Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`122. The teaching in Schreiber regarding the effector domain of rapamycin
`
`provides additional motivation for a person of ordinary skill in the art to view
`
`modifications at C28 as less favorable, because it was known to be proximal to the
`
`interaction of rapamycin with
`
`the unidentified biological
`
`target of
`
`the
`
`rapamycin/FKBP-12 complex. (Id.) Further, because the interaction between the
`
`rapamycin/FKBP-12 complex and this second target had not been fully
`
`characterized, a person of ordinary skill in the art would have been motivated to
`
`start with small modifications at the C40 position in order to avoid introducing
`
`modifications that interfered with this binding. (Id.)
`
`123. Therefore, the teaching of Van Duyne regarding the interactions of
`
`rapamycin with FKBP-12 and its second biological target highlighted that the
`
`hydroxyl group at C40 was the best position to modify rapamycin without
`
`disrupting its biological activity. Further, because the interaction between
`
`rapamycin, FKBP-12, and the unknown target were not fully characterized, a
`
`person of ordinary skill in the art would have been motivated to start with small
`
`modifications at C40 so as to avoid unnecessarily disrupting binding to the
`
`unknown target as well as FKBP-12.
`
`
`
`55
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`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`122. The teaching in Schreiber regarding the effector domain of rapamycin
`
`provides additional motivation for a person of ordinary skill in the art to view
`
`modifications at C28 as less favorable, because it was known to be proximal to the
`
`interaction of rapamycin with
`
`the unidentified biological
`
`target of
`
`the
`
`rapamycin/FKBP-12 complex. (Id.) Further, because the interaction between the
`
`rapamycin/FKBP-12 complex and this second target had not been fully
`
`characterized, a person of ordinary skill in the art would have been motivated to
`
`start with small modifications at the C40 position in order to avoid introducing
`
`modifications that interfered with this binding. (Id.)
`
`123. Therefore, the teaching of Van Duyne regarding the interactions of
`
`rapamycin with FKBP-12 and its second biological target highlighted that the
`
`hydroxyl group at C40 was the best position to modify rapamycin without
`
`disrupting its biological activity. Further, because the interaction between
`
`rapamycin, FKBP-12, and the unknown target were not fully characterized, a
`
`person of ordinary skill in the art would have been motivated to start with small
`
`modifications at C40 so as to avoid unnecessarily disrupting binding to the
`
`unknown target as well as FKBP-12.
`
`
`
`55
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`6.
`
`Standard Assays to Test Immunosuppressive Activities and
`Properties of Rapamycin Derivatives Were Well-Known to
`Those of Ordinary Skill in the Art
`124. A person of ordinary skill in the art making modifications to
`
`rapamycin in October 1992 would also be strongly motivated to consider the
`
`assays known in the prior art for evaluating a compound’s immunosuppressive
`
`activity.
`
`125. And, as reflected in the prior art references disclosing other
`
`modifications to rapamycin, after synthesizing a rapamycin derivative, it was
`
`routine by October 1992 for those of ordinary skill in the art to assess the
`
`compound’s immunosuppressive activity in standard assays. For example, Hughes
`
`and Schiehser identify a number of derivatives of rapamycin and indicate that
`
`“[i]mmunosuppressive activity was evaluated
`
`in an
`
`in vitro standard
`
`pharmacological test procedure . . . and in two in vivo standard pharmacological
`
`test procedures.” (Ex. 1009, Hughes at 2:62-65 (emphases added).) One of the in
`
`vivo procedures described in Hughes assesses the ability of the rapamycin
`
`derivatives to prevent the rejection of a skin graft transplant in mice. (Id. at 3:51-
`
`4:12.)
`
` Hughes indicates that “[b]ased on the results of these standard
`
`pharmacological test procedures, the compounds are useful in the treatment of
`
`transplantation rejection such as, heart, kidney, liver, bone marrow, and skin
`
`transplants; [and] autoimmune diseases.” (Id. at 4:48-56.) These same types of
`
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`standard biological assays for evaluating compounds for immunosuppressant
`
`activity was also disclosed in Schiehser. (Ex. 1011.) Further, as detailed in
`
`Morris, these are precisely the types of immunosuppressant activities, including
`
`allograft rejection, that had been widely reported for rapamycin. (Ex. 1005, Morris
`
`at 54-64.)
