`Par Petition for Inter Partes Review of U-S. Patent No. 5,665,772
`
`117. This portion of the structure informs a person of ordinary skill in the
`
`art that the carbon at rapamycin’s C10 position lies in a “pocket” in the FKBP-12
`
`protein. A person of ordinary skill in the art therefore understands from the
`
`structure that the C10 position is a poor candidate for molecular modification,
`
`because any substituents added to the carbon at the C10 position (which will be
`
`larger than the hydroxyl group) are likely to interfere with rapamycin’s ability to
`
`bind to FKBP-12 and therefore interfere with rapamycin’s immunosuppressive
`
`activity. The C10 hydroxyl group is also part of an acetal, ROCI-H{'OH. Making
`
`ketal O{OCHR'OR") derivatives of acetals is generally undesirable as they may be
`
`easily hydrolyzed back to the acetal.
`
`52
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`118.
`
`In the next figure below, the local environments of the hydroxyl
`
`groups attached to the carbons at rapamycin’s C28 and C40 positions are depicted.
`
`119. Like the carbon at rapamycin’s C10 position, a person of ordinary
`
`skill in the art would understand from the structure that the carbon at rapamycin’s
`
`C28 position is a poor candidate for molecular modification, because any
`
`substituents added to the carbon at the C28 position (which will be larger than the
`
`hydroxyl group) are likely to interfere with rapamycin’s ability to bind to FKBP-
`
`12.
`
`120. The carbon at rapamycin’s C40 position, by contrast, is farther from
`
`the core of the FKBP-12 and adjacent to empty space (the white space in the
`
`Figure above, which is only filled with water). A person of ordinary skill in the art
`
`53
`
`
`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`would recognize that substituents could be attached to the C40 oxygen atom that
`
`would extend into this water-filled space without interfering with rapamycin’s
`
`binding to FKBP—l2. As such, the structure directs a person of ordinary skill in the
`
`art that the C40 hydroxyl group is the optimal position for modifying rapamycin to
`
`avoid disrupting binding with FKBP-12 and thus its immunosuppressive activity.
`
`c.
`
`Rapamycin Was Further Known to Bind to Another
`Unidentified Biological Target
`
`121. By October 1992, as noted above,
`
`it was further known that the
`
`rapamycin/FKBP-12 complex interacted with a second unknown biological target
`
`that was essential for the immunosuppressant activity of rapamycin.
`
`(See, e.g., Ex.
`
`1012, Schreiber at 286.) Although,
`
`the biological
`
`target had not yet been
`
`identified, the effector domain, the portion of rapamycin that interacted with this
`
`second target, had been identified, as shown in the figure below- (Id. at Fig. 5(B).)
`
`
`
`54
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