.” Id.
`
`EX1004 (Christians Declaration), ¶26.
`
`Dr. Christians explains that:
`
`[T]he dosing was found based on routine dose ranging studies,
`consistent with applicable FDA guidelines. As a clinical
`pharmacologist, this is the sort of work I engage in today, as well as in
`2011 and well before. Moreover, while unexpected deviations in
`dosing might have occurred earlier in the process when converting
`animal model doses to human dose trials, this did not happen here.
`Indeed, the doses are the same order of magnitude as what was found
`
`-13-
`
`

`

`to be effective in a proof-of-concept mouse study. See EX1014
`(Hegazi4); EX1015 (CDER Guidance5).
`EX1004 (Christians Declaration), ¶197.
`
`Claims of the ’231 Patent
`
`The ’231 patent includes 12 claims. Only the first claim is
`
`independent. The remaining claims all depend directly or indirectly from claim 1. I
`
`understand a dependent claim includes all limitations of the claim from which it
`
`depends.
`
`Each claim is directed to the same composition consisting of a known
`
`peptide, an inert low-moisture carrier, and a lubricant. In addition, all claims
`
`include a purity limitation, the claimed composition has a chromatographic purity
`
`of no less than 91% after storage for at least three months.
`
`Independent claim 1, for example, recites:
`
`4 R. Hegazi et al., Sp304, An Anolog of Uroguanylin, Ameliorates Inflammation
`
`in a Model of Experimental Colitis, Abstract M1696, AGA Abstracts, A-351
`
`(2006) (“Hegazi,” EX1014).
`
`5 CDER, Guidance for Industry: Estimating the Maximum Safe Starting Dose in
`
`Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005)
`
`(“CDER Guidance,” EX1015).
`
`-14-
`
`

`

`1. An oral dosage formulation of a Guanylate Cyclase-C (GCC)
`agonist peptide consisting of SEQ ID NO:1, wherein said peptide is a
`(4,12; 7,15) bicycle, an inert low moisture carrier and a lubricant,
`wherein the peptide has a chromatographic purity of no less than 91%
`after storage for at least three months.
`
`Claims 2, 3, and 5 each depend directly from claim 1 and recite
`
`limitations relating to purity or stability against degradation.
`
`Claims 4 and 6 each depend directly from claim 1 and recite
`
`limitations relating to the composition being in, e.g., a capsule or tablet form.
`
`Claim 7 depends from claim 6 and recites that the capsule or tablet is in a blister
`
`pack or strip.
`
`Claims 8 and 9 each depend directly from claim 1 and recite
`
`limitations relating to the lubricant. Claims 10-12 each depend directly from claim
`
`1 and recite limitations relating to the inert carrier.
`
`As I set forth in more detail below, each of these formulation
`
`components and properties were known in the prior art well before the ’231 patent.
`
`Claims of the ’097 Patent
`
`The ’097 patent also includes 12 claims and, again, only the first
`
`claim is independent. The claims of the ’097 patent are almost identical to those of
`
`the ’231 patent, discussed above in Section IV.A. I provide a table below
`
`comparing the two patents’ claims, highlighting the sole difference in red.
`
`-15-
`
`

`

`’231 PATENT CLAIM
`1. An oral dosage formulation of a
`Guanylate Cyclase-C (GCC) agonist
`peptide consisting of SEQ ID NO:1
`wherein the peptide is a (4,12; 7,15)
`bicycle, an inert low moisture, and a
`lubricant, wherein the peptide has a
`chromatographic purity of no less
`than 91% after storage for at least
`three months.
`
`2. The oral dosage formulation of
`claim 1, wherein the GCC agonist
`peptide has a chromatographic purity
`of no less than 92% to 95%.
`3. The oral dosage formulation of
`claim 1, wherein the formulation
`contains less than 0.2% inorganic
`acids and carboxylic acids.
`4. The oral dosage formulation of
`claim 1, wherein the formulation is a
`solid formulation and the unit dose is
`powder, granule, sachet, troche,
`tablet, or capsule.
`5. The oral dosage formulation of
`
`’097 PATENT CLAIM
`1. An oral dosage formulation of a
`Guanylate Cyclase-C (GCC) agonist
`peptide consisting of a per unit dose
`of 3.0 mg or 6.0 mg of a peptide
`consisting of SEQ ID NO:1 wherein
`the peptide is a (4,12; 7,15) bicycle,
`an inert low moisture, and a
`lubricant, wherein the peptide has a
`chromatographic purity of no less
`than 91% after storage for at least
`three months.
`2. The oral dosage formulation of
`claim 1, wherein the GCC agonist
`peptide has a chromatographic purity
`of no less than 92% to 95%.
`3. The oral dosage formulation of
`claim 1, wherein the formulation
`contains less than 0.2% inorganic
`acids and carboxylic acids.
`4. The oral dosage formulation of
`claim 1, wherein the formulation is a
`solid formulation and the unit dose is
`powder, granule, sachet, troche,
`tablet, or capsule.
`5. The oral dosage formulation of
`
`-16-
`
`