`
`126. With respect to immunosuppressant compound candidates, those of
`
`ordinary skill in the art would routinely instruct technicians or collaborators to
`
`perform such standard assays to assess the activity of these candidates. Similarly,
`
`measurement of a compound’s solubility in aqueous solution was well known to
`
`those of ordinary skill in the art long before October 1992, and such measurements
`
`were reported for the rapamycin derivatives disclosed in Stella. (Ex. 1010, Stella
`
`at Tables 2 and 3.) Those of ordinary skill in the art would routinely instruct
`
`technicians or collaborators to perform such standard measurements.
`
`B.
`
`Prior Art Relevant to Obviousness Grounds 3 and 4
`1.
`
`Computer Based Modeling Allowed for Rapid Screening of
`Possible Modifications
`127. In addition to the rational structure based drug discovery process
`
`described above, those of ordinary skill in the art were also familiar with
`
`computer-aided drug design by October 1992. This included interactive display of
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`protein-ligand complexes and the modeling of analogues of the ligand bound to the
`
`protein.
`
`128. One particular advance aided by developments
`
`in computer
`
`technology was the use of molecular graphics to visualize and virtually manipulate
`
`drug compounds bound to their target receptors. (Ex. 1015, Silverman, Drug
`
`Discovery, Design, and Development, THE ORGANIC CHEMISTRY OF DRUG DESIGN
`
`& ACTION 11, 44-47 (1992) (“Silverman”).)
`
` Such a
`
`three-dimensional
`
`representation allowed the operator to “visualize the interactions of small
`
`molecules with biologically important macromolecules,” superimpose structures,
`
`and assemble new structures from known molecular fragments. (Id. at 45.) The
`
`applicability of this technique was best applied to ligand-receptor structures that
`
`had already been identified through crystallographic means. (See id.) Thus, for
`
`compounds whose structure in complex with its biological target had been
`
`characterized, the ability to use molecular graphics and modeling techniques
`
`provided a significant advantage to screen and evaluate potential modifications to
`
`identify
`
`those with favorable steric and electronic characteristics before
`
`undertaking the efforts to actually synthesize each of the potential new compounds.
`
`(Id. at 44-47.)
`
`129. By obtaining
`
`the
`
`three-dimensional coordinates of
`
`the bound
`
`rapamycin/FKBP-12 molecule available from Van Duyne as described above, a
`
`
`
`58
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`person of ordinary skill in the art could use software that was available by October
`
`1992 to produce computer models of complexes of rapamycin and derivatives with
`
`FKBP-12. Using such models allow those of skill in the art to investigate the
`
`complexes of various derivatives of rapamycin bound to FKBP-12. Software was
`
`specifically used for designing new potential drugs; key examples are the programs
`
`GROW (Ex. 1013, Joseph B. Moon & W. Jeffrey Howe, Computer Design of
`
`Bioactive Molecules: A Method for Receptor-Based de Novo Ligand Design, 11
`
`PROTEINS: STRUCTURE, FUNCTION, & GENETICS 314 (1991)), LEGEND (Ex.
`
`1028, Yoshihiko Nisibata et al., Automatic Creation of Drug Candidate Structures
`
`Based on Receptor Structure. Starting Point for Artificial Lead Generation., 47
`
`TETRAHEDRON 8985 (1991)), and LUDI (Ex. 1014, Hans-Joachim Böhm, LUDI:
`
`rule-based automatic design of new substituents for enzyme inhibitor leads, 6 J.
`
`COMPUTER-AIDED MOLECULAR DESIGN 593 (1992)). These represent core
`
`activities of “structure-based drug design;” the computer programs allowed
`
`researchers to quickly build models of complexes of potential drugs with their
`
`protein targets.
`
`X.
`
` CLAIMS 1-3 & 8-10 OF THE ’772 PATENT WOULD HAVE BEEN
`OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART
`130. I have reviewed the claims of the ’772 Patent. I understand from
`
`counsel for Par that because the specific compound claimed in claim 10 of the ’772
`
`
`
`59
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`Patent falls within the genus of compounds claimed in each of claims 1-3 and
`
`included in claims 8 and 9 of the ’772 Patent, if the compound claimed in claim 10
`
`is obvious over the prior art, then each of claims 1-3 is also obvious over the prior
`
`art. Similarly, I understand that if the immunosuppressant activity of the
`
`compound in claim 10 would have been obvious, then the methods claiming those
`
`activities in claims 8 and 9 would also have been obvious.
