On behalf of: Par Pharmaceutical, Inc. et al.
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`Entered: December 5, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PAR PHARMACEUTICAL, INC., BRECKENRIDGE PHARMACEUTICAL,
`INC., AND ROXANE LABORATORIES, INC.
`Petitioners
`
`v.
`
`NOVARTIS AG
`Patent Owner
`_______________________
`Case IPR2016-000841
`U.S. Patent No. 5,665,772
`_______________________
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`SUPPLEMENTAL DECLARATION OF WILLIAM L. JORGENSEN, PH.D.
`IN SUPPORT OF PETITIONERS’ REPLY IN THE INTER PARTES
`REVIEW OF U.S. PATENT NO. 5,665,772
`
`
`1 Breckenridge Pharmaceutical, Inc. was joined as a party to this proceeding via a
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`Motion for Joinder in IPR2016-01023; Roxane Laboratories, Inc. was joined as a
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`party via a Motion for Joinder in IPR2016-01102.
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`Ex. 1118-0001
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`

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`
`
`CONTENTS
`
`I.
`
`II.
`
`Introduction and Qualifications ....................................................................... 1
`
`Summary of Opinions Regarding the Declarations of Dr. Roush and
`Dr. Klibanov .................................................................................................... 2
`
`III. A POSA Would Have Been Motivated to Modify Rapamycin to
`Improve Its Solubility .................................................................................... 10
`
`A.
`
`B.
`
`The Prior Art Taught that Rapamycin Had Poor Water
`Solubility ............................................................................................. 14
`A POSA Would Have Been Motivated to Modify Rapamycin to
`Improve Its Solubility .......................................................................... 17
`1.
`A POSA would not have first selected formulation
`approaches to address rapamycin’s poor solubility .................. 18
`A POSA would not have first elected to make a prodrug
`of rapamycin to address its poor solubility ............................... 20
`A POSA would not have first elected to modify
`rapamycin to make water-soluble salts to improve its
`solubility .................................................................................... 22
`
`2.
`
`3.
`
`IV. A POSA Would Have Been Motivated to Modify Rapamycin With a
`Reasonable Expectation of Obtaining a Derivative With
`Immunosuppressant Activity and Improved Solubility ................................. 25
`
`A.
`
`B.
`
`The Prior Art Taught that Modifications to C40 Would Be the
`Most Likely to Produce Derivatives that Retain Rapamycin’s
`Activity ................................................................................................ 28
`A POSA Would Not Prefer the Alternate Modifications
`Suggested by Dr. Roush and Dr. Klibanov in Making a
`Derivative of Rapamycin with Immunosuppressant Activity and
`Improved Water Solubility .................................................................. 32
`1.
`Dr. Roush and Dr. Klibanov mischaracterize how a
`POSA would modify rapamycin’s C40 hydroxyl group .......... 32
`A POSA would not prefer modifications that change or
`disrupt the stereochemistry of rapamycin ................................. 34
`A POSA would not have made unstable modifications ............ 37
`A POSA would not have limited modifications to
`improve water solubility to ionizable groups based on the
`teachings of Lemke ................................................................... 38
`
`3.
`4.
`
`2.
`
`i
`
`Ex. 1118-0002
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`

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`
`
`5.
`
`A POSA would have understood that primary alcohols
`have more water-solubilizing potential than secondary
`alcohols in drug candidates ....................................................... 42
`Yalkowsky’s Teachings Apply to the Water Solubility of
`Rapamycin Derivatives ....................................................................... 43
`1.
`Dr. Klibanov’s “relevant fragment” argument
`inappropriately ignores the entire structure of rapamycin ........ 46
`Yalkowsky’s teachings are not limited to ideal solubility ........ 50
`2.
`D. A POSA Would Have Had a Reasonable Expectation of
`Obtaining a Derivative of Rapamycin with Immunosuppressant
`Activity ................................................................................................ 54
`A POSA Would Have Had a Reasonable Expectation of
`Obtaining a Derivative of Rapamycin with Improved Solubility ....... 58
`
`C.
`
`E.
`
`V.
`
`Conclusion ..................................................................................................... 59
`
`
`
`ii
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`Ex. 1118-0003
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`

