Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
1. The Amendment filed June 16, 2026, in response to the Office Action of January 16, 2026, is acknowledged and has been entered. Claim 232 has been amended.
2. Claims 232-234, 236-238, 242 and 243 are currently being examined as drawn to the elected species.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
3. Claims 232-234, 236-238, 242 and 243 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2005/0027109 A1 (Mezo et al. Feb. 3, 2005), “Mezo” in view of WO 2013/00355 (Ploegh et al. Jan. 03, 2013, IDS), “Ploegh” for the reasons of record.
Mezo teaches producing chimeras comprising biologically active molecules, including polypeptides, and the immunoglobulin Fc region and portions thereof that bind the Fc receptor, wherein a) the portion of an immunoglobulin constant region comprises an N terminus cysteine and b) the biologically active molecule comprises a functional group capable of reacting with an N terminus cysteine to form a bond. See claims 1-13.
The bond formed in the chimeric protein is a native peptide bond formed by native ligation via a thioester functional groups. See ¶¶ 0006-0009, 0014, 0039 and Figs. 1 and 4.
Mezo teaches the chimeric protein can comprise linkers such as polyethylene glycol (PEG) or peptides. See ¶¶ 0155-0166. Mezo teaches that the linker can be linked to the Fc cysteine by native peptide ligation. See ¶¶ 0162-0163.
The N-terminal cysteine sequence includes CPPCP. See Figs. 2 and 4.
Mezo teaches that the chimeric proteins can bind to FcRn via the Fc domain thereby increasing the half-life of the protein. See ¶¶ 0096, 0104 and 0146-0148 and claims 12 and 13.
Mezo does not teach a chemical structure with a reactive terminal azide or alkyne linked to the Fc domain.
Ploegh teaches a method of installing click chemistry handles to the N- or C-terminus of a target protein with a sortase to generate protein conjugates. See abstract, [0005-0015]. claims 1 and 3, and Figs. 1 and 2.
Ploegh teaches that the click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC). See ¶¶ [0065], [0238-0242], and [0260-0262], Figs. 1, 12, 13 and claims 11, 18, and 61.
Ploegh teaches the key advantages of using a sortase transacylation strategy to modify a target protein are the ease of synthesis, and execution of the reaction on native proteins under physiological conditions. ¶¶ [0085] and [0204]. Ploegh also teaches that the method allows for N to N and C to C proteins fusions to allow optimal protein activity. See ¶¶ [0202-0203]
Ploegh teaches adding detectable labels, including fluorescent proteins, and PEG to extend the half-life of the proteins with the sortase method. See ¶¶ [0068-0069] and [0211-0212] and claims 43-45.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Mezo and Ploegh and use the method of Ploegh to add click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC) to the chimeric Fc proteins of Mezo to add detectable labels for detection or PEG to extend the half-life of the chimeric Fc proteins as taught by Ploegh. One would have been motivated to use the method of Ploegh to add click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC) to the chimeric Fc proteins of Mezo because Ploegh teaches the key advantages of using a sortase transacylation strategy to modify a target protein are the ease of synthesis, and execution of the reaction on native proteins under physiological conditions and that the method allows for various orientation of the conjugates to optimize the activity of the fusion proteins.
4. Claims 232-234, 236-238, 242 and 243 are alternatively rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2005/0027109 (Mezo et al. Feb. 3, 2005), “Mezo” in view of WO 2013/003555 (Ploegh et al. Jan. 03, 2013, IDS), “Ploegh” as applied to claims 232-241 above, and further in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom” for the reasons of record.
Mezo and Ploegh teach as set forth above.
Mezo additionally teaches that the chimeric proteins can contain a hinge region of immunoglobulin. See ¶¶ [0140, 0144, and 0145].
Mezo and Ploegh teach as set forth above, but do not teach EPKSCDKTHTCPPCP (SEQ ID NO: 135) in the chimeric Fc proteins.
Strom teaches making fusion proteins with immunoglobulin hinge linker regions. See abstract, claims 1-23, and Table on p. 8.
Strom teaches that the proteins can be attached to the hinge region by the amino or carboxyl terminus of the proteins. Strom teaches that this is advantageous in that allows the carboxyl terminus of the protein to interact or bind ligands. See p. 2-line 23-30.
Strom teaches that the hinge regions are flexible and allow freedom of movement. See p. 6-lines 17-22.
Strom teaches that the IgG1 hinge peptide comprises EPKSCDKTHTCPPCP. See Table p. 8.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of Mezo, Ploegh and Strom and use a hinge at the N-terminus of a Fc chimera using the hinge peptide linkers of Strom because Mezo teaches that the chimeric proteins can contain a hinge region of an immunoglobulin and Strom teaches that the hinge regions are flexible and allow freedom of movement and allow the carboxyl terminus of the protein to interact or bind ligands. Thus, one would have been motivated to use the hinge peptide linkers of Strom to provide flexibility to the conjugates of Mezo and Ploegh so that their activity could be maintained.