`
`131. It is my opinion that a person of ordinary skill in the art in October
`
`1992 would have found the specific rapamycin derivative claimed in claim 10 of
`
`the ’772 Patent, including its use as an immunosuppressant and for allograft
`
`rejection, obvious.
`
`A. Ground 1: Claims 1-3 and 10 of the ’772 Patent Would Have Been
`Obvious In View of Morris, Lemke, Yalkowsky, and Van Duyne
`and Rossmann
`1.
`
`A Person of Ordinary Skill in the Art Would Have Selected
`Rapamycin as a Lead Compound
`132. Initially, I was asked by counsel for Par to evaluate whether a person
`
`of ordinary skill in the art developing a new compound for immunosuppressant
`
`therapy in October 1992 would have begun by identifying a lead compound, and if
`
`so, what compound the person of ordinary skill in the art would select. As
`
`described below, in my opinion, based on the teachings exemplified in Morris, a
`
`
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`person of ordinary skill in the art in October 1992 would have identified and
`
`selected rapamycin as a lead compound for numerous reasons.
`
`133. As Morris describes, rapamycin was widely known as a potent
`
`immunosuppressant. (Ex. 1005, Morris at 39.) And by October 1992, those of
`
`skill in the art were very familiar with rapamycin’s structure and properties. Its
`
`potent immunosuppressant activity provided significant motivation for a person of
`
`ordinary skill in the art to select rapamycin as a lead compound. Indeed, although
`
`rapamycin had been discovered decades before, Morris describes that in the early
`
`1990s there was a renaissance of interest in rapamycin given its exciting potential
`
`as a treatment for the prevention of transplant rejection, stating that an
`
`Investigational New Drug Application (“IND”) had been approved only two years
`
`after this promising activity had first been reported. (Id.)
`
`134. Further, as admitted in the ’772 Patent and expressed in Morris,
`
`rapamycin’s utility as a pharmaceutical was limited by its relatively poor
`
`solubility. (Ex. 1001, ’772 Patent at 1:36-40; Ex. 1005, Morris at 46.) A person of
`
`ordinary skill in the art would have been motivated to select rapamycin as a lead
`
`compound in order to improve upon its poor solubility while maintaining its well-
`
`established immunosuppressive activity. Additionally, a person of ordinary skill in
`
`the art would have recognized that although rapamycin was poorly soluble, it was
`
`not completely insoluble. (Ex. 1005, Morris at 46.) Therefore, as evidenced by the
`
`
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`teachings in Morris, a person of ordinary skill in the art would have recognized that
`
`even modest
`
`improvements
`
`could
`
`significantly
`
`improve
`
`rapamycin’s
`
`characteristics as a drug candidate. For this additional reason, a person of ordinary
`
`skill in the art would have been motivated to select rapamycin as a lead compound
`
`in October 1992.
`
`135. Additionally, shortly before October 1992, Van Duyne revealed the
`
`structure of rapamycin bound to FKBP-12. A person of ordinary skill in the art
`
`would have been motivated to select rapamycin as a lead compound because they
`
`would have been guided by this additional structural information from Van Duyne
`
`in selecting and evaluating derivatives to make. Having the structural information
`
`from Van Duyne provided a person of ordinary skill in the art a map to the
`
`rapamycin molecule and increased the expectation of synthesizing derivatives with
`
`the desired properties. For this additional reason, a person of ordinary skill in the
`
`art would have been motivated to select rapamycin as a lead compound in October
`
`1992.
`
`136. Finally, rapamycin derivatives could be readily synthesized and were
`
`known to retain immunosuppressant activity. (See § IX.A.4.) A person of
`
`ordinary skill in the art would have been motivated to select rapamycin as a lead
`
`compound because they would have had a reasonable expectation of successfully
`
`
`
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`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`synthesizing additional rapamycin derivatives that retained immunosuppressant
`
`activity.
`
`137. For at least these reasons, a person of ordinary skill in the art would
`
`have been motivated to select rapamycin as a lead compound for modification.
