REDACTED PUBLIC VERSION
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`MSN LABORATORIES PRIVATE LTD.,
`and MSN PHARMACEUTICALS INC.
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`_____________________________
`
`IPR2022-007221
`Patent No. 7,041,786
`_____________________________
`
`DECLARATION OF MICHAEL S. EPSTEIN, M.D.
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`MYLAN EXHIBIT - 1064
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`MSN LABORATORIES PRIVATE LTD.,
`and MSN PHARMACEUTICALS INC.
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`_____________________________
`
`IPR2022-007221
`Patent No. 7,041,786
`_____________________________
`
`DECLARATION OF MICHAEL S. EPSTEIN, M.D.
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`MYLAN EXHIBIT - 1064
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`
`
`REDACTED PUBLIC VERSION
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`TABLE OF CONTENTS
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` Page
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`I.
`II.
`III.
`IV.
`V.
`VI.
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`QUALIFICATIONS............................................................................................... 1
`SCOPE OF WORK ............................................................................................... 2
`LEGAL STANDARDS .......................................................................................... 4
`LEVEL OF ORDINARY SKILL .............................................................................. 7
`THE GASTROINTESTINAL TRACT ....................................................................... 8
`TREATMENT OF THE SMALL INTESTINE WOULD HAVE BEEN
`UNDERSTOOD TO BE BENEFICIAL .................................................................... 14
`VII. TOPOISOMERISM WOULD NOT HAVE BEEN VIEWED AS A CONCERN .............. 16
`VIII. THE HIGHER POTENCY OF ENTEROTOXINS WOULD NOT HAVE BEEN
`VIEWED AS THE ONLY DESIRABLE STARTING POINT ...................................... 19
`PLECANATIDE’S BINDING AFFINITY, CGMP POTENCY, AND PH
`SENSITIVITY ARE NOT “UNEXPECTED” .......................................................... 22
`CONCLUDING STATEMENTS ............................................................................ 24
`X.
`XI. APPENDIX – LIST OF EXHIBITS ....................................................................... 25
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`IX.
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`I, Michael S. Epstein, declare as follows:
`
`I.
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`QUALIFICATIONS
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`1.
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`I am Founder and President of Investigative Clinical Research,
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`Founder and President of Maryland Diagnostic & Therapeutic Endo Center
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`(MDTEC), and Principal Physician at Gastro Health (formerly, Digestive
`
`Disorders Associates), all based in Annapolis, Maryland. I am currently licensed
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`to practice medicine in the state of Maryland and I am Board-certified with the
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`American Board of Internal Medicine, with a subspecialty in Gastroenterology.
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`2.
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`I obtained by Doctor of Medicine in 1981 at the Robert Wood
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`Johnson School of Medicine of the New Jersey College of Medicine and Dentistry
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`(which later merged with Rutgers University). I joined the Internship and
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`Residency Program at George Washington University Hospital and School of
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`Medicine and then a Fellowship in Gastroenterology and Hepatology at the
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`Veterans Administration Medical Center in Washington, D.C. Since then, I have
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`been a practicing gastroenterologist in the state of Maryland for more than thirty
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`years.
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`3.
`
`I am experienced as both a practicing physician and a clinical
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`researcher in the treatment of gastrointestinal (GI) disorders and diseases. For
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`instance, as a physician at Gastro Health, I regularly see patients who are
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`experiencing symptoms associated with chronic constipation, including those
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`diagnosed with chronic idiopathic constipation (CIC) and irritable bowel syndrome
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`with constipation (IBS-C). I am familiar with ordinarily-prescribed treatments
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`used to alleviate symptoms associated with chronic constipation and I often
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`prescribe such treatments to my patient. This includes, in some cases, prescription-
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`based treatments intended to relieve chronic constipation, including guanylate
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`cyclase-C (GCC) activators, such as plecanatide (Trulance®) and linaclotide
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`(Linzess®).
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`4.
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`Through my research facility, Investigative Clinical Research, I am
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`also experienced in the clinical development of treatments for those with CIC or
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`IBS-C, including study protocols testing the safety and efficacy of drugs like
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`plecanatide and linaclotide. I have also published several journal articles
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`discussing treatments for chronic constipation and irritable bowel syndrome.
