Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`art would be guided by the structure to avoid modifying the hydroxyl group on
`
`C28
`
`to
`
`avoid
`
`disrupting
`
`interactions with FKBP-12
`
`and
`
`thus
`
`the
`
`immunosuppressant activity.
`
`177.
`
`In contrast to these other two hydroxyl groups, the bound structure
`
`shows that the hydroxyl group on C40 is a substituent that could be modified to
`
`improve the solubility of the rapamycin molecule. As shown in the figure below,
`
`the FKBP-12 protein when bound to rapamycin is positioned in such a way that the
`
`C40 hydroxyl group resides on the periphery of the complex and could
`
`accommodate modifications.
`
`space to extend
`T
`
`80
`
`
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`art would be guided by the structure to avoid modifying the hydroxyl group on
`
`C28
`
`to
`
`avoid
`
`disrupting
`
`interactions with FKBP-12
`
`and
`
`thus
`
`the
`
`immunosuppressant activity.
`
`177.
`
`In contrast to these other two hydroxyl groups, the bound structure
`
`shows that the hydroxyl group on C40 is a substituent that could be modified to
`
`improve the solubility of the rapamycin molecule. As shown in the figure below,
`
`the FKBP-12 protein when bound to rapamycin is positioned in such a way that the
`
`C40 hydroxyl group resides on the periphery of the complex and could
`
`accommodate modifications.
`
`space to extend
`T
`
`80
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`178. From this information based on the structure, a person of ordinary
`
`skill in the art in October 1992 would have been motivated to make modifications
`
`to rapamycin at the C40 position.
`
`179. Further, because coordinates of Van Duyne structure could be
`
`obtained and because computer-aided drug design software was available and
`
`widely in use, a person of ordinary skill in the art would have been able to model
`
`substitutions in detail at C40 in order to determine which substitutions would be
`
`structurally promising and permissible sterically. (See § IX.A.5.b.) In addition,
`
`the structure of FKBP-12 in solution had been published, providing further
`
`information valuable for modeling the interactions with rapamycin using these
`
`computer programs. (Ex. 1029, Stephen W. Michnick et al., Solution Structure of
`
`FKBP, a Rotamase Enzyme and Receptor for FK506 and Rapamycin, 252 SCI. 836
`
`(1991).) Such modeling would have allowed a person of ordinary skill in the art to
`
`filter out substitutions that would be sterically unfavorable. Thus, a person of
`
`ordinary skill in the art would have been motivated to evaluate substitutions at C40
`
`using molecular modeling tools.
`
`180. Additionally, as discussed above, a person of ordinary skill in the art
`
`would have been motivated to screen modifications to rapamycin that would
`
`improve rapamycin’s known poor solubility. (See, § IX.A.2, above.) Based on the
`
`(1) teachings from Lemke, (2) the knowledge that introducing side chains with
`
`
`
`81
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`flexible and rotatable bonds provides a free energy driving force toward dissolution
`
`from Yalkowsky, and (3) the underlying principle of drug design
`
`that
`
`modifications should be as small as possible to avoid disrupting the target
`
`biological behavior or introducing off-target metabolic or toxicity problems (see
`
`§ IX.A.3, above), a person of ordinary skill in the art would model potential
`
`substitutions to rapamycin at the C40 position.
`
`181. With these general concepts in mind, a person of ordinary skill in the
`
`art in October 1992 would screen a number of potential modifications to
`
`rapamycin at the C40 position. Among these modifications, one of skill in the art
`
`would model (1) a 2-hydroxyethoxy group (OCH2CH2OH); (2) a 2-aminoethoxy
`
`group (OCH2CH2NH2); and (3) a carboxymethoxy group (OCH2COOH). Each of
`
`these possible substitutions would have resulted in a small modification to
`
`rapamycin that would have reasonably been expected to improve solubility without
`
`disrupting binding to FKBP-12.
`
`182. Additionally, each of the 2-hydroxyethoxy group (OCH2CH2OH), the
`
`2-aminoethoxy group
`
`(OCH2CH2NH2), and
`
`the carboxymethoxy group
`
`(OCH2COOH) substitutions would be accommodated in the model of the
`
`rapamycin backbone bound to FKBP-12. These groups could project into the
`
`solvent and benefit from hydrogen bonds with water molecules and/or possibly
`
`make hydrogen bonds, for example, with the side chain amide group of the Gln53
`
`
`
`82
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`or backbone carbonyl group of Val55 of FKBP-12, as show in the Figure below.
`
`The substitutions at C40 would cause loss of the hydrogen bond between the C40
`
`hydroxyl group and the carbonyl oxygen of Gln53 that is present in the Van Duyne
`
`crystal structure. 03x. 1006, Van Duyne at 7434.) However, a person of ordinary
`
`skill in the art would recognize that in aqueous solution, the water structure in this
`
`region could adjust to accommodate a hydrogen bond between a water molecule
`
`and the carbonyl oxygen of Gh153
`
`
`
`183. A person of ordinary skill in the art would have recognized that
`
`modifications at C40 could be made and retain immunosuppressant activity, as
`
`shown by the results of Hughes, which modified the C40 hydroxyl of rapamycin
`
`and showed that the resulting derivatives maintained immunosuppressant activity.
`
`(See § IX.A.4, above.)