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`
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`I, William L. Jorgensen, Ph.D. resident of Deep River, Connecticut, hereby
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`declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`1.
`
`I am the same William L. Jorgensen, Ph.D. who submitted an opening
`
`declaration (Ex. 1003) in support of Par Pharmaceutical, Inc.’s (“Par”) petition for
`
`the Inter Partes Review of U.S. Patent No. 5,665,772 (Ex. 1001, “the ’772
`
`Patent”). My qualifications and experience in medicinal and organic chemistry are
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`fully laid out in my opening declaration. (Ex. 1003 ¶¶ 2-9.)
`
`2.
`
`I submit this supplemental declaration to respond to certain opinions
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`offered in two declarations submitted by Dr. William Roush (Ex. 2093) and Dr.
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`Alexander Klibanov (Ex. 2092) in support of the Response of Patent Owner
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`Novartis AG (“Novartis”) in this proceeding.
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`3. My work in this matter is being billed at a rate of $600 per hour, with
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`reimbursement for necessary and reasonable expenses. My compensation is not in
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`any way contingent upon the outcome of any inter partes review. I have no
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`financial or personal interest in the outcome of this proceeding or any related
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`litigation.
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`4.
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`In forming my opinions, I have relied on the ’772 Patent’s claims,
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`disclosure, and file history, on the materials cited in my opening declaration (Ex.
`
`1003), as well as on materials cited in this supplemental declaration, and my own
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`1
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`Ex. 1118-0004
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`

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`
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`experience, expertise, and knowledge of the person of ordinary skill in the art in
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`the relevant timeframe.
`
`II.
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`SUMMARY OF OPINIONS REGARDING THE DECLARATIONS
`OF DR. ROUSH AND DR. KLIBANOV
`5.
`
`As I stated in my opening declaration, the prior art taught that
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`rapamycin was a prominent compound that generated intense interest in the
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`medicinal chemistry community and that rapamycin had low water solubility that
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`would have motivated a POSA to make modifications to improve its properties.
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`(Ex. 1003 ¶¶ 132-140.) A POSA would have initially modified rapamycin at its
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`hydroxyl groups, because such groups are the easiest and most straightforward to
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`modify, and in particular would have selected C40 as the primary candidate for
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`modification because the prior art taught that of the three hydroxyl groups it was
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`least involved in binding to FKBP-12 and was not implicated in binding to the
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`then-unknown effector protein. (Id. ¶¶ 141-145.) A POSA would have sought to
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`add flexible side chains containing polar groups with known water-solubilizing
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`potential as reflected in the teachings of Yalkowsky and Lemke. (Id. ¶¶ 146-156.)
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`A POSA, seeking to maximize the probability of achieving a derivative with
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`immunosuppressant activity and increased water solubility, would have started
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`with the smallest substitutions that included flexible side chains and the most
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`water-solubilizing potential. (Id. ¶¶ 150-153.) Among the first modifications that
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`a POSA would have been motivated to use would be the 2-hydroxylethoxy group
`
`2
`
`Ex. 1118-0005
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`

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`
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`resulting in the compound of claim 10 of the ’772 Patent. (Id. ¶¶ 153-155, 161.)
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`None of Dr. Roush’s and Dr. Klibanov’s various critiques change my opinions.
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`6.
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`Dr. Roush and Dr. Klibanov separately analyze the teachings of the
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`prior art and the motivation of a POSA to make a derivative of rapamycin. By
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`separating the two key subjects (rapamycin’s solubility and immunosuppressant
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`activity), Dr. Roush and Dr. Klibanov each fail to address the entire understanding
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`a POSA would have based on their knowledge and experience and the teachings of
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`the prior art as a whole. For example, Dr. Roush does not analyze the teachings of
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`the prior art with respect to how to make modifications to improve solubility (Ex.
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`2093 ¶ 85 n.4), while Dr. Klibanov does not analyze the teachings of the prior art
`
`with respect to how to avoid disrupting rapamycin’s biological activity (Ex. 2092
`
`¶ 29 n.3). Similarly, Dr. Klibanov analyzes the teachings of Lemke on the type of
`
`substituents that would be expected to have a favorable impact on water solubility
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`(id. ¶¶ 33-67) separately from the teachings of Yalkowsky on the favorable impact
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`on solubility resulting from the addition of flexible side chains (id. ¶¶ 68-125). But
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`it is the entire analysis, as I outlined in my opening declaration, balancing
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`solubility with activity and polar substituents with flexibility, that a POSA would
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`consider in determining how to modify rapamycin to achieve a derivative with
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`immunosuppressant activity and improved solubility.
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`3
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`Ex. 1118-0006
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`