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`5.
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`For a more detailed listing of my credentials and publications, please
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`see my curriculum vitae, EX1071.
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`II.
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`SCOPE OF WORK
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`6.
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`I understand that Mylan Pharmaceuticals Inc. (“Mylan”) filed a
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`petition with the United States Patent and Trademark Office for Inter Partes
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`Review of claims 1-6 of U.S. Patent No. 7,041,786 to Shailubhai (“Shailubhai,”
`
`EX1001). I also understand that the Patent Trial and Appeal Board instituted inter
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`partes review of the claims of Shailubhai. I understand that Patent Owner Bausch
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`Health Ireland Ltd. (“Bausch”) filed a Patent Owner Response to the petition. In
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`support of that response, I have been informed that Bausch has submitted, among
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`other things, the declaration of Dr. Scott A. Waldman (EX2025).
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`7.
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`I have been asked to review the declaration of Dr. Waldman and
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`provide my opinions regarding the testimony Dr. Waldman provides. In particular,
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`I have been asked to opine on Dr. Waldman’s testimony “regarding the state of the
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`art as of January 17, 2002,” including “information about the gastrointestinal (‘GI’)
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`tract; constipation, including chronic idiopathic constipation (‘CIC’) and irritable
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`bowel syndrome with constipation (‘IBS-C’); and guanylate cyclase C (‘GCC’)
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`receptors and ligands.” EX2025 (Waldman Declaration), ¶3. I have also been
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`asked to opine on Dr. Waldman’s testimony “regarding the activity of plecanatide
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`versus the activity of human uroguanylin.” Id., ¶4. In connection with this, I have
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`also reviewed the transcript of the deposition of Dr. Waldman (EX1062). I
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`understand that Dr. Waldman is “a clinical pharmacologist, physician, and
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`biomedical scientist,” but he is not Board-certified in internal medicine or certified
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`in the subspecialty of gastroenterology. EX2025 (Waldman Declaration), ¶6;
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`EX1062 (Waldman Deposition Transcript), 10:11-11:10.
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`8.
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`My opinions are based on my skills, knowledge, training, education,
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`and experience in matters of this nature, and my examination of the materials used
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`in preparing this testimony. For convenience, documents cited in this declaration
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`are listed in the Appendix in Section XI. My opinions are based on the current
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`record, so I reserve the ability to refine my opinions based on additional facts.
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`9.
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`Mylan is compensating me at the rate $750 per hour for my time spent
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`in connection with this declaration. No part of my compensation is dependent on
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`my opinions or the outcome of this proceeding, and I have no other financial
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`interest in the outcome of this matter.
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`III. LEGAL STANDARDS
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`10.
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`I have been advised that the burden in this proceeding is on Mylan to
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`demonstrate the unpatentability of the challenged claims.
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`11.
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` I have been advised that a claimed invention is not patentable for
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`obviousness if the differences between the claimed invention and the prior art are
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`such that the subject matter as a whole would have been obvious at the time the
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`claimed invention was made the person of ordinary skill in the art to which the
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`subject matter of the invention pertains.
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`12.
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`I understand that a determination of obviousness requires inquiries
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`into: (i) the scope and content of the art when the claimed invention was made;
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`(ii) the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the claimed invention was made; and, to the extent
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`any exist, (iv) secondary considerations indicating non-obviousness.
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`13.
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`I understand that hindsight must not be used when comparing the
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`prior art to the claimed invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on the knowledge and skill of the artisan at the
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`time the claimed invention was made, without the use of post-filing knowledge.
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`14.
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`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some rational underpinning for combining cited references
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`as proposed. I further understand that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the claimed invention. Obviousness may be shown by
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`demonstrating that the skilled artisan would have found it obvious to combine the
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`teachings of more than one element disclosed by prior art.
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`15.
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`I understand that the following examples are approaches and
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`rationales that may be considered in determining whether a piece of prior art could
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`have been combined with other prior art or with other information within a skilled
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`artisan’s knowledge:
`
`(i)
`
`(ii)
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`combining prior-art elements according to known methods to yield
`predictable results;
`substituting one known element for another to obtain predictable
`results;
`(iii) using a known technique to improve similar devices (methods, or
`products) in the same way;
`(iv) applying a known technique to a known device (method, or product)
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`(v)
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`that was ready for improvement to yield predictable results;
`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);
`(vi) applying variations based on known work in one field of endeavor 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
`(vii) 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” will be
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`16.
