Bicyclerd Ltd v. PepScan Systems BV

1. Case Identification

• Case #: IPR2020-01626
• Patent #: 8,748,105
• Filed: September 14, 2020
• Petitioner(s): Bicyclerd, Ltd.
• Patent Owner(s): Pepscan Systems BV.
• Challenged Claims: 1-17 and 19

2. Patent Overview

• Title: Synthesis of Peptide Macrocycles
• Brief Description: The ’105 patent claims methods for synthesizing conformationally restricted cyclic peptides (peptide macrocycles). The methods involve coupling a peptide containing at least two thiol (-SH) groups to an aromatic scaffold molecule containing at least two halomethyl groups to form stable thioether linkages in a buffered aqueous solution.

3. Grounds for Unpatentability

Ground 1: Claims 1-9, 11-17, and 19 are obvious over Rich, Nakhle, and Yu

• Prior Art Relied Upon: Rich (a 1992 journal article), Nakhle (a 1999 journal article), and Yu (a 1998 journal article).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the prior art collectively teaches every element of the challenged claims. Rich was asserted to disclose the core method: synthesizing peptide macrocycles by reacting a peptide containing two thiol groups with a bis(bromomethyl)benzene scaffold to form two thioether linkages. Rich’s method was conducted in the presence of an unprotected alcohol functional group, satisfying the claim requirement for an unprotected side chain. The key element missing from Rich, Petitioner argued, is the use of a buffered aqueous solution. Petitioner asserted that Nakhle and Yu supply this missing element. Nakhle taught coupling peptides to a tris(bromomethyl)benzene scaffold in a buffered 1:1 acetonitrile:water solution. Similarly, Yu taught the intramolecular cyclization of peptides via thioether formation in a buffered aqueous solution, demonstrating high yields even in the presence of various unprotected amino acid side chains (lysine, arginine, aspartic acid).
  • Motivation to Combine: Petitioner contended a person of ordinary skill in the art (POSITA) would combine these references to create a more efficient and safer synthetic process. The motivation stemmed from the well-known goals in synthetic chemistry to minimize steps (by avoiding protection/deprotection of side chains, as taught by Rich and Yu), increase yield, and use less hazardous solvents. A POSITA looking at Rich's synthesis would be motivated by the successful aqueous reactions in Nakhle and Yu to adapt Rich’s method to a more desirable buffered aqueous system, thereby avoiding toxic organic solvents and potentially simplifying the procedure.
  • Expectation of Success: Petitioner argued a POSITA would have had a reasonable expectation of success. The underlying reaction, thiol alkylation, is a robust and well-understood nucleophilic substitution. Rich demonstrated its effectiveness for creating the target macrocycles, while Nakhle and Yu demonstrated that this specific chemistry proceeds efficiently and selectively in buffered aqueous solutions, even with unprotected side chains. The collective teachings provided a clear and predictable path to the claimed invention.

Ground 2: Claim 10 is obvious over Rich, Nakhle, Yu, and Akamatsu

• Prior Art Relied Upon: Rich (a 1992 journal article), Nakhle (a 1999 journal article), Yu (a 1998 journal article), and Akamatsu (a 1997 journal article).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground builds upon the combination asserted in Ground 1 to specifically address the limitation of claim 10, which requires the aqueous solution to be "buffered at about pH 7.8." The combination of Rich, Nakhle, and Yu taught performing the thioether coupling reaction in a buffered, alkaline aqueous solution. Petitioner asserted that Akamatsu provided the final piece by teaching a nearly identical reaction—the cyclization of a peptide via thiol alkylation—that was initiated by adjusting the solution to a pH of 7-8. This pH range disclosed by Akamatsu directly encompasses the pH 7.8 recited in claim 10.
  • Motivation to Combine: Petitioner argued that a POSITA, having arrived at the method of claim 9 through the combination of Rich, Nakhle, and Yu, would be motivated to optimize reaction conditions to improve yield. Since pH is a known result-effective variable for thiol alkylation reactions (as it affects the deprotonation of the thiol to the more nucleophilic thiolate), a POSITA would consult the art for guidance on optimal pH ranges. Akamatsu provided a direct suggestion to use a pH of 7-8 for a similar reaction, motivating the artisan to select a pH within this narrow, disclosed range, such as the claimed 7.8, in a straightforward case of optimizing a known process.
  • Expectation of Success: Given that Akamatsu explicitly taught successful cyclization at pH 7-8, a POSITA would reasonably expect that applying this condition to the process from Ground 1 would be successful. Petitioner contended this was not a case of unpredictable trial and error, but rather the implementation of a known, successful condition for a result-effective variable.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that the Board should not discretionarily deny institution under 35 U.S.C. § 325(d). The core prior art references for this petition—Rich, Nakhle, Yu, and Akamatsu—were never considered by the USPTO during prosecution of the ’105 patent or related patents. Petitioner asserted these references are not cumulative of the previously considered art and directly contradict the arguments and inventor declarations submitted by the applicant to overcome rejections, particularly regarding the feasibility of conducting such reactions in aqueous solutions with unprotected side chains.

5. Relief Requested

• Petitioner requests the institution of an inter partes review and the cancellation of claims 1-17 and 19 of the ’105 patent as unpatentable.