Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 21-25, 27-30, and 32 of the instant application are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claims 21-25 and 27-30 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21-25, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Geyer et al. (WO2008/083493A1, IDS entered on 23 May 2022), Bernhard (Thesis: Engineering intracellular antibody libraries, 2008; PTO-892), Wilson (Syst Rev 7, 191 (2018); PTO-892), and Rast et al. (US 2014/0271636 A1; cited in OA 01/08/2024).
Regarding claim 21, Geyer et al. teaches wherein the extein domain comprises an immunoglobulin encoding region that encodes an immunoglobulin molecule comprised of a heavy chain variable region attached by linkers to a light chain variable region, a first linker attaching the C-terminal region of the heavy chain variable region to the N-terminal region of the light chain variable region and a second linker attaching the N-terminal region of the heavy chain variable region to the C-terminal region of the light chain variable region, wherein the linkers comprise a polypeptide chain of at least 10 amino acids, (claim 3), wherein the immunoglobulin molecule is cyclic and has no linear terminal end (claim 11). Geyer further teaches that ScFv cyclization and supercharging will reduce conformational breathing and hydrophobic aggregation and thus enhance stability and solubility (Page 71, lines 11-12). Geyer further teaches that head to tail peptide cyclization in a continuous amide peptide backbone is known in the art and that recent methods use intein to synthesize head to tail cyclic peptides (page 19, lines 10-15) and in further detail: (iii): Asn cyclization - The lc+a Asn undergoes side chain cyclization, which cleaves the lc domain and generates the extein product as a lactone. Step (iv): Lactone to Lactam Shift - The lactone cyclized intein is converted to the lactam by the thermodynamically favored X to N acyl shift, which results in a cyclic structure formed only by peptide bonds (Figure 11; page 14 lines 1-11) it is only by inhibiting this last cyclization step that the lariat structure is maintained. Geyer et al. further teaches that the cyclic peptides can be used as drugs to inhibit disease-causing targets (page 5, line 20).
Regarding claims 22-23, Geyer teaches wherein the VH and the VL are associated intramolecularly to form an antigen-binding site and wherein the cyclic single-chain antibody has one antigen-binding site in a molecule (page 3, lines 1-7; Figure 4B and 6B).
Regarding claims 24-25, Geyer further teaches two linker polypeptides comprising 14 to 25 amino acids in length (claim 15), including 15 amino acids in length (Page 11, lines 3-5). Geyer et al. discloses that the first linker is recombinant to enable single chain variable fragment production as established in the art (Page 3, lines 5-7) and that both linkers are flexible covalent molecular links such as polypeptide chains of about 15 amino acids in length (Page 11, lines 3-5).
Regarding claim 30, Geyer further teaches wherein the second peptide linker is formed by a trans-splicing reaction by a split intein (Figures 2, 4B and 12).
Geyer does not teach wherein the cyclic peptide drug is in aqueous form; that the aqueous solution is prepared by redissolution of the freeze-dried product of the antibody; or that the antibody selectively binds to HER2.
Regarding claims 21-23, and 30, Bernhard teaches that scFvs with identical CDRs to a natural antibody bind the same targets with similar binding affinity and therefore any full-length antibody isolated against a target can be made more versatile by creating its scFv counterpart (page 9, section 2.2, para 1). Bernhard further teaches that scFvs can be constructed in the VH-linker-VL or the VL-linker-VH orientation, which shows that no structural barriers exist concerning the construction of cyclic scFvs (page 20). Bernhard further teaches that cyclization of two proteins with a split intein stabilizes a binary complex and this provides strong evidence suggesting that cyclization can be used to stabilize scFvs (page 20). Bernhard further teaches that the intein is a self-splicing protein whose potential has been harnessed to successfully cyclize proteins in vivo (page 58, section 4.1.2, 1st para). Bernhard further teaches generation of cyclic scFv libraries (table 3-2; page 33) using intein technology and a second linker on the scFv (Fig 3-10), and that screens revealed that the cyclic scFv libraries had a larger binding capacity than the linear scFv libraries (page 54, para 1). Bernhard further teaches that the intra-domain disulphide bonds, which normally assist in stability, do not form within the cell, thus intracellular scFvs can unfold leading to aggregation and decreased solubility, which hinders binding (page 55, last para). Bernhard further teaches that by cyclizing the scFv it should prevent aggregation and increased stability which would increase the number of properly folded scFvs within the library and the ability of the scFvs to interact with their target; thus, increasing the binding capacity of the cyclic libraries versus the linear libraries (page 55, last para). Bernhard further teaches that the increased binding capacity of the cyclic libraries can be attributed to the stabilization of the scFv structure (page 64, last para).