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`
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`7.
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`Dr. Roush states that I failed to compare rapamycin to other known
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`immunosuppressant compounds in forming my opinion that a POSA would select
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`rapamycin as a lead compound. (Ex. 2093 ¶ 158.) I agree that other biologically
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`active compounds, including compounds with immunosuppressant activity, were
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`known in 1992. However, rapamycin was extraordinarily well-publicized in 1992
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`because of its novel structure and activity, generating intense interest in the
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`medicinal chemistry community. Indeed, as Dr. Roush identifies, a significant
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`number of researchers had already selected rapamycin to make derivatives and
`
`assess the immunosuppressant activity of the resulting compounds. (Id. ¶¶ 64-83.)
`
`This intense interest in rapamycin is consistent with the description in Morris that
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`“[p]rogress in rapamycin (RPM) research has been rapid and is poised to accelerate
`
`even more dramatically.” (Ex. 1005 at 39.) Rapamycin was certainly a lead
`
`compound that a POSA would have selected (and researchers did select) for
`
`modification.
`
`8.
`
`Dr. Klibanov states that a POSA would not have been motivated to
`
`modify rapamycin to improve its solubility because it was known to be “soluble
`
`enough” and the statement in the ’772 Patent that rapamycin’s poor solubility
`
`made it difficult to formulate was “based on [the inventors’] own work.” (Ex.
`
`2092 ¶ 150.) But, the ’772 Patent does not demonstrate that the patentees
`
`“discovered” rapamycin’s poor water solubility. The ’772 Patent references
`
`4
`
`Ex. 1118-0007
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`

`
`
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`rapamycin’s poor solubility in the Background section and contains no discussion,
`
`experiments, or data analyzing rapamycin’s solubility. (See generally Ex. 1001.)
`
`9.
`
`In fact, the prior art identified rapamycin’s water solubility to be very
`
`low and others, in particular Stella, specifically selected rapamycin to modify to
`
`improve its water solubility. (Ex. 1003 ¶¶ 75-76, 90-92; Ex. 1010.) Further,
`
`contrary to Dr. Klibanov’s assumption that the ’772 patentees “discovered” this
`
`problem, the prior art identified rapamycin’s poor water solubility as a problem
`
`and explicitly suggested synthesizing rapamycin analogs to address this issue. (Ex.
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`1034 at 116.)
`
`10. Dr. Roush states that a POSA would not have selected the C40
`
`hydroxyl group of rapamycin to modify, identifying several other positions on
`
`rapamycin that researchers were modifying. (Ex. 2093 ¶¶ 206-216.) But, as I
`
`stated in my opening declaration, a POSA would have selected the hydroxyl
`
`groups among the first groups for modification because they are among the easiest
`
`groups to modify, with simple and straightforward reactions. (Ex. 1003 ¶ 142.)
`
`Dr. Klibanov does not dispute that the hydroxyl groups are among the easiest
`
`groups to modify. In fact, Dr. Klibanov acknowledged at his deposition that the
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`only rapamycin derivatives he has made were modified at the hydroxyl groups
`
`because they are easily modified. (Ex. 1114, Klibanov Dep. Tr. at 16:4-17:21.) A
`
`POSA would therefore have selected the hydroxyl groups as among the first
`
`5
`
`Ex. 1118-0008
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`