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`considered when present. Counsel have informed me that such secondary
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`considerations, where evident, may include: (i) commercial success of a product
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`due to the merits of the claimed invention; (ii) a long-felt but unsatisfied need for
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`the claimed invention; (iii) failure of others to find the solution provided by the
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`claimed invention; (iv) deliberate copying of the claimed invention by others; (v)
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`unexpected results achieved by the claimed invention; (vi) praise of the claimed
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`invention by others skilled in the art; (vii) lack of independent, simultaneous
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`invention within a comparatively short span of time; and (viii) teaching away from
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`the claimed invention in the prior art. I am informed that secondary considerations
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`are relevant where there is a nexus between the evidence and the claimed
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`invention.
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`17.
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`I am informed that the patent owner, Bausch Health Ireland Ltd.
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`(“Bausch”), bears the burden to establish any secondary considerations indicating
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`non-obviousness.
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`IV. LEVEL OF ORDINARY SKILL
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`18.
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`I have been advised that the person of ordinary skill in the art is a
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`hypothetical person who is presumed to have known the relevant art at the time of
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`the claimed invention. The skilled artisan is also a person of ordinary creativity. I
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`have been advised that the skilled artisan is someone to whom one could assign a
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`routine task with reasonable confidence that the task would be successfully carried
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`out.
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`19.
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`I have been advised that the relevant timeframe for my analysis is the
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`time period prior to January 17, 2002. Unless otherwise specifically noted, all of
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`my opinions expressed here regarding the skilled artisan apply to the skilled artisan
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`as of January 17, 2002.
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`20.
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`I have been advised that Mylan has stated that a skilled artisan as of
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`January 17, 2002, would typically have a Ph.D. in chemistry or protein engineering
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`or a related field. Skilled artisans could also include individuals with a master’s
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`degree in one of these fields plus two-to-five years of experience in drug
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`development. This individual would have worked in consultation with a team
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`including, e.g., a pharmaceutical chemist or a pharmacist familiar with formulating
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`peptides for administration.
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`21.
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`I have also been advised that Bausch has stated that a person of
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`ordinary skill in the art would have a B.S. degree in chemistry or a related field and
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`2-5 years of experience in drug development that could include experience with
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`peptide chemistry and/or peptide engineering. The person of ordinary skill could
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`have worked in consultation with individuals with knowledge and experience with
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`the target drug receptor and of the disease condition to be treated. This team could
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`include a clinical pharmacologist with experience with the target drug receptor
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`(i.e., GCC receptors) or a medical doctor with experience in treating GI disorders,
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`who may also have experience designing and running clinical trials or a
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`pharmaceutical formulator.
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`22. By January 17, 2002, I was a medical doctor with knowledge and
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`experience in treating GI disorders and additionally had experience designing and
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`running clinical trials. In my opinion, a person of ordinary skill would have
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`consulted with someone with such experience to gain further insight on appropriate
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`dosage regimens and other treatment considerations for chronic constipation.
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`V.
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`THE GASTROINTESTINAL TRACT
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`23. Dr. Waldman first provides a brief background on the gastrointestinal
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`tract (also called GI tract or digestive tract), focusing primarily on pH values
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`measured along the intestinal tract. EX2025 (Waldman Declaration), ¶¶20-21.
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`The values Dr. Waldman reports for the small and large intestines range from
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`about pH 5.5 in the proximal small intestine to close to neutral throughout the
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`colon. Id., ¶21; see also EX2033 (Nugent), 572 (Table 1).
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`24.