Regarding claims 21 and 32, Wilson teaches that the development of HER2-targeted therapies has revolutionized the treatment of HER2+ BC that was previously associated with high relapse and mortality rates (background). Wilson further teaches that Herceptin (trastuzumab) binds to the extracellular domain IV of HER2, thereby inhibiting downstream cell signaling implicated in cell proliferation, motility, adhesion, and survival, which has been approved for clinical use metastatic breast cancer and early stage breast cancer (background). Wilson further teaches that Herceptin in combination with chemotherapy is the recommended standard of care for early breast cancer (background).
Regarding claim 1, Rast teaches a method of providing an aqueous formulation of an antibody by reconstituting the lyophilized formulation (claim 12). Rast et al further teaches that the reconstituted antibody can be used as a medicament for treating a patient (abstract; paragraph 0153). Rast et al. further teaches a method of treating a patient comprising providing a lyophilized formulation of an antibody, reconstituting the lyophilized formulation and administering the reconstituted formulation to a patient (claim 27). Rast et al. further teaches that freeze-drying antibody formulations increase stability, decreases aggregation and allows for longer shelf-life formulation of high concentrations of antibody which are often needed for patient treatment (Background; claim 12).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to take the cyclic antibody formulation as taught by Geyer, with increased binding capacity and improved stability as taught by Bernhard, targeting HER2 as taught by Wilson and freeze/ dry, then reconstitute that formulation for use as an aqueous drug as described in Rast. The ordinary artisan would have been motivated to do so because Bernhard and Geyer are analogous arts, both teaching cyclization of scFv constructs. Bernhard teaches that any full-length antibody isolated against a target can be made more versatile by creating its scFv counterpart. Bernhard further teaches that cyclic scFv libraries have increased binding capacity versus linear scFv that can be attributed to the stabilization of the scFv structure. Wilson teaches that Herceptin (trastuzumab) binds to HER2 and has revolutionized the treatment of breast cancer and in combination with chemotherapy is the recommended standard of care. Rast teaches that freeze-drying antibody formulations increase stability, decreases aggregation and allows for longer shelf-life formulation. Therefore the ordinary artisan has a reasonable expectation of success in generating a HER2 targeted cyclic scFv based on the trastuzumab sequence that would increase versatility and stability, and further freeze-drying the cyclic antibody formulation for later reconstitution as a drug would be beneficial to the patient by preventing aggregate formation in a high concentration antibody formulation that is needed for treatment, as well as benefiting treatment providers and producers by extending the shelf-life of antibody formulations.
Claims 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Geyer (WO2008/083493A1, IDS entered on 23 May 2022), Bernhard (Thesis: Engineering intracellular antibody libraries, 2008; PTO-892), Wilson (Syst Rev 7, 191 (2018); PTO-892), and Rast (US 2014/0271636 A1; cited in OA 01/08/2024) as applied to claims 21-25, 30, and 32 above, and further in view of van’s Hof et al. (Biol. Chem. 396(4): 283-293, 2015, IDS entered on 7 April 2021).
The teachings of Geyer, Bernhard, Wilson and Rast regarding claims 21-25, 30, and 32 are detailed above.
Geyer, Bernhard, Wilson and Rast do not teach wherein the second peptide linker is formed by a transpeptidase, specifically sortase, or that the second peptide linker comprises an amino acid sequence: LPXTG wherein X represents any amino acid residue.
However, van ’t Hof teaches the use of sortase to cyclize peptides and proteins with an amino acid sequence LPXTG motif (figure 4 and conclusion). Further, van t’ Hof teaches that sortase is easily produced on a large scale, it cyclizes with high yield, and there is low risk of adverse or immunological side reactions in vivo while increasing thermal and proteolytic stability of the protein (conclusion, page 291-292).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of cyclization as described by van ’t Hof to achieve the reduced aggregation by cyclization as described by Geyer, Bernhard, Wilson and Rast. The ordinary artisan would have been motivated to do so because as detailed above, sortase is easily produced on a large scale, it cyclizes with high yield, and there is low risk of adverse or immunological side reactions in vivo while increasing thermal and proteolytic stability of the protein. The ordinary artisan has a reasonable expectation of success to use sortase as the second peptide linker to efficiently cyclize the polypeptide.
Response to Arguments
Applicant's arguments filed 07/02/2026 have been fully considered but they are not persuasive.