`
`2.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Modify Rapamycin to Improve Its Solubility
`As Taught in the Prior Art
`138. Once a person of ordinary skill in the art selected rapamycin as a lead
`
`compound, that person would have next determined how to modify its structure—
`
`using well-known techniques—to achieve the desired increase in solubility. As
`
`discussed above, based on the teachings exemplified in Morris and acknowledged
`
`in the ’772 Patent, a person of ordinary skill in the art seeking to modify the
`
`structure of rapamycin would have been motivated to look to other references that
`
`would help to reveal how to maintain rapamycin’s immunosuppressive activity,
`
`while at the same time, improving on its relatively poor solubility.
`
`139. With respect to improving on rapamycin’s properties, it was well-
`
`known to those of ordinary skill in the art by October 1992 (and well before) that
`
`rapamycin had poor solubility. (Ex. 1005, Morris at 46.) This is unsurprising
`
`when looking at rapamycin’s chemical structure, as it is a large molecule with
`
`relatively few hydrophilic moieties and with large hydrophobic regions.
`
`
`
`63
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`140. Aqueous solubility of a molecule influences its absorption in animals.
`
`A person of ordinary skill in the art therefore understood by October 1992 that by
`
`improving the solubility of a poorly soluble drug, one can improve the drug’s
`
`bioavailability. Increased bioavailability allows for lower doses of the drug to be
`
`administered to patients, while still achieving the same effect, as well as allows for
`
`oral administration, as opposed to injection. Further, as explained above,
`
`derivatives of rapamycin had been successfully synthesized that had dramatically
`
`improved solubility. (See § IX.A.4, above.) Therefore, a person of ordinary skill
`
`in the art would have been motivated to modify rapamycin to improve its solubility
`
`while maintaining its immunosuppressant activity.
`
`3.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Select C40 of Rapamycin for Modification to
`Avoid Disrupting Its Activity
`141. In modifying rapamycin to improve its solubility, a person of ordinary
`
`skill in the art would further be motivated to make modifications that would
`
`maintain rapamycin’s immunosuppressant activity. As such, a person of ordinary
`
`skill in the art would be motivated to look to references that taught what portions
`
`of the rapamycin molecule should not be modified so as to maintain biological
`
`activity. Therefore, a person of ordinary skill in the art would be highly motivated
`
`to look to the teaching of Van Duyne. As explained in Section IX.A.5.a, Van
`
`Duyne and Rossmann taught a person of ordinary skill in the art in October 1992
`
`
`
`64
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`how the atoms of the rapamycin molecule are interacting with FKBP-12. (Ex.
`
`1006, Van Duyne at 7434.) By October 1992, as acknowledged by the ’772
`
`Patent, those of ordinary skill in the art knew that rapamycin worked by first
`
`binding to FKBP-12, and additionally knew the structure of the rapamycin/FKBP-
`
`12 complex. (Ex. 1001, ’772 Patent at 5:63-67.) A person of ordinary skill in the
`
`art in October 1992 would thus be motivated to look to Van Duyne to know
`
`precisely which portion of the rapamycin molecule—the portion of rapamycin in
`
`greatest contact with the binding pocket of FKBP-12—to avoid modifying so as
`
`not to interfere with rapamycin’s immunosuppressive activity.
`
`142. A person of ordinary skill in the art would have focused on the
`
`hydroxyl groups on rapamycin as initial targets for modification. Chemical
`
`reactions of hydroxyl groups are among the most fundamental and elementary
`
`reactions taught in beginning organic chemistry courses. As such, hydroxyl groups
`
`would have been, and still are, the first positions a person of ordinary skill in the
`
`art would modify on a lead compound because they are synthetically easy to
`
`modify. The hydroxyl groups at rapamycin’s C10, C28, and C40 positions are
`
`highlighted in the figure below.
`
`
`
`65
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`
`
`Moreover, it was already known in the art that modifications to rapamycin had
`
`been made at the hydroxyl groups at C40 and C28 and had been shown to maintain
`
`immunosuppressant activity. (See § IX.A.4; § IX.A.6, above.)
`
`143. One of ordinary skill in the art in October 1992 would have known
`
`from the structure disclosed in Van Duyne that both the C10 and C28 atoms are
`
`central to rapamycin’s binding domain and therefore its interactions with FKBP-
`
`12’s binding pocket. (Ex. 1006, Van Duyne at 7434 (“protein-ligand interface
`
`involves atoms from the pyranose ring through the C28 hydroxyl, with the
`
`remainder, including the C17-C22 triene, exposed.”); § IX.A.5.a, above.) And
`
`because they are both part of that protein/ligand interface, one of ordinary skill in
`
`the art would conclude from the teaching of Van Duyne that C10 and C28 are less
`
`desirable sites for modification. Further, one of ordinary skill in the art knew that
`
`
`
`66
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`C28 is proximal to the effector domain, the portion of rapamycin that interacts with
`
`a second unknown target, important to its resulting immunosuppressant activity.