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`
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`groups for modification. And, as I stated in my opening declaration, of the three
`
`hydroxyl groups, the C40 hydroxyl was known to be on the periphery of the
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`complex with FKBP-12 and was not implicated in binding to the then-unknown
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`effector protein. (Ex. 1003 ¶¶ 143-144.) Further, Dr. Roush identifies a significant
`
`number of prior art patents in which researchers were indeed modifying rapamycin
`
`at the C40 hydroxyl group and obtaining derivatives that had immunosuppressant
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`activity. (Ex. 2093 ¶¶ 64-83.) The prior art taught that the C40 position would
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`have been (and was) among the first positions that a POSA would have modified
`
`because it is an easy-to-modify hydroxyl group and, among rapamycin’s hydroxyl
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`groups, a modification at the C40 would have been the most likely to result in a
`
`derivative with immunosuppressant activity.
`
`11. Dr. Roush also states that a POSA would not have been limited to
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`small modifications at the C40 position because other researchers had made large
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`modifications at C40 that retained immunosuppressive activity. (Ex. 2093 ¶¶ 64-
`
`83.) Contradicting himself, Dr. Roush also states that a POSA would not have a
`
`reasonable expectation that a derivative at C40 would have immunosuppressant
`
`activity because certain derivatives at C40 had been reported to have weak
`
`immunosuppressant activity. (Id. ¶¶ 114-130.) I agree with Dr. Roush that the
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`prior art disclosed a number of rapamycin derivatives at the C40 position and
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`reported that a significant number of these derivatives retained substantial
`
`6
`
`Ex. 1118-0009
`
`

`
`
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`immunosuppressant activity. But even though some derivatives with large
`
`modifications retained substantial activity, a POSA would have elected to make
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`small modifications first because a POSA would have understood that smaller
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`modifications would have a greater probability of not interfering with biological
`
`interactions that convey biological activity. Further, as I explained in my opening
`
`declaration, a POSA would also seek to avoid unnecessarily increasing molecular
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`weight and possibly introducing metabolic problems. (Ex. 1003 ¶ 150.) And for
`
`these reasons, a POSA would start with small modifications to achieve the desired
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`goal of improving solubility and retaining immunosuppressant activity before
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`moving on to larger groups. This normal, systematic approach provides order and
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`logic to a drug development program, rather than Dr. Roush’s unmoored
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`suggestion to make wide-ranging, disparate modifications. Further, Dr. Roush
`
`does not provide any analysis of why a POSA, seeking to make a derivative of
`
`rapamycin with immunosuppressant activity but improved solubility, would prefer
`
`any of the possible modifications he proposes to those I identified in my opening
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`declaration.
`
`12. Dr. Klibanov states that a POSA would not have modified rapamycin
`
`with a hydroxyl group, but rather that the teachings from Lemke would have
`
`directed a POSA to modify rapamycin with amine and carboxylate groups because
`
`they are ionizable. (Ex. 2092 ¶¶ 49-56.) As I stated in my opening declaration, I
`
`7
`
`Ex. 1118-0010
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`

`
`
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`agree that a POSA would have selected amine and carboxylic acid groups to
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`modify the hydroxyl group at rapamycin’s C40. (Ex. 1003 ¶¶ 149-150.) However,
`
`I disagree that a POSA would have excluded hydroxyl groups in selecting
`
`modifications for rapamycin, because Lemke identifies these groups as having the
`
`greatest solubilizing potential. In fact, of the twelve groups identified in Table 16-
`
`1 of Lemke as having solubilizing potential, only two (amine and carboxylic acid)
`
`are ionizable under physiological conditions. Dr. Klibanov does not identify any
`
`reason why a POSA would ignore this explicit teaching and focus exclusively on
`
`ionizable groups in selecting modifications.
`
`13. Dr. Klibanov also states that a POSA would not have considered
`
`Yalkowsky in selecting modifications to rapamycin to improve its water solubility
`
`primarily because Yalkowsky is (1) irrelevant because it is limited to ideal
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`solubility and a solution of rapamycin in water is not ideal; and (2) the 2-
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`hydroxyethoxy modification made to rapamycin to arrive at everolimus does not
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`qualify as a “long chain” according to Yalkowsky. As Dr. Klibanov acknowledged
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`at his deposition, Dr. Yalkowsky is a noted expert in solubility and his work would
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`have been (and was) well-known to medicinal chemists. (Ex. 1114, Klibanov Dep.
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`Tr. at 49:18-50:12.) When reading Yalkowsky, a POSA would have recognized
`
`that it is not limited to ideal solubility, but rather explicitly addresses entropy
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`issues, which are basic to thermodynamics and apply to all systems, ideal or not.
`
`8
`
`Ex. 1118-0011
`
`