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`The GCC receptor that uroguanylin activates is concentrated in the
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`proximal small intestines. EX1018 (Joo) G639 (“Evaluation of sequential
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`intestinal segments suggested that proximal duodenal epithelium appeared to have
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`a higher receptor density compared with other segments of the intestinal tract.”),
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`G641 (“I-STa receptor autoradiography demonstrated that the receptors
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`responsible for uroguanylin action are distributed throughout the intestinal tract but
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`appear to be more densely populated in the proximal duodenum.”); EX2025
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`(Waldman Declaration), ¶40. The body regularly eliminates the GCC-activating
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`ligand (in this case, uroguanylin) after the ligand complexes with GCC. EX1065
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`(Urbanski), Abstract, 34-36. Accordingly, a large proportion of the uroguanylin
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`naturally will be used up and eliminated before spending any appreciable amount
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`of time in the intestinal lumen. For the uroguanylin that remains in the GI tract
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`after the proximal small intestines, the pH of the lumen approaches neutrality and
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`the uroguanylin would be expected to find its GCC target and be eliminated by the
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`body within a few hours.
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`25.
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`Even if uroguanylin were not eliminated naturally by the body’s GCC
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`receptors as it is used, it was known by 2001 that a small peptide like uroguanylin
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`would not need to spend more than just a short time in the body before reaching
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`the neutral or slightly alkaline environment of the colon. For example, J.W. Fara
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`wrote chapter 15 of the book titled Rate Control in Drug Therapy, which was
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`edited by L.F. Prescott and W.S. Nimmo and published by Churchill Livingstone
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`in 1985. Chapter 15, which spans pages 144-150 of the book, is entitled
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`“Physiological limitations: gastric emptying and transit of dosage forms.” Fara’s
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`chapter 15 (together with the cover page and bibliographic information) has been
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`marked as EX1070 for ease of reference in my discussion.
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`26. Consistent with the knowledge of a physician before 2001, Fara
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`indicates that it takes about 6-8 hours after oral administration for even large,
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`stomach-stable objects (e.g., 11 mm fluoroscopy tablet or enteric coated
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`salicylazosulphapyridine) to reach the colon. EX1070, 147-149. This transit time
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`included the objects spending an additional 2 hours in the stomach awaiting the
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`“housekeeper” stomach motility response when administered with food (delaying
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`the motility response), whereas smaller pellets appeared in the stool in as few as
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`six hours. EX1070, 147-149. A person of ordinary skill in the art thus would not
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`conclude that any appreciable amount of orally-administered uroguanylin would
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`need to spend anything near 16 or 24 hours in acidic conditions at or below pH 4.5
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`in the GI tract.
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`27.
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`Indeed, the expected transit time for uroguanylin through the stomach
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`would be much shorter. The stomach essentially acts as a grinder and mixer that
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`reduces the size of consumed materials until they are small enough to be suspended
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`in the stomach fluid called chyme, which fluid passes from the stomach into the
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`small intestines. EX1070, 146. Liquids, and particles small enough to be
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`suspended in the stomach fluid, thus generally spend no more than about 30
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`minutes to an hour in the stomach. In addition to the flow of liquid from the
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`stomach acting to remove the suspended particles to the duodenum of the small
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`intestines, the stomach also periodically empties its contents into the duodenum en
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`mass to eliminate materials that remain too large to exit with the stomach fluid.
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`For example, Fara teaches that the undigested fluoroscopy objects left the stomach
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`within 1-3 hours in a fasting state.
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`28.
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`Smaller particles pass even more rapidly out of the stomach. As Fara
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`explains, liquids and particles small enough to be suspended in liquid empty from
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`the stomach nearly 100% within 1 hour. EX1070, 146 (Fig. 15.1). Pellets no larger
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`than 2 mm “behave more or less like liquids and digested particles and leave the
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`stomach fairly soon after administration.” EX1070, 149. In such cases, it had
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`been observed that “complete emptying occurs over only 10-15 minutes” and the
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`particles “are swept rapidly along the intestine.” Id. It was known that standard
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`tablets disintegrate rapidly in the stomach into particles much smaller than 1-2 mm,
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`such that the active ingredient (e.g., 16-amino-acid peptide) is rapidly suspended or
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`dissolved in the chyme and exits the stomach within about an hour of
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`administration. Accordingly, for a small peptide like uroguanylin, the expectation
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`would have been that individual molecules would spend no more than about one
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`hour exposed to the pH of the stomach as the tablet disintegrated and the fluid
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`departed from the stomach.
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`29.