Applicant submits: First, Applicant respectfully maintains that neither Geyer nor Rast teach or provide proper motivation to link an N-terminus and a C-terminus of the single-chain antibody with a second peptide linker to form a cyclic single-chain antibody, wherein a single-chain antibody that has a cyclic structure formed by only peptide bonds. Rather, Geyer's constructs are explicitly "lariats," meaning they retain a linear transcription activation domain "tail" branching off. In contrast, Claim 21 requires linking the N- terminus and C-terminus together to form a cyclic structure formed by only peptide bonds. Geyer's expressed lariats are inherently branched or topologically constrained by their binding domains, rather than being a self-contained, head-to-tail cyclized single- chain antibody.
In response: As detailed in the 103 rejection sent 03/02/2026, the prior art discloses the cyclic structure of an scFv formed from only peptide bonds taught by Geyer by lactone to lactam conversion after extein formation.
Further, newly cited Bernhard also teaches formation of a cyclic scFv with 2 linkers by split intein technology that generates an N to C- terminus cyclic structure from only peptide bonds (Figure 2-5, page 19).
Applicant submits: Additionally, Applicant respectfully maintains that Rast fails to disclose or suggest the stability of a cyclic scFv in an aqueous solution prepared by redissolution after freeze-drying, as required in independent claim 21. Geyer teaches that mutating the lactone-cyclized lariats made it easier to purify and store lariats (See Geyer, page 64, lines 34-35), and therefore, Applicant respectfully submits that one of ordinary skill in the art would not have been motivated to combined the disclosure of Rast with Geyer, at least because one of ordinary skill in the art would expect such a combination to yield an unpredictable result.
In response: This argument was previously addressed in the OA mailed 03/02/206.
The teaching of Geyer of mutating the lactone-cyclized lariats made it easier to purify and store the lariat is contrary to the goal of the instant application as the mutation was introduced to prevent the cyclization and lactone to lactam conversion that naturally occurred and maintain the intermediate lariat form (which is detailed in the updated rejection above; Fig 11). Geyer does teach that cyclization improves stability and solubility but it is not redundant to further improve stability by freeze drying for longer term storage.
One of ordinary skill in the art would recognize that while cyclizing the scFv would stabilize the construct and help prevent aggregation as taught by both Geyer and Bernhard (supra), there is always room for further improvement especially in the conditions that Rast teaches including high concentration therapeutic antibodies to be shipped and stored for longer periods of time.
Applicant submits: Regardless, Applicant respectfully submits that neither Geyer nor Rast teach or provide any motivation for a single-chain antibody that has a cyclic structure formed by only peptide bonds and that is capable of selectively binding to HER2. Applicant respectfully submits that this unique combination is not trivial. For instance, the specification demonstrates that the claimed HER2-binding cyclic single-chain antibody retains its antigen-binding function following cyclization. Specifically, the specification describes a trastuzumab-derived single-chain antibody (Tras-scFv) that specifically binds to HER2 and reports that surface plasmon resonance analysis showed that cyclic and acyclic Tras-scFv constructs exhibited substantially equivalent HER2-binding activity, confirming that cyclization does not adversely affect antigen recognition. See, e.g., [00163], Comparative Example 1, Example 2, and Table 3. The specification further demonstrates that the cyclic Tras-scFv suppresses intermolecular association, exhibits reduced aggregate formation and maintains HER2-binding affinity following freeze-drying and redissolution, thereby supporting the presently claimed HER2-binding cyclic single-chain antibody for pharmaceutical use. See, e.g., [0107], Example 4 and Tables 5-7.
In Response: The amendments to the claims are addressed in the updated 103 rejection detailed above. The benefits demonstrated in the instant specification are expected benefits taught by the prior art including decreased aggregation and improved stability, while maintaining binding capability.
Applicant submits: Dependent claims 27-29 were rejected under 35 U.S.C. § 103 as being allegedly unpatentable over Geyer and Rast as applied to claims 21-25 and 30 above, and further in view van't Hof et al. (Biol. Chem. 396(4): 283-293, 2015). Applicant respectfully submits that van't Hof does not cure the failings of Geyer in reaching elements of independent claim 21. For instance, van't Hof does not disclose or suggest a cyclic single-chain antibody. Accordingly, Applicant further submits that these dependent claims patentably define over the cited references, taken either alone or in any proper combination.
In response: This argument was addressed previously but was included here again: As the rejection of independent claim 21 has been maintained the argument that van’t Hof does not cure the failings of Geyer and Rast in the independent claim is not persuasive, as van’t Hof are not relied upon to teach any of the limitations of claim 21. van’t Hof was utilized to teach the use of sortase to cyclize peptides and proteins with an amino acid sequence LPXTG motif . Therefore, the rejection of the dependent claims 27-29 is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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