`
`
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`14. Further, Dr. Klibanov focuses his analysis only on what he terms to be
`
`the “relevant fragment” of everolimus, but that limited analysis fails to account for
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`the entire rapamycin molecule. (Ex. 2092 ¶¶ 30-31, 99.) If the entire molecule is
`
`considered, as POSA would have done, then the chain length would not be limited
`
`to the everolimus side chain, as Dr. Klibanov suggests, but rather would include all
`
`flexible bonds within the compound. Once the entire compound is considered, a
`
`POSA would have understood that appending the additional flexible bonds of the
`
`hydroxyethyoxy group is not just to the C40 carbon but to the already flexible
`
`molecule as a whole. The potential benefits to solubility of the increased number
`
`of rotatable bonds, as reflected in Yalkowsky’s analysis, would be well understood
`
`by a POSA.
`
`15. A POSA would have had a reasonable expectation that a derivative of
`
`rapamycin containing additional flexible bonds and water-solubilizing groups
`
`would have improved water solubility based on the teachings of Lemke and
`
`Yalkowsky. Further, as I noted in my opening declaration, Stella made prodrugs
`
`of rapamycin by modifying rapamycin’s C40 and C28 hydroxyl groups with
`
`CO(CH2)mNR1R2 groups and reported the derivatives had up to 2500-fold increase
`
`in solubility. (Ex. 1003 ¶¶ 89-92, 140.) This approach illustrates precisely the
`
`impact on rapamycin’s water solubility of modifications with flexible side chains
`
`containing polar groups as taught by Lemke and Yalkowsky.
`
`9
`
`Ex. 1118-0012
`
`

`
`
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`16. A POSA would have had a reasonable expectation of obtaining a
`
`derivative of rapamycin that had immunosuppressant activity by making small
`
`modifications at the C40 hydroxyl group. That Dr. Roush identifies a significant
`
`number of large modifications at the C40 hydroxyl that nevertheless had been
`
`reported to retain immunosuppressant activity, only further supports the reasonable
`
`expectation that a small modification would retain immunosuppressant activity.
`
`(Ex. 2093 ¶¶ 64-83.) The examples of modifications at C40 that Dr. Roush
`
`identifies with reported weak immunosuppressant activity merely indicate that
`
`there is no absolute guarantee that a particular modification will have activity. (Id.
`
`¶¶ 114-130.) But, based on the prior art as a whole, a POSA would have had a
`
`reasonable expectation that small modifications would result in a rapamycin
`
`derivative with immunosuppressant activity.
`
`III. A POSA WOULD HAVE BEEN MOTIVATED TO MODIFY
`RAPAMYCIN TO IMPROVE ITS SOLUBILITY
`17. As I discussed in my opening declaration, a POSA would have
`
`selected rapamycin as a lead compound for modification. (Ex. 1003 ¶¶ 132-137.)
`
`In response, Dr. Roush identifies a number of other immunosuppressant
`
`compounds that were known as of October 1992. (Ex. 2093 ¶¶ 171-185.) Even
`
`assuming that a POSA might also select these (or any other) compounds for further
`
`modification, my opinion that a POSA would select rapamycin as a lead compound
`
`does not change. Rapamycin was extremely well-known in the prior art, and, in
`
`10
`
`Ex. 1118-0013
`
`