Response to Arguments
5. Applicant argues that regarding applicant's prior argument, that the protein resulting from the sortase reaction taught in Ploegh would have at least the following amino acids at its N-terminus: LPXTG, where the click chemistry handle is attached to the N-terminal "L" either directly or via a linker, the Examiner alleged:
(1) the structures of J include "a bond, an amide, and an amino acids" and that these structures are not particularly limited and include peptides like the LPTXTG sortase recognition motif;
(2) a peptide bond does not exclude peptides like LPXTG that contains peptide bonds; and
(3) the claims do not exclude peptides like LPXTG as set forth above.
Applicant argues that in response, regarding (1) applicant has amended the claims to no longer recite "an amide" or "an amino acid" and have amended the claims to clarify that "a bond" means "a covalent bond".
Applicant argues that thus, the claim requires that J is either "a covalent bond" or is "an organic structure consisting of" specifically enumerated structures. The enumerated structures do not include "amino acids" generally, or the proline (P), threonine (T), or glycine (P) in the LPXTG recognition motif. Thus, because LPXTG is neither "a covalent bond" nor an organic structure "consisting of" the specifically enumerated structures, J cannot comprise the LPXTG motif that must necessarily be present in the protein that is allegedly obvious based on the teachings of the cited art.
Applicant argues that Regarding (2), Applicant has also amended claim 232 to recite that the dotted line between B'' and the N-terminus of C is a "peptide bond between the C-terminus of B'' and the N-terminus of C". The bond between the carboxyl group of one amino acid and the amino group of another amino acid is referred to in the art as "a peptide bond". Thus, in the context of the claim, Applicant submits that it is clear that "a peptide bond" refers to a single (i.e. "a") bond between the carboxyl group of one amino acid and the amino group of another amino acid. This is particularly clear because, as amended, the claim recites that the peptide bond is between the C-terminus of B'' and the N-terminus of C, which are two peptide components of the recited structure.
Applicant argues that moreover, a motif LPXTG is composed of a sequence of amino acids. Where a linkage of amino acids is intended to be recited, the specification recites either "amino acids", names a specific amino acid such as cysteine, or explicitly recites the intended sequence of amino acids. A "peptide bond" is never used in the specification to refer to a sequence of multiple amino acids. See In re Abbott Diabetes Care Inc., 696 F.3d 1142, 1149-50, 104 USPQ2d 1337, 1342-43 (Fed. Cir. 2012) ("disavowal of a broader claim scope may be made by implication, such as where the specification contains only disparaging remarks with respect to a feature and every embodiment in the specification excludes that feature. ")
Applicant argues that thus, regarding (3), the dashed line between B'' and C does not allow for the inclusion of additional structures being attached to B like the LPXTG sortase recognition motif.
Applicant argues that since the claimed compound is not, and cannot, be produced using the methods described in Ploegh, the claims cannot be obvious in view of Ploegh's teachings, even if Strom teaches fusion proteins comprising EPKSCDKTHTCPPCP (SEQ ID NO: 135).
Applicant's arguments have been considered but have not been found persuasive.
Regarding (1) and "a covalent bond", LPXTG contains covalent peptide bonds and neither the claims nor the specification limit the structure, composition or number of moieties encompassed by the term “a covalent bond”. All that is required is a covalent bond. Thus, LPXTG meets this limitation.
Regarding (2) and (3) and the amendment of claim 232 to recite that the dotted line between B'' and the N-terminus of C is a "peptide bond between the C-terminus of B'' and the N-terminus of C", the art meets the limitations of the claims. In particular, the C polypeptide can contain, in part, a cysteine or CP at its C terminus and the B structure is or is present SEQ ID NO: 135-138. Joining a cysteine or CP (the C, N-terminal part) to CPP of SEQ ID NO: 135 or 136 (the B''-C-terminal part) by a single peptide bond would be the sequence CPPCP of Mezo. The LPXTG motif is not required to form this linkage because it is already taught by Mezo. Thus, Applicant’s arguments are not found persuasive, and the rejection is maintained.
6. Claims 232, 233, 242 and 243 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO 07048127 A2 (Barbas III, C. l. 26 April 2007, IDS), “Barbas” in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom” for the reasons of record below.