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`In contrast to a standard tablet, delivery of medication to the small
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`intestines can be purposely delayed or stretched out. One way this was done was
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`by protecting the tablet from the stomach fluids to prevent disintegration, such as
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`by using an enteric coating. When Fara administered an 11 mm fluoroscopy tablet,
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`that 11 mm object remained in the stomach for several hours without exposing its
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`contents to the acidic pH of the stomach fluid. This same effect was routinely
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`achieved using an enteric coating. As an alternative to an enteric coating, Fara
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`describes an ALZA oral dosage form that is retained in the stomach for a time
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`while emitting the active drug in solution, which drug “rapidly leaves the stomach
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`with other fluids” until the delivery system itself transits the remainder of the GI
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`tract. EX1070, 149-50. Accordingly, it was routine before January 2002 for active
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`pharmaceutical ingredients to have limited (~1 hour or less) or no exposure to the
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`acidic pH of the stomach.
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`30.
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`In the event medication is administered with a complex meal, these
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`additional stomach contents ordinarily act to raise the pH of the stomach (as
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`demonstrated by the references cited by Dr. Waldman). EX2025 (Waldman
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`Declaration), ¶21; EX2032 (Dressman), 759 (reporting mean value of pH 5.0
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`during meal, with an interquartile range of pH 4.3-5.4 and a peak value of 6.7).
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`Even if the meal as a whole spends more time in the stomach, the smaller particles
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`(e.g., uroguanylin) would still be expected to become suspended in the stomach
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`fluid and rapidly exit the stomach as they encounter the stomach fluid.
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`31.
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`Thus, at the relevant date, a medical doctor with experience in treating
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`GI disorders (such as a gastroenterologist), especially one with experience
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`designing and running clinical trials, would have understood that the amount of
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`time uroguanylin might be subject to acidic conditions of pH 4.5 or below in the
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`GI tract would be relatively brief, on the order of thirty minutes to an hour.
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`32. Any experienced clinician would have known that, if exposure to
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`prolonged acidic conditions were a concern, there were routine approaches that
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`were reasonably likely to limit exposure of uroguanylin to pH (cid:148)4.5 to an hour.
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`These included instructions about taking the medication with or without food or
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`formulating the medication for release at a pH higher than 4.5. By the relevant
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`date, a medical doctor with experience in treating GI disorders (such as a
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`gastroenterologist), especially one with experience designing and running clinical
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`trials, would have been well-satisfied that Dr. Waldman’s alleged topoisomeric
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`interconversion presented no reason to avoid uroguanylin.
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`VI. TREATMENT OF THE SMALL INTESTINE WOULD HAVE BEEN
`UNDERSTOOD TO BE BENEFICIAL
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`33. Dr. Waldman also discusses treatment options for patients diagnosed
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`with IBS-C and CIC available at the relevant time. See EX2025 (Waldman
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`Declaration), ¶¶22-38. Dr. Waldman concludes his overview with the assertion
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`that, “[a]s of 2002, all available treatment options targeted the colon or both the
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`colon and small intestine as the site of action,” “the colon was universally accepted
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`as a necessary site of action for treating constipation,” and “[t]hus, persons of
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`ordinary skill in the art would have focused on developing a drug acting in the
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`colon rather than the small intestine.” Id., ¶¶37-38. I disagree with how Dr.
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`Waldman describes the treatment aims for patients with chronic constipation at the
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`relevant time. In my experience, those in the art at the time appreciated the
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`benefits of targeting the small intestines for fluid secretion to treat constipation,
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`alone or in combination with treatments directed to the colon.
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`34. As Dr. Waldman acknowledges, in healthy individuals, “fluid
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`volumes are balanced by secretory and absorption mechanisms, with highest net
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`secretion in the proximal small intestine and highest net absorption in the colon.”
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`Id., ¶44. This means that, under normal circumstances, relatively more fluid is
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`secreted into the proximal small intestine (via activation of GCC receptors by
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`uroguanylin), while relatively more fluid is absorbed in the colon. See EX1062
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`(Waldman Deposition Transcript), 55:3-57:11, 59:4-21. Clinicians at the time
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`understood that appropriate secretion of fluid into the proximal regions of the small
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`intestine was crucial for digestion and contributed to the eventual formation and
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`consistency of stool. See id., 57:12-58:10 (Dr. Waldman agreeing secretion into
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`the small intestine was an important factor to digestion).