`
`
`
`fact, there was significant excitement and interest in rapamycin in the late 1980s
`
`and early 1990s. As Morris notes, in 1992 “[p]rogress in rapamycin (RPM)
`
`research has been rapid and is poised to accelerate even more dramatically.” (Ex.
`
`1005 at 39.) This was certainly my experience in the field: by the early 1990s,
`
`there was great interest in rapamycin, as it was well-known to be a potent
`
`immunosuppressant, and a number of medicinal chemists were studying and
`
`modifying it. Indeed, Dr. Roush himself identifies a significant number of patents
`
`disclosing derivatives of rapamycin from this time period, which further supports
`
`my opinion that a POSA would have selected (and researchers did in fact select)
`
`rapamycin as a lead compound to make modifications. (Ex. 2093 ¶¶ 64-83, 114-
`
`130.)
`
`18. Dr. Roush
`
`contends
`
`that
`
`“rapamycin’s
`
`utility
`
`as
`
`an
`
`immunosuppressive agent was unknown because there was no reported clinical
`
`data.” (Ex. 2093 ¶ 158.) I disagree. Rapamycin was known to be a potent
`
`immunosuppressant with potential for further development, and in the early 1990s
`
`there was a surge of interest in rapamycin, which was the subject of an
`
`Investigational New Drug application for the treatment of transplant rejection just
`
`two years before. (E.g., Ex. 1003 ¶¶ 53, 69, 72-74, 133; Ex. 1005 at 39.)
`
`19. Further, I disagree that a POSA would wait to select a compound to
`
`modify until there were clinical data. Not all promising compounds are advanced
`
`11
`
`Ex. 1118-0014
`
`

`
`
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`to the clinic but that does not eliminate them from consideration for modification.
`
`A POSA would have recognized that such promising compounds could benefit
`
`from routine modifications to improve unfavorable characteristics. I also note that
`
`Dr. Roush does not dispute that rapamycin was known to be a potent
`
`immunosuppressant or that many researchers were in fact experimenting with it,
`
`despite the lack of clinical data.
`
`20. Dr. Roush also contends that rapamycin is not fit to be a lead
`
`compound because a “high dose” was toxic in monkeys as were large doses (e.g., 2
`
`mg/kg to 50 mg/kg) in baboons. (Ex. 2093 ¶¶ 161-164.) But as I testified at my
`
`deposition, improving solubility often improves bioavailability, which allows
`
`decreasing the dosage, which in turn “is nothing but good news from a toxicity
`
`standpoint.” (Ex. 2091 at 183; see also id. at 133, 184-85, 188, 204-05, 261.)
`
`Thus, a POSA would have not have eliminated rapamycin from consideration as a
`
`lead compound simply because certain doses had been found to be toxic in certain
`
`animal models.
`
`21. Dr. Roush also contends that a POSA would not have selected
`
`rapamycin because its effector protein was unknown. (Ex. 2093 ¶¶ 168-170.) I
`
`disagree. As I stated in my original declaration, Schreiber identified the portion of
`
`rapamycin described to interact with the effector target. (Ex. 1003 ¶¶ 121-122.) A
`
`12
`
`Ex. 1118-0015
`
`

`
`
`
`POSA would therefore have known which portions of rapamycin to avoid
`
`modifying to avoid disrupting this interaction. (Id.)
`
`22. Dr. Roush also contends that a POSA would not have selected
`
`rapamycin based on Van Duyne. (Ex. 2093 ¶¶189-191.) Dr. Roush again looks at
`
`a reference in isolation rather than as a part of the prior art as a whole. Van Duyne
`
`characterizes in detail the interface between rapamycin and FKBP12, and the
`
`portions of rapamycin interacting with the effector had been identified by
`
`Schreiber. (Ex. 1003 ¶¶ 121, 122, 143.) Thus, a POSA would have understood
`
`that the structural information disclosed in Van Duyne and Schreiber would be
`
`useful in guiding the selection and evaluation of potential derivatives of
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`rapamycin. (Ex. 1003 ¶ 135.)
`
`23. Dr. Roush also contends that a POSA would not have selected
`
`rapamycin as a lead compound based on Stella, Hughes, and Schiehser. (Ex. 2093
`
`¶¶ 192-196.) Dr. Roush further states that I made the “broad conclusion . . . that
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`all rapamycin derivatives . . . were known to (or would be reasonably expected to)
`
`retain rapamycin’s immunosuppressant activity.” (Ex. 2093 ¶ 193 (emphasis
`
`added).) Dr. Roush misstates my testimony. I did not testify that all derivatives
`
`have (or would have been expected to have) rapamycin’s activity. Rather, I
`
`testified that rapamycin derivatives were readily synthesized and a POSA would
`
`have had a reasonable expectation of successfully making derivatives that retained
`
`13
`
`Ex. 1118-0016
`
`