Barbas teaches a method for labeling a protein molecule that includes therein the Fc portion of an antibody molecule comprising the steps of: (1 ) providing a protein molecule that includes therein the Fc portion of an antibody molecule, the protein molecule having a reactive amino acid residue selected from the group consisting of an azide-substituted amino acid residue and an alkyne-substituted amino acid residue; (2) providing a targeting molecule, the targeting molecule having a reactive residue selected from the group consisting of an azide and an alkyne such that the protein molecule and the targeting molecule, taken together, have an azide modification and an alkyne modification; and (3) reacting the protein molecule with the targeting molecule by azide-alkyne [3 + 2] cycloaddition to produce a labeled protein molecule such that the targeting molecule solely directs the targeting of the labeled protein molecule to a target that is a soluble molecule or a cell-surface molecule. See ¶ [0010] and claim 3 and Figs. 1 and 12a.
Barbas teaches that an aldehyde-containing Fc protein is reacted with a hydroxylamine bearing an azide functionality to provide an azide-Fc. See ¶¶ 0044, 0112, 0113 and Fig. 12a.
Barbas teaches that the amino terminus can be mutated to a reactive cysteine. See ¶¶ 0066, 0114, 0165, 0166, 0172, 0188, 0203, and 0204 and claims 26 and 90.
Barbas teaches that the Fc fragment can include the hinge region. See ¶¶ 0064 and 0179 and claims 19-21.
Barbas teaches using linker molecules like polyethylene glycol (PEG). See abstract, ¶¶ 0019, 0023, 0068, 0069, 0191, 0201 and claims 27, 67 and 68.
Barbas teaches as set forth above, but does not teach EPKSCDKTHTCPPCP (SEQ ID NO: 135) in the chimeric Fc proteins.
Strom teaches as set forth above.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of Barbas and Strom and use a hinge at the N-terminus of the labeled Fc proteins using the hinge peptide linkers of Strom because Barbas teaches that the labeled Fc proteins can contain a hinge region of an immunoglobulin and Strom teaches that the hinge regions are flexible and allow freedom of movement and allow the carboxyl terminus of the protein to interact or bind ligands. Thus, one would have been motivated to use the hinge peptide linkers of Strom to provide flexibility to the labeled Fc proteins of Barbas so that their activity could be maintained.
Response to Arguments
7. Applicant argues:
I. Barbas Teaches Placing the Click Handle on the Fc Protein (C), Not on a Separate B'' Molecule, and Thus Teaches Away From the Claimed Arrangement
Applicant argues that as an initial matter, Applicant notes that Barbas does not disclose a hinge sequence at all in the context relevant to the claimed structure. While Barbas acknowledges that the Fc fragment can include a hinge region (¶ 0064, claims 19-21), in Barbas, the azide reactive group is installed directly on the Fc protein by oxidizing an N-terminal serine on the Fc to an aldehyde and reacting with a hydroxylamine-azide reagent to generate azide-Fc. See Barbas, II 0057-0062, 0113, Fig. 12a.
Applicant argues that in the claimed compound, the terminal azide or alkyne is on B'' (not on C), and C is connected to B'' through a peptide bond at C's N- terminus. This is not what Barbas teaches. Barbas does not disclose, teach, or suggest creating a protein using a bifunctional B'' molecule carrying both a terminal click handle and a peptide bond-forming capability for conjugation to the N-terminus of an Fc fragment. Barbas's approach is specifically designed to modify the Fc protein itself to carry the reactive group, not to create a small molecule or peptide B'' as an intermediary.
Applicant's arguments have been considered but have not been found persuasive. The claimed structures B of B'' are antibody hinge domains or portions thereof and the claimed C domains comprises an Fc domain or portions thereof. Barbas teaches, as previously set forth, that the Fc fragment can include the hinge region. Barbas teaches the hinge structure as a part of the Fc domain on the N-terminus of the Fc domain. See ¶¶ 0064 and 0179 and claims 19-21. Thus, the disclosure of linking a terminal click handle to an Fc fragment includes linking the click handle to the hinge Fc domain structure, which comprises the C and B structures as claimed. The claimed B structure is linked to the terminal azide or alkyne by a covalent bond (J), which does not limit the structure of the covalent connection. So, Barbas teaches the claimed structure except for the specific sequence of the hinge region. Thus, Applicant’s arguments are not found persuasive.
II. Strom Does Not Teach B'' as a Discrete Bifunctional Molecule
Applicant argues that in moreover, Strom discloses hinge sequences as part of recombinantly expressed fusion proteins, not as components of a bifunctional linker. Strom does not teach a discrete B'' molecule consisting of a hinge sequence linked to a terminal click reactive group via J. The motivation the Examiner provides-flexibility of hinge regions-does not explain why an artisan would create a discrete B'' molecule with the claimed bilateral architecture. At most, the flexibility of hinge regions provides a general motivation to include a hinge region for flexibility in an Fc-containing protein. It does not provide any reason why an artisan would: (a) excise a hinge sequence peptide from its native recombinant context (as used in Strom); (b) attach a terminal azide or alkyne to one end via a defined J linker; (c) join this B'' molecule to the N-terminus of the Fc via a peptide bond; and (d) connect the other face of B'' to a separate targeting molecule through a triazole or other nonpeptidyl bond. These are four distinct non-obvious steps, none of which is taught or suggested by the combination.