`
`83
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`184. Given these ultimately favorable indications from the model, a person
`
`of ordinary skill in the art in October 1992 would have been motivated to
`
`synthesize rapamycin derivatives with these substitutions to evaluate their
`
`biological and physiochemical properties using standard and routine techniques.
`
`(See IX.A.6, above.) Further, because of the model, a person of ordinary skill in
`
`the art in October 1992 would have a reasonable expectation that, when
`
`synthesized,
`
`these derivatives would
`
`result
`
`in a compound
`
`that has
`
`immunosuppressant activity and improved solubility.
`
`185. Therefore, it is my opinion that based on (1) the structure of the
`
`rapamycin/FKBP-12 complex, (2) the available modeling software for three-
`
`dimensional drug-protein interactions, and (3) the teachings of Lemke and
`
`Yalkowsky on improving solubility, a person of ordinary skill in the art would
`
`have been motivated to synthesize at least the –OCH2CH2OH, -OCH2CH2NH2, and
`
`–OCHCOOH derivatives at the C40 hydroxyl of rapamycin.
`
`186. Claim 1 of the ’772 Patent claims a compound of the formula:
`
`
`
`
`
`84
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`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.
`
`187. 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.
`
`188. Claim 3 depends from claim 1 and recites a compound according to
`
`claim 1 in which R1 is hydroxy(C1-3)alkyl.
`
`189. 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.
`
`190. Because the compound claimed in claim 10 of the ’772 Patent is the –
`
`OCH2CH2OH rapamycin derivative, it is my opinion that claim 10 is obvious.
`
`
`
`85
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`191. Further, because the –OCH2CH2OH rapamycin derivative falls within
`
`the scope of the compounds claimed in claim 1, it is my opinion that claim 1 is
`
`obvious.
`
`192. Additionally, because the –OCH2CH2OH rapamycin derivative falls
`
`within the scope of the compounds claimed in claim 2, it is my opinion that claim 2
`
`is obvious.
`
`193. Finally, because the –OCH2CH2OH rapamycin derivative falls within
`
`the scope of the compounds claimed in claim 3, it is my opinion that claim 3 is
`
`obvious.
`
`D. Ground 4: Claims 8 and 9 Would Have Been Obvious to a Person
`of Ordinary Skill in the Art in October 1992
`194. 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.”
`
`195. 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.”
`
`
`
`86
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`196. In my opinion these method claims would have been obvious to a
`
`person of ordinary skill in the art in October 1992.
`
`197. As explained above in Ground 3, 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
`
`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 Solubilizing Modifications to Rapamycin at C40
`Would Retain Immunosuppressive Activity
`198. 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 was likely to retain its
`
`immunosuppressive activity, including the ability to prevent allograft rejection.
`
`
`
`87
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`199. 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.
`
`200. Furthermore, as explained above, Van Duyne 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 C40 of rapamycin would be unlikely to
`
`eliminate rapamycin’s immunosuppressive activity, which is dependent upon the
`
`rapamycin/FKBP-12 complex. Indeed, it would have been readily expected by one
`
`of ordinary skill in the art in October 1992, based on the structure in Van Duyne,
`
`that the rapamycin/FKBP-12 complex could accommodate the 2-hydroxyethyl
`
`substituent at the C40 position.
`
`201. A person of ordinary skill in the art in October 1992 knew from
`
`Hughes that rapamycin derivatives with substitutions at the C40 position had
`
`immunosuppressive activity like rapamycin, including the ability to prevent
`
`allograft rejection. As such, a person of ordinary skill in the art would have
`
`reasonably expected the 2-hydroxyethyl derivative of rapamycin at C40 would
`
`have immunosuppressive activity, including the ability to prevent allograft
`
`rejection.
`
`
`
`88
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`202. Moreover, a person of ordinary skill in the art would have routinely
`
`evaluated rapamycin derivatives in standard in vitro and in vivo assays to
`
`determine their immunosuppressive activity. As described above, Hughes teaches
`
`such assays to evaluate the immunosuppressive activity of rapamycin derivatives,
`
`including the administration of rapamycin derivatives to mice to evaluate the
`
`ability of the derivatives to prevent allograft rejection. (See § IX.A.6, above.)
`
`203. Following the teachings of Hughes, a person of ordinary skill in the
`
`art would have administered immunosuppressant effective amounts of the
`
`synthesized rapamycin derivatives, including the 40-(2-hydroxyethyl)-rapamycin
`
`that falls within the scope of claim 1, to mice in order to evaluate the
`
`immunosuppressant activity, including the ability to prevent allograft rejection. As
`
`such, a person of ordinary skill in the art would have practiced each and every
`
`element of claims 8 and 9 following the teachings of Hughes.
`
`204. Therefore, it is my opinion that claims 8 and 9 would have been
`
`obvious to a person of ordinary skill in the art as of October 1992.
`
`XI.
`
` SECONDARY CONSIDERATIONS FAIL TO OVERCOME THE
`STRONG EVIDENCE OF OBVIOUSNESS
`205. I am unaware of any secondary considerations that would make
`
`Claims 1-3 & 8-10 in the ’772 Patent non-obvious over the prior art as described
`
`above. In my opinion, the presence of any such secondary considerations does not
`
`
`
`89
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