`
`
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`immunosuppressant activity. (Ex. 1003 ¶ 136.) Dr. Roush points to Hughes
`
`examples 1 and 2, which at worst, had a 50% success rate (Ex. 2093 ¶ 194
`
`(discussing Hughes, where Example 2 retained activity but Example 1’s results
`
`were “unclear”)), which a POSA would have considered a reasonable expectation
`
`of success when making multiple derivatives as I proposed in my original
`
`declaration.
`
`24.
`
`In sum, as I testified in my opening declaration, a POSA would have
`
`been motivated to select rapamycin as a lead compound. None of Dr. Roush’s
`
`critiques of rapamycin change my opinion.
`
`A. The Prior Art Taught that Rapamycin Had Poor Water Solubility
`25.
`In my opening declaration, I testified that rapamycin was known in
`
`the art to have poor water solubility and that a POSA would have been motivated
`
`to modify rapamycin to improve its solubility. (E.g., Ex. 1003 ¶¶ 75-76.) Dr.
`
`Klibanov states that “A [POSA] would not have considered rapamycin’s water
`
`solubility to be a problem that needed to be addressed.” (Ex. 2092 at Section VII
`
`(Heading).) Perhaps recognizing his opinion directly contradicts the ’772 Patent,
`
`Dr. Klibanov states that the express admission in the Background of the ’772
`
`Patent that “‘rapamycin is highly insoluble, making it difficult to formulate in
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`stable galenic compositions’ is based on [the patentees’] own work.” (Ex. 2092
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`¶ 150.) The ’772 Patent includes no discussion, experiments, or data to support
`
`14
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`Ex. 1118-0017
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`

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`that the patentees discovered rapamycin’s poor solubility. (See generally Ex.
`
`1001.) To the extent Dr. Klibanov contends that rapamycin’s poor solubility was
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`not an issue known in the art, I disagree.
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`26. Rapamycin’s poor water solubility was identified in the prior art. The
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`patentees of the ’772 Patent were not the first scientists to identify the low water
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`solubility of rapamycin or to identify that this low solubility made rapamycin
`
`difficult to formulate. As I cited in my opening declaration, Morris identifies
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`rapamycin is “only minimally soluble in water” and Stella explicitly selected
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`rapamycin to make prodrugs so as to improve water solubility. (Ex. 1003 ¶¶ 54,
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`75-76, 89-92.) Further, the National Cancer Institute (NCI), in the course of
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`screening rapamycin in in vitro and in vivo antitumor assays, states that “[f]urther
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`development of rapamycin was stopped due to solubility problems and toxicity
`
`associated with the cremophor used in the experimental formulations.” (Ex. 1034,
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`Heinz-Herbert Fiebig et al., In Vitro and In Vivo Evaluation of US-NCI
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`Compounds in Human Tumor Xenografts, 17 CANCER TREATMENT REVS. 109,
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`Abstract, 116 (1990).) The NCI further stated that “[m]ajor emphasis is placed on
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`the development of new analogs of rapamycin.” (Id. at 116.) This corroborates
`
`my opinion as expressed in my opening declaration. Rapamycin was known to
`
`have poor solubility that led to problems with formulations. And to solve this
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`15
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`Ex. 1118-0018
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`

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`
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`problem, medicinal chemists would have looked to make analogs of rapamycin
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`with improved solubility.
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`27. Dr. Klibanov further states that “rapamycin’s solubility was evidently
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`sufficient to be used as a pharmaceutical (without chemical modification) because
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`. . . an IND application seeking authorization to administer rapamycin to humans
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`had been filed with the FDA.” (Ex. 2092 ¶ 151.) I disagree with Dr. Klibanov’s
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`analysis. A minimally effective solubility does not eliminate the motivation for a
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`POSA to improve upon that solubility. In particular, as I noted in my opening
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`declaration, a POSA would have been motivated to improve solubility with the
`
`aims of easier formulation and lower dosages. (Ex. 1003 ¶¶ 54, 75-76, 140.) As I
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`stated in my deposition, even modest improvements in solubility, e.g., by a factor
`
`of two, can have significant practical advantages in reducing the size of a pill and
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`reducing toxicity. (Ex. 2091 at 167:2-168:3.) A POSA would not have simply
`
`considered rapamycin’s water solubility to be “good enough,” as Dr. Klibanov
`
`appears to suggest.
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`28. Further, the opinion that a POSA would cease studying rapamycin
`
`once it is “good enough” is contrary to the entire field of drug discovery and every
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`piece of prior art demonstrating researchers actively modifying rapamycin The
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`normal progression is that subsequent drugs in a class improve upon the earlier
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`ones.
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`16
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`Ex. 1118-0019
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`