`
`(See § IX.A.5.c, above.) As such, a person of ordinary skill in the art would have
`
`viewed C28 as a less favorable position at which to make modifications.
`
`144. Because Van Duyne discloses that the hydroxyl group at C40 by
`
`comparison is on the periphery of rapamycin’s interaction with FKBP-12 and that
`
`C40 is not part of rapapmycin’s effector domain, a person of ordinary skill in the
`
`art would have selected the C40 hydroxyl as the primary candidate for
`
`modification of rapamycin through the addition of new groups. (See Ex. 1006,
`
`Van Duyne at 7434.)
`
`145. Therefore, a person of ordinary skill in the art would have selected the
`
`C40 hydroxyl of rapamycin at which to make modifications and would have done
`
`so with a reasonable expectation of obtaining derivatives that maintained their
`
`immunosuppressive activity.
`
`4.
`
`A Person of Ordinary Skill in the Art Would Have Modified
`Rapamycin to Add Short, Flexible Side Chains with
`Solubilizing Substituents at C40
`146. As explained above, when considering how to modify rapamycin at
`
`the C40 position to improve its poor solubility, a person of ordinary skill in the art
`
`would be highly motivated to consider prior art references that disclose the
`
`solubilizing properties of substituents. Lemke and Yalkowsky teach that adding
`
`
`
`67
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`solubilizing substituents and side chains with rotatable bonds are expected to
`
`increase the solubility of molecules like rapamycin. (Ex. 1008, Lemke at 116; Ex.
`
`1007, Yalkowsky at 110-111.) A person of ordinary skill in the art would be
`
`motivated by the teaching of Morris about rapamycin’s poor solubility to apply the
`
`teachings of Lemke and Yalkowsky to modify rapamycin at C40 to improve its
`
`solubility.
`
`147. Yalkowsky teaches that adding rotatable bonds provides a free energy
`
`benefit that favors dissolution of a molecule. (Ex. 1007, Yalkowsky at 110-111.)
`
`Thus, modifications that add such rotatable bonds would be expected to result in
`
`increased solubility. (Id.; see § IX.A.3.)
`
`148. Lemke teaches that the substituents with the most solubilizing
`
`potential are alcohol (hydroxyl), phenol, amines, carboxylic acid, ester and amide
`
`groups.
`
`
`
`68
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`
`149. Phenol groups, which contain six carbon atoms and a hydroxyl group;
`
`ester groups, which contain at least two carbon atoms and two oxygen atoms; and
`
`amide groups, which contain at least one carbon atom, one nitrogen atom, and one
`
`oxygen atom, are larger than the other substituents identified by Lemke as having
`
`the largest solubilizing potential. Based on the teaching of Van Duyne that the
`
`C40 position of rapamycin is peripheral to the binding to FKBP-12 and the known
`
`fact that the rapamycin/FKBP-12 complex binds to an unidentified target, a person
`
`of ordinary skill in the art would not select these larger groups as the first to
`
`modify rapamycin to obtain a derivative with increased solubility and retained
`
`immunosuppressive activity because they would want to start with the smallest
`
`
`
`69
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`substitutions possible to avoid unnecessarily increasing the molecular size and
`
`potentially interfering with rapamycin’s biological activity. (See § IX.A.5.c,
`
`above.) Further, as noted above, ester and amide groups are also prone to
`
`hydrolysis and would not be among the first substituents selected for modification.
`
`(See § IX.A.3, above.) Further still, addition of carboxylic acid groups may lead to
`
`formation of dimers in the solid state, which can adversely affect solubility.
`
`Therefore, based on the teaching of Lemke in view of the teaching of Van Duyne
`
`regarding the binding of rapamycin to FKBP-12, a person of ordinary skill in the
`
`art would have first selected alcohol (hydroxyl), amine, and lastly carboxylic acid
`
`groups with which to modify rapamycin to improve its solubility and retain
`
`activity.
`
`150. When making substitutions at the C40 position, a person of ordinary
`
`skill in the art would be highly motivated to use relatively small substituents,
`
`because they recognized that, as a general rule, it is preferable to start with the
`
`smallest, simplest substitutions possible and to progress to larger groups, if needed.