`

`’231 PATENT CLAIM
`claim 1, wherein the GCC agonist
`peptide is stabilized against
`degradation for a period of at least 18
`months at 30 ˚C. and 65% relative
`humidity, or at least 18 months at 25
`˚C. and 60% relative humidity, or at
`least 18 months at 2-8 ˚C.
`6. The oral dosage formulation of
`claim 1, wherein the formulation is
`in the form of a capsule or tablet.
`7. The oral dosage formulation of
`claim 6, wherein the capsule or tablet
`is in a blister pack or strip.
`8. The oral dosage formulation of
`claim 1, wherein the lubricant is
`magnesium stearate.
`9. The oral dosage formulation of
`claim 1, wherein the lubricant is at
`0.25% (w/w).
`10. The oral dosage formulation of
`claim 1, wherein the inert carrier is
`microcrystalline cellulose.
`11. The oral dosage formulation of
`claim 1, wherein the inert carrier is at
`
`’097 PATENT CLAIM
`claim 1, wherein the GCC agonist
`peptide is stabilized against
`degradation for a period of at least
`18 months at 30 ˚C. and 65% relative
`humidity, or at least 18 months at 25
`˚C. and 60% relative humidity, or at
`least 18 months at 2-8 ˚C.
`6. The oral dosage formulation of
`claim 1, wherein the formulation is
`in the form of a capsule or tablet.
`7. The oral dosage formulation of
`claim 6, wherein the capsule or tablet
`is in a blister pack or strip.
`8. The oral dosage formulation of
`claim 1, wherein the lubricant is
`magnesium stearate.
`9. The oral dosage formulation of
`claim 1, wherein the lubricant is at
`0.25% (w/w).
`10. The oral dosage formulation of
`claim 1, wherein the inert carrier is
`microcrystalline cellulose.
`11. The oral dosage formulation of
`claim 1, wherein the inert carrier is
`
`-17-
`
`

`

`’231 PATENT CLAIM
`least 96% (w/w).
`12. The oral dosage formulation of
`claim 1, wherein the inert carrier has
`a particle size of from 50 to 900
`microns.
`
`’097 PATENT CLAIM
`at least 96% (w/w).
`12. The oral dosage formulation of
`claim 1, wherein the inert carrier has
`a particle size of from 50 to 900
`microns.
`
`Thus, the only difference between the claims of the ’097 patent and
`
`those of the ’231 patent is that independent claim 1 of the ’097 patent recites
`
`dosage amounts in a known range of the known peptide.
`
`Claims of the ’024 Patent
`
`The ’024 patent includes 16 claims. Claims 1 and 3 are independent,
`
`while the remaining claims all depend directly or indirectly from one of these two
`
`independent claims.
`
`Unlike the ’231 and ’097 patents, the claims of the ’024 patent are
`
`directed towards methods of treatment. However, each claim of the ’024 patent
`
`still recites administration of the same composition consisting of the known
`
`peptide, the inert low-moisture carrier, and the lubricant. In addition, all claims
`
`again include a basic purity limitation, where the claimed composition has a
`
`chromatographic purity of no less than 91% after storage for at least three months.
`
`Independent claims 1 and 3 recite substantively similar claim
`
`limitations. To illustrate the differences between the claims, I have provided a
`
`-18-
`
`