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`
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`29. Dr. Klibanov also states that I contend that “rapamycin had unsuitable
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`bioavailability due to its alleged poor water solubility” but that Morris does not
`
`support this “contention.” (Ex. 2092 ¶ 152.) Dr. Klibanov further states that
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`Morris indicates that rapamycin’s bioavailability could have been due to “poor
`
`absorption, degradation before absorption, or significant first-pass hepatic
`
`metabolism.” (Id.) I agree that bioavailability is impacted by a number of factors,
`
`including permeability and metabolism. But, one of the principal factors affecting
`
`bioavailability is water solubility. This is because only drug that is in solution is
`
`available to be absorbed, as one of the references Dr. Klibanov cites explicitly
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`states. (Ex. 2111 at 185-186 (“The primary role of solubility in determining drug
`
`absorption is obvious since only the drug that is in solution is available for
`
`absorption.”).) Thus, although improving water solubility is not guaranteed to
`
`improve bioavailability, improving water solubility remains an important approach
`
`employed by POSAs to address poor bioavailability. And, as I stated above and in
`
`my opening declaration, improving solubility may positively impact other factors
`
`beyond bioavailability,
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`including
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`the ability “to construct
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`satisfactory
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`pharmaceutical formulations.” (Ex. 1003 ¶ 75.)
`
`B. A POSA Would Have Been Motivated to Modify Rapamycin to
`Improve Its Solubility
`30. Dr. Klibanov states that a POSA would not have modified rapamycin
`
`to improve its solubility but would rather have pursued “such attractive and well-
`
`17
`
`Ex. 1118-0020
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`

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`
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`established alternatives as formulation, prodrug, or water-soluble salt approaches.”
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`(Ex. 2092 ¶ 156.) I disagree.
`
`1.
`
`A POSA would not have first selected formulation
`approaches to address rapamycin’s poor solubility
`31. First, Dr. Klibanov agrees with me that a POSA would have a Ph.D.
`
`in medicinal or organic chemistry and would be working in the field of drug
`
`discovery. (Ex. 2092 ¶ 22; Ex. 1003 ¶ 45.) Dr. Klibanov does not indicate that a
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`POSA would be working in drug design, as I opined in my opening declaration.
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`(Ex. 1003 ¶ 45.) However, drug design is an intrinsic element of drug discovery
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`and an integral part of a POSA’s expertise.
`
`32. Dr. Klibanov
`
`identifies his
`
`research
`
`interests as
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`including
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`“stabilization and formulation of macromolecular pharmaceuticals” and “medicinal
`
`and formulation chemistry.” (Ex. 2402 at 2.) Dr. Klibanov’s focus on formulation
`
`may explain his apparent preference for alternative solutions to poor water
`
`solubility. However, based on my over 30 years of experience of directly working
`
`on addressing poor water solubility in drug candidates, it is my opinion that a
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`POSA, as an organic or medicinal chemist, would have elected to address water
`
`solubility via chemical modification rather than relying on formulators to address
`
`the problems associated with rapamycin’s poor water solubility. In vitro assays are
`
`a critical aspect of preclinical drug discovery. They are typically performed on
`
`synthesized compounds with no formulation. If the solubility of the compound is
`
`18
`
`Ex. 1118-0021
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`

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`poor, it may not be possible to perform the assays and the compound cannot
`
`advance in development. For example, initial screening and off-target assays are
`
`often performed at a fixed concentratio