`
`As the size of a modification increases so do the risks of metabolic difficulties and
`
`other side effects. Further, a person of ordinary skill in the art would be aware that
`
`rapamycin is already unusually large for a pharmaceutical drug and, therefore,
`
`would have been additionally motivated to consider smaller substitutions so as to
`
`avoid further increases in molecular size.
`
`
`
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`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`151. In addition, a person of ordinary skill in the art would have
`
`understood that as the size of the new groups increases, the likelihood that the
`
`added group could interfere with the biological activity of the molecule increases.
`
`It was known that the rapamycin-FKBP-12 complex bound to a second protein that
`
`had not yet been identified in 1992. (See § IX.A.5.c.) As such, a person of
`
`ordinary skill in the art would have been motivated to start by making small
`
`substitutions to rapamycin in order to avoid disrupting the binding to this unknown
`
`target and thus interfering with rapamycin’s immunosuppressant activity.
`
`152. The smallest modification possible that would add rotatable bonds and
`
`a solubilizing substituent would be a single carbon atom linking group to the
`
`substituent. A one-carbon linker to an alcohol group, an amine group, and a
`
`carboxyl group would result in a hydroxymethoxy (OCH2OH), aminomethoxy
`
`(OCH2NH2), and carboxymethoxy (OCH2COOH). However, one of ordinary skill
`
`in the art in October 1992 would have known that a hydroxymethoxy and
`
`aminomethoxy groups—an acetal and a hemiaminal—are unstable in aqueous
`
`solution and would rapidly decompose back to the original rapamycin structure.
`
`As such, a person of ordinary skill in the art in October 1992 would not have
`
`selected these substitutions as they would have recognized that these modifications
`
`would not have led to a compound with improved solubility, given that the
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
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`compound would simply revert back to rapamycin and all of its known properties,
`
`including its poor solubility, during attempted synthesis or purification.
`
`153. Thus, the smallest flexible carbon linker a person of ordinary skill in
`
`the art would first consider using in order to add the alcohol and amine substituents
`
`taught by Lemke and the rotatable bonds taught by Yalkowsky would be two alkyl
`
`carbons (CH2CH2). As such, the first three groups that a person of ordinary skill in
`
`the art would be motivated to modify rapamycin in order to improve its solubility
`
`without disrupting its activity by applying the teachings of Lemke and Yalkowsky
`
`would be the 2-hydroxyethoxy group (OCH2CH2OH), the 2-aminoethoxy group
`
`(OCH2CH2NH2), and the carboxymethoxy group (OCH2COOH).4
`
`154. It was standard practice in the field of medicinal chemistry as of 1992
`
`that once a target group of promising compounds had been identified, several
`
`candidate compounds would be synthesized and simultaneously evaluated for
`
`
`4 Indeed, the ’772 Patent describes modifications at the C40 position that
`
`encompass both the 2-hydroxyethoxy group as well as the aminoethoxy group.
`
`(Ex. 1001, ’772 Patent at 2:6 (disclosing an “aminoalkyl” substitution).) Further,
`
`the carboxymethoxy modification was included in the disclosure of Hughes. (Ex.
`
`1009, Hughes at 2:25-26 (disclosing that R2 includes a hydrogen, making a
`
`carboxymethoxy group).)
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
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`activity. In other words, medicinal chemists in 1992 would not have proceeded to
`
`make and assay compounds one by one. Rather, multiple compounds would have
`
`been made and evaluated in parallel in groups.
`
`155. In my opinion, a person of ordinary skill in the art in 1992 would have
`
`sought to improve the solubility of rapamycin by making derivatives at the C40
`
`position, and in the course of so doing, would have synthesized and evaluated each
`
`of 40-(2-hydroxyethyl)-rapamycin, 40-(2-aminoethyl)-rapamycin,
`
`and 40-
`
`(carboxymethyl)-rapamycin.
`
`156. Therefore, based on the teachings of Morris, Van Duyne and
`
`Rossman, Lemke, and Yalkowsky, it is my opinion that a person of ordinary skill
`
`in the art would have been motivated (1) to select rapamycin as a lead compound;
`
`and (2) to modify rapamycin to improve its solubility by making small, routine
`
`substitutions at
`
`the C40 hydroxyl,
`
`including 2-hydroxyethoxy group
`
`(OCH2CH2OH), 2-aminoethoxygroup (OCH2CH2NH2), and carboxymethoxy
`
`group (OCH2COOH), with a reasonable expectation of obtaining a rapamycin
`
`derivative with improved solubility that has immunosuppressant activity.