`
`35.
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`Though many existing treatments were known to act in both the colon
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`and the small intestines, it was well understood that the small intestines were the
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`primary GI tissue for fluid secretion into the intestinal lumen (as Dr. Waldman
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`admitted) and that this action was useful for treating those with CIC and IBS-C.
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`This was because any water content added to the small intestines would have
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`continued on to the colon, and thus would have promoted better formation and
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`consistency of stool that would help address symptoms associated with
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`constipation (e.g., hard and lumpy stool). The body’s natural processes were
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`known to focus on fluid secretion at the small intestines with less fluid secretion
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`occurring at the colon, as discussed above. As I noted above, uroguanylin was
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`known to have enhanced activity precisely in that environment. EX1018 (Joo)
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`G639, G641; EX2025 (Waldman Declaration), ¶40. A medical doctor with
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`experience in treating GI disorders (such as a gastroenterologist), especially one
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`with experience in designing and running clinical trials, would have had good
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`reason to retain uroguanylin’s enhanced activity in that target environment rather
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`than follow the pH-independent GCC activation pathway of enterotoxins. Indeed,
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`the clinician would have recognized that this latter approach risked inducing
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`excessive fluid secretion in the colon, where this late concentration of fluid
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`secretion would necessarily increase the risk of diarrhea, as even Dr. Waldman
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`admits. EX2025 (Waldman Declaration), ¶110.
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`36.
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`That those in the art appreciated the benefits in targeting the small
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`intestine for fluid secretion is supported by the treatment options available at the
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`time, as noted by Dr. Waldman. For example, Dr. Waldman notes treatment
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`options, such as hyperosmolar agents, promoted fluid secretion throughout the
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`intestinal lumen, including the small intestines. See EX2025, ¶33; EX1062, 54:18-
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`55:8 (Waldman Deposition Transcript).
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`VII. TOPOISOMERISM WOULD NOT HAVE BEEN VIEWED AS A CONCERN
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`37. Dr. Waldman discusses GCC receptor agonists known at the time: of
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`which there were three categories: the two endogenous peptides guanylin and
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`uroguanylin, as well as their molecular mimics, the heat-stable enterotoxins or STs.
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`EX2025 (Waldman Declaration), ¶¶39-73. Dr. Waldman argues that uroguanylin
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`naturally exists as a mixture of two, interconverting topoisomers (having the same
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`amino acid structure but adopting different three-dimensional shapes), one of
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`which was known to be biologically active. Id., ¶¶46-52. Due to these
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`topoisomers and their apparent rate of interconversion in certain solutions, Dr.
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`Waldman asserts that he “would not have considered human uroguanylin as a good
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`starting point to develop a drug product because of uroguanylin’s reduced stability
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`resulting from the interconversion of its topological isoforms.” Id., ¶53. From the
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`perspective of a medical doctor with experience in treating GI disorders (such as a
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`gastroenterologist), especially one with experience designing and running clinical
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`trials, I disagree that topoisomerism would have been viewed as a concern by those
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`in the field at the time.
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`38.
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`First of all, if Dr. Waldman is correct that uroguanylin naturally
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`undergoes topoisomeric interconversion in the intestinal tract, a physician would
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`have understood that this feature is at least compatible with its natural function of
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`inducing fluid secretion into the lumen, and potentially provided a benefit achieved
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`as a result of natural selection.
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`39.
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`Furthermore, Dr. Waldman’s topoisomerism opinions fail to account
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`appropriately for the expected transit time through the GI tract. For example, the
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`exhibits Dr. Waldman relies upon for uroguanylin’s rate of interconversion in
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`solution show that the rate is influenced by pH conditions over time, with
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`apparently a 25% interconversion after 24 hours at pH 4.5. See EX2010 (Marx
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`1998), 236, FIG. 6C. As I noted above, however, the physician would expect that
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`uroguanylin ordinarily would be exposed to a pH of 4.5 or lower for no more than
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`REDACTED PUBLIC VERSION
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`approximately one hour after oral administration. See supra, section V. Given this
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`brief exposure (and assuming even no conventional measures are taken to time
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`uroguanylin’s release after digestion in the stomach), it would not have been
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`expected that appreciable interconversion would occur (perhaps 1%). In more
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`alkaline environments, such as in the intestines, the interconversion rate is even
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`slower, thus producing even less likelihood of interconversion as uroguanylin
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`binds to its targeted receptor, as I explained above. See EX2010 (Marx 1998), 236,
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`FIG. 6C.