`

`chart below that compares their limitations. As can be seen below, the only
`
`difference between claims 1 and 3 resides in the claims’ preambles in Elements
`
`1.[a] and 3.[a]. The remaining claim Elements 1.[b]-[d] and 3.[b]-[d] are identical.
`
`CLAIM 1
`ELEMENT
`NUMBER
`
`CLAIM 1
`
`CLAIM 3
`
`CLAIM 3
`ELEMENT
`NUMBER
`
`A method for treating
`chronic constipation in
`a human subject
`comprising orally
`administering to said
`human subject a
`composition consisting
`of SEQ ID NO:1
`wherein the peptide is a
`[4,12; 7,15] bicycle,
`
`1.[a]
`
`1.[b]
`
`1.[c]
`
`1.[d]
`
`an inert low moisture
`carrier,
`and a lubricant,
`and wherein the
`peptide has a
`
`A method of treating
`or alleviating a
`symptom associated
`with chronic
`idiopathic constipation
`or irritable bowel
`syndrome in a human
`subject comprising
`orally administering to
`said human subject a
`composition consisting
`of SEQ ID NO:1
`wherein the peptide is a
`[4,12; 7,15] bicycle,
`an inert low moisture
`carrier,
`and a lubricant,
`and wherein the
`peptide has a
`
`3.[a]
`
`3.[b]
`
`3.[c]
`
`3.[d]
`
`-19-
`
`

`

`CLAIM 1
`ELEMENT
`NUMBER
`
`CLAIM 3
`ELEMENT
`NUMBER
`
`CLAIM 1
`
`CLAIM 3
`
`chromatographic purity
`of no less than 91%
`after storage for at least
`three months.
`
`chromatographic purity
`of no less than 91%
`after storage for at least
`three months.
`
`Dependent claims 2, 5-11, and 11-13 depend directly or indirectly
`
`from claim 1 and merely recite known conditions associated with constipation,
`
`known formulation components, or the additional administration of other known
`
`treatments for constipation (such as a laxative). Dependent claims 4, 8-10, and 14-
`
`16 depend directly or indirectly from claim 3, and recite substantially the same
`
`limitations as the other dependent claims. To illustrate the differences between
`
`these two groups of dependent claims, I have provided a chart below that compares
`
`their limitations. As can be seen below, the only difference appears in comparing
`
`claim 2 to claim 4, while the remaining dependent claim sets are identical. I
`
`discuss these limitations further in my detailed claim analysis below.
`
`CLAIM DEPENDS FROM CLAIM 1 DEPENDS FROM CLAIM 3 CLAIM
`The method of claim 1,
`The method of claim 3,
`wherein the symptom is
`wherein the constipation
`is associated with
`constipation or
`irritable bowel
`abdominal pain.
`
`4
`
`2
`
`-20-
`
`

`

`CLAIM DEPENDS FROM CLAIM 1 DEPENDS FROM CLAIM 3 CLAIM
`syndrome or chronic
`idiopathic constipation.
`The method of claim 1,
`further comprising
`administering to said
`patient an effective dose
`of an inhibitor of cGMP-
`dependent
`phosphodiesterase either
`concurrently or
`sequentially with said
`guanylate cyclase
`receptor agonist.
`The method of claim 5,
`wherein said inhibitor of
`cGMP-dependent
`phosphodiesterase is
`selected from the group
`consisting of sulindac
`sulfone, zaprinast, and
`motapizone.
`The method of claim 1,
`further comprising
`administering to said
`patient an effective dose
`
`The method of claim 3,
`further comprising
`administering to said
`patient an effective dose
`of an inhibitor of cGMP-
`dependent
`phosphodiesterase either
`concurrently or
`sequentially with said
`guanylate cyclase
`receptor agonist.
`The method of claim 8,
`wherein said inhibitor of
`cGMP-dependent
`phosphodiesterase is
`selected from the group
`consisting of sulindac
`sulfone, zaprinast, and
`motapizone.
`The method of claim 3,
`further compr