`
`157. Claim 1 of the ’772 Patent claims a compound of the formula:
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
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`R1O
`
`40
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`
`
`wherein R1 is hydroxyl(C1-6)alkyl or hydroxyl(C1-3)alkoxy(C1-3)alkyl.
`
`158. Claim 2 depends from claim 1 and recites a compound according to
`
`claim 1 in which R1 is hydroxy(C1-3)alkyl or hydroxy(C1-3)alkoxy(C1-3)alkyl.
`
`159. Claim 3 depends from claim 1 and recites a compound according to
`
`claim 1 in which R1 is hydroxy(C1-3)alkyl.
`
`160. Claim 10 depends from claim 1 and, as corrected by the Certificate of
`
`Correction attached to the ’772 Patent, recites the compound according to claim 1
`
`which is 40-O-(2-hydroxyethyl)-rapamycin.
`
`161. The 2-hydroxyethoxy derivative of rapamycin at C40 is the compound
`
`recited in claim 10 and falls within the scope of the compounds claimed in claims
`
`1, 2, and 3. Therefore, claim 10 would have been obvious to a person of ordinary
`
`skill in the art as of October 1992. Further, claim 1 would have been obvious to a
`
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
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`person of ordinary skill in the art as of October 1992. Additionally, claim 2 would
`
`have been obvious to a person of ordinary skill in the art as of October 1992.
`
`Finally, claim 3 would have been obvious to a person of ordinary skill in the art as
`
`of October 1992.
`
`B. Ground 2: Claims 8 and 9 of the ’772 Patent Would Have Been
`Obvious In View of Morris, Lemke, Yalkowsky, and Van Duyne
`and Rossmann, in further view of Hughes
`162. Claim 8 recites a “method of inducing an immunosuppressant effect in
`
`a subject in need of immunosuppression, which comprises administering to said
`
`subject an immunosuppressant effective amount of a compound according to of
`
`claim 1.”
`
`163. Claim 9 recites a “method of preventing allograft rejection in a subject
`
`in need of such treatment, which comprises administering to said subject a
`
`compound according to claim 1 in an amount effective to prevent allograph
`
`rejection.”
`
`164. In my opinion these method claims would have been obvious to a
`
`person of ordinary skill in the art in October 1992.
`
`165. As explained above in Ground 1, a person of ordinary skill in the art
`
`would have found the 40-(2-hydroxyethyl)-rapamycin derivative, which falls
`
`within the scope of claim 1, obvious, based in part on the reasonable expectation
`
`that such a derivative would retain immunosuppressant activity. The only
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`additional limitations present in claims 8 and 9 of the ’772 Patent, the use of the
`
`compound as an immunosuppressant or to prevent allograft rejection, would also
`
`have been obvious. As explained in more detail below, based on the prior art
`
`modifications made to rapamycin at the C40 position, a person of ordinary skill in
`
`the art would have a reasonable expectation that additional rapamycin derivatives
`
`at C40 would possess immunosuppressant activity, including the ability to prevent
`
`allograft rejection, as its parent compound rapamycin was known to possess.
`
`1.
`
`A Person of Ordinary Skill in the Art Would Reasonably
`Expect that Small Solubilizing Modifications to Rapamycin
`at C40 Would Retain Immunosuppressive Activity
`166. Based on the teachings of Hughes, a person of ordinary skill in the art
`
`in October 1992 would have reasonably expected that the 40-(2-hydroxyethyl)-
`
`rapamycin derivative included in the scope of claim 1 would retain its
`
`immunosuppressive activity, including the ability to prevent allograft rejection.
`
`167. Initially, as explained above, a person of ordinary skill in the art in
`
`October 1992 knew that others, such as Hughes, had successfully synthesized
`
`derivatives of rapamycin at the C40 position.
`
`168. Furthermore, as explained above in § IX.A.5, Van Duyne and
`
`Rossmann elucidated the structure of the three-dimensional complex of rapamycin
`
`and FKBP-12. With this teaching from Van Duyne, a person of ordinary skill in
`
`the art in October 1992 would have understood that such small modifications at
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`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Pa
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