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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/26/2026 has been entered.
Application Status
Claims 21-25 and 27-30 of the instant application are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claim 26 are rendered moot in view of claim cancellation.
Claim Rejections - 35 USC § 103
New Rejection
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 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Geyer et al. (WO2008/083493A1, IDS entered on 23 May 2022) 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 et al. further 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 et al. 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 et al. further teaches wherein the second peptide linker is formed by a trans-splicing reaction by a split intein (Figures 2, 4B and 12).
Geyer et al. does not teach wherein the cyclic peptide drug is in aqueous form or that the aqueous solution is prepared by redissolution of the freeze-dried product of the antibody.
However, Rast et al. 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 increases 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 et al. and freeze dry and then reconstitute that formulation for use as an aqueous drug as described in Rast et al. The ordinary artisan would have been motivated to do so because as detailed above, Rast et al. teaches that freeze-drying antibody formulations increases stability, decreases aggregation and allows for longer shelf-life formulation. Therefore, 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 et al. (WO2008/083493A1, IDS entered on 23 May 2022) and Rast et al. (US 2014/0271636 A1; cited in OA 01/08/2024) as applied to claims 21-25 and 30 above, and further in view of van’t Hof et al. (Biol. Chem. 396(4): 283-293, 2015, IDS entered on 7 April 2021).
Geyer et al. and Rast et al. teach a method of reducing scFv aggregation by cyclization as detailed above.
Geyer et al. and Rast et al. 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 et al. 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 et al. 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 et al. to achieve the reduced aggregation by cyclization as described by Geyer et al. 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.
Response to Arguments
Applicant's arguments filed April 22, 2025 have been fully considered but they are not persuasive.
Applicant submits: Concerning the "single-chain antibody has a cyclic structure formed by only peptide bonds," the Office Action points to Figure 5A and claim 11 of Geyer. Applicant respectfully disagrees. Fig. 5A of Geyer focuses on the formation of dicysteine intein (reproduced below).
The dicysteine intein contains one Cys after the C-lntein domain (le) and one Cys at in the first amino acid position of the N-lntein domain (IN) ( circled in red in Figure 5a above). When read as a whole, it is clear that Geyer discloses that "[the] cysteines at each end of the peptide insert in the dicysteine intein can also be used to cyclize peptide, genomic fragment, or ScFv inserts either through the formation of a disulfide bond or by cross linking the cysteines through a thiol reactive cross linker." (See Geyer, page 24, lines 8-11 ). In other words, a skilled artisan would readily understand that Geyer merely discloses cyclization through Cys-Cys disulfide bond (e.g., sidechain linkage) or covalent linkage involving cysteine side chains (e.g., cross linking the cysteines through a thiol reactive cross linker). Fundamentally, the mechanism of cyclization in Geyer is distinct from the Present Application. Nowhere does Geyer disclose or suggest a single-chain antibody has a cyclic structure formed by only peptide bonds, as set forth in independent claim 21. Further, Applicant respectfully submits that a skilled artisan would readily understand that "a cyclic structure formed by only peptide bonds," refers to cyclization of the backbone of the structure via an amide bond.
In response: The examiner apologizes for the incorrect reference to the dicysteine intein structure in 5A and has rectified the error in the updated rejection above detailing the cyclic structure of an scFv formed from only peptide bonds taught by Geyer by lactone to lactam conversion after extein formation.
Applicant submits: Applicant respectfully submits 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). Thus, Applicant respectfully submits that combining Geyer and Rast would yield a redundant result.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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.
Applicant submits: The distinctions of the present application compared to Geyer and Rast are not merely trivial. For instance, experimental results seen in Figure 19 of the Present Application shows preparation of a cyclic single-chain antibody stability thereof in an aqueous solution. In particular, Figure 19 of the Present Application indicates that the cyclic scFv maintains a single peak in the aqueous solution after 1 day from preparation, while acyclic scFv forms an aggregation having a larger radius. The claimed subject matter of the Present Application discloses a significant effect of the cyclic scFv.
In response: This argument was addressed previously but was included here again: As the motivation to cyclize is clearly stated by Geyer to increase stability and solubility (supra) and with all the steps of the method and the structural characteristics of the scFv as recited in the instant claims, the ordinary artisan would have had a reasonable expectation of success to expect an increase in stability and solubility by cyclization of an scFv as demonstrated in the instant application. Further Figure 19 is generated with a specific cyclic scFv, linker and antigenic target which is not commensurate in scope with the claims as written.
Applicant submits: Further, the Present Application includes specific experimental results regarding the stability of a cyclic scFv in an aqueous solution prepared by redissolution after freeze-drying (See Example 4 of the Present Application). For instance, surprisingly, the present inventors found that cyclic Tras-scFv had a large maximum (RU) value, and cyclic Tras-scFv had higher residual activity after freeze-drying as compared with acyclic Tras-scFv (See Example 4 of the Present Application).
In response: This argument was addressed previously but was included here again: Rast teaches that freeze drying antibody formulations increases stability, decreases aggregation and allows for longer shelf life formulation of high concentration antibodies, which are often needed to treat patients (claim 12 and background). The ordinary artisan therefore would have a reasonable expectation of increased stability, decreased aggregation, increased solubility and longer shelf life by combining the teachings of Geyer and Rast. With increased stability and solubility it would naturally flow that there would be an increase in RU in the cyclic versus non-cyclic scFv after lyophilization. Further, van’t Hof teaches that the effect of sortase-mediated backbone cyclization on the biological activity and thermal- and proteolytic stability of several proteins and peptides is impressing and that the variety of substrates reviewed here illustrates the versatility of sortase and promises a broad application in the search for backbone-cyclized protein- and peptide-based therapeutics in the years to come (page 292, col 1, para 2).
Further, the surprising results are not commensurate in scope with the recited claims. The increase in RU as determined in Example 4 are specific to the Trans-scFv, whereas the claims as written are not drawn to a particular scFv, linker or antigen target.
Applicant submits: Applicants also respectfully submit that for at least the reasons indicated above relating to the corresponding independent claims, the pending dependent claims patentably define over the references cited. However, Applicants also note that the patentability of the dependent claims certainly does not hinge on the patentability of the independent claims. In particular, it is believed that some or all of these claims may possess features that are independently patentable, regardless of the patentability of the independent claims.
Dependent claims 27-29 were rejected under 35 U.S.C. § 103 as being allegedly unpatentable over Geyer 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
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643