Applicant's arguments have been considered but have not been found persuasive. Strom does not need to provide motivation to perform steps (a)-(d) as outlined by Applicant because Barbas teaches the claimed structure, B'' (reactive group and hinge) peptide bond linked to C (Fc domain), except for the specific sequence of the hinge region as set forth above. Thus, one would have been motivated to use the hinge peptide linkers of Strom to provide flexibility to the labeled Fc proteins of Barbas so that their activity could be maintained.
III. Barbas's method places the reactive group at the N-terminus of the Fc via an oxime linkage structure
Applicant argues that importantly, the claims recite that B'' consists of chemical structure B (which is a stretch of consecutive amino acid residues) linked to an azide or an alkyne terminal reactive group via J, wherein J is a covalent bond or an organic structure consisting of specifically recited components. Barbas's methods of installing click handles on Fc proteins generates an oxime linkage structure (R-CH=N-O-R') by reacting an aldehyde (from oxidized N-terminal serine) with a hydroxylamine-azide. See Barbas, paragraphs 0059 to 0062 and Figure 12a. Even if one used Barbas's click chemistry and Strom's hinge sequence, it would not produce B linked to an azide or an alkyne terminal reactive group via J as recited in the claims. In short, the chemistry Barbas uses to attach a reactive group to the N-terminus of an Fc protein generates a linkage type that is excluded from J.
Applicant's arguments have been considered but have not been found persuasive. Barbas teaches the claimed structure, B'' (reactive group and hinge) peptide bond linked to C (Fc domain), except for the specific sequence of the hinge region as set forth above. The claimed B structure is linked to the terminal azide or alkyne by a covalent bond (J), which does not limit the structure of the covalent connection. An oxime linkage structure is not excluded by a covalent bond. So, Barbas teaches the claimed structure except for the specific sequence of the hinge region. Thus, Applicant’s arguments are not found persuasive, and the rejection is maintained.
8. Claims 234 and 236-238 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO 07048127 A2 (Barbas III, C. l. 26 April 2007, IDS), “Barbas” in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom” as applied to claims 232, 233, 242 and 243 above, and further in view of Debets et al. (Chem. Commun. 2010 46: 97-99, of record), “Debets” for the reasons of record below.
Barbas and Strom teach as set forth above, but do not teach using a cycloalkyne or cyclooctyne.
Debets teaches that the Huisgen cycloaddition “click” reaction is a powerful method in the field of bio-conjugation because it is selective, fast, and high-yielding. See p. 97-left column.
Debets teaches an improvement to the reaction using a functionalized aza-cyclooctyne that eliminates the need for copper, which can interfere in subsequent uses and is toxic to cells. See abstract and p. 97.
Debets teaches the hybrid cyclooctyne structure aza-dibenzocyclooctyne (DIBAC), for performing the copper free click reaction. See p. 97 and Fig. 1-structure E and Scheme 1.
Debets teaches linking DIBAC and DIBC to PEG2000 and azide-containing CalB (AHA-CalB) or HRP. See pp. 98-99 and scheme 2.
Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. See p. 99-last two paragraphs.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of the Barbas and Strom and Debets to use the DIBCs, particularly DIBAC, of Debets as the alkyne of the method of Barbas and Strom because Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. One would have been motivated to use the reagents of Debets for copper free cycloaddition reactions given their efficiency and the elimination of copper reduces the potential for unwanted effects such as toxicity to cells.
Response to Arguments
9. Applicant argues that Debets discloses DIBAC as a cyclooctyne for copper-free click reactions. Claims 234 and 236-238 are dependent on claim 232 and incorporate all of claim 232's limitations. If claim 232 is not rendered obvious (as argued above), claims 234 and 236-238 cannot be rendered obvious by the additional teaching of DIBAC, regardless of DIBAC's utility as a click reagent. The dispositive structural deficiency lies in the architecture of B'' required by claim 232, which Debets does not address.
Applicant argues that for these reasons, the rejections of claims 232, 233, and 242-243 under based on Barbas and Strom and of claims 234 and 236-238 under based on Barbas, Strom and Debets should be withdrawn.
Applicant's arguments have been considered but have not been found persuasive because Applicant is reiterating the arguments set forth above. Thus, for the reasons set forth above, Applicant’s arguments are not found persuasive, and the rejection is maintained.
Conclusion
10. The nonstatutory double patenting rejection recited in the Office Action of January 16, 2026, is withdrawn in view of Applicant filing a terminal disclaimer.
11. No claims allowed.
12. THIS ACTION IS MADE FINAL. 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 extension fee 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.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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/Peter J Reddig/
Primary Examiner, Art Unit 1646