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`40. Although Dr. Waldman cites interconversion as causing “interpatient
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`variability because a reliable set dosage of the drug product would have been
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`impossible to determine,” I disagree. Any interpatient variability that may have
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`occurred would have been viewed as likely minimal given the biological
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`conditions that uroguanylin would have been expected to encounter. In my
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`opinion, any effects would have been reasonably expected to be adequately
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`addressed with routine dosing studies.
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`41.
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`Further, Dr. Waldman expresses concern over “the characteristics of
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`the GCC-inactive topological isoform,” being “not fully known in 2002.” EX2025
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`(Waldman Declaration), ¶53. According to Dr. Waldman, “a person of ordinary
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`skill in the art would not have known whether it was active at some other receptor
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`site or would otherwise result in adverse effects.” Id. I disagree with Dr.
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`Waldman because this opinion ignores the fact that uroguanylin is a natural ligand.
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`As a natural ligand, those in the art would have appreciated that even the inactive
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`topoisomer was reasonably likely to not have adverse effects, especially given that
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`the ligand is targeting the same natural receptor site, the intestines. Moreover,
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`because uroguanylin is a natural GCC ligand that acts locally on receptors on the
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`intestinal mucosa rather than primarily through systemic absorption, the likelihood
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`of adverse off-target effects is even further reduced.
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`VIII. THE HIGHER POTENCY OF ENTEROTOXINS DID NOT EXCLUDE
`UROGUANYLIN AS A DESIRABLE STARTING POINT
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`42. Dr. Waldman also argues that, in view of the relatively higher potency
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`of enterotoxins, “[o]ne knowledgeable about GCC agonists would have considered
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`heat-stable enterotoxins as an ideal starting point for further improvement.”
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`EX2025 (Waldman Declaration), ¶69. Dr. Waldman characterizes heat-stable
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`enterotoxins as “known to be more stable, be more potent, having higher binding
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`affinities, and have less pH-dependent activity than uroguanylin and guanylin.”
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`Id., ¶64; see also id., ¶67 (“heat-stable enterotoxins were known to have
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`‘extraordinarily high binding affinities’ and ‘remarkable potencies’). In my
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`opinion, Dr. Waldman views these peptides with a singular focus on potency that
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`would not have been shared by a medical doctor at the relevant time with
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`experience in treating GI disorders (such as a gastroenterologist), especially one
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`with experience designing and running clinical trials. In my experience, those in
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`the art at the time would not have viewed these peptides in such a vacuum and
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`would have considered other factors, such as safety and efficacy, in determining
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`what would be a natural choice for drug development.
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`43.
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`First, Dr. Waldman’s focus on maximizing potency ignores the reason
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`why enterotoxins became so potent. As Dr. Waldman acknowledges, STs are the
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`product of pathogenic bacteria designed to propagate the pathogen through
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`molecular mimicry. See id., ¶71; EX1062 (Waldman Deposition Transcript), 62:5-
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`64:13, 77:11-79:5; EX2062 (Beltowski), 352. When nutrients within the intestinal
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`environment are depleted, the bacteria synthesize and secrete STs to exploit the
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`host’s GCC receptor systema and promote excess fluid secretion into the intestines,
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`thus triggering diarrhea and facilitating the finding of new hosts for nutrient
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`consumption. See EX1062 (Waldman Deposition Transcript), 77:11-79:5.
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`44.
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`In contrast, the endogenous peptides, uroguanylin and guanylin, were
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`known to naturally coordinate intestinal fluid secretion and promote proper
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`digestion. In this case, while not as potent as enterotoxins, it was understood that,
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`as natural ligands, they were safe and effective in producing the desired eff
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