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 .
Claim Status
Claims 1-16, 32, and 36 have been cancelled; claims 17-18, 20, and 33-34 have been amended; and, claims 37-48 have been newly added, as requested in the amendment filed on 11/27/2025. Following the amendment, claims 17-31, 33-35, and 37-48 are pending in the instant application.
Claims 17-31, 33-35, and 37-48 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claims 17-31, 33-35, and 37-48 have an effective filing date of February 13, 2020 corresponding to EP20305138.8.
Drawings - Objection Updated
The objection to the drawings as failing to comply with 37 CFR 1.84(p)(4) because reference characters “1”, “2”, and “3” had been used to designate both a component of a process and a process step is withdrawn in view of the submitted replacement drawing sheet; it is acknowledged that Applicant has submitted a replacement sheet for Figure 1 wherein the reference characters “1”, “2”, and “3” have been removed, and reference characters “1”, “2”, “3”, and “4” remain and appear to designate steps of the process. However, the drawings are now objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: the description of Figure 1 in the instant specification (see Page 13) still refers to reference characters “(1)”, “(2)” and “(3)”, which are not shown in he drawings. It is recommended that Applicant correct the drawings/specification such that the Figure description, specifically with regard to the reference characters discussed above, correspond to those shown in the Figure. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification - Objection Withdrawn
The specification was objected to for the use of trade names and/or marks used in commerce. Applicant has amended the specification to capitalize the identified terms and recite the required symbols. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claims 18 and 20 were objected to for minor informalities. It is noted that Applicant has amended the claims such that they now recite, for example, “SEQ ID NO: 2” when referencing sequences. As such, the objection to claims 18 and 20 is withdrawn.
Claim 27 was objected to for minor informalities. The claim has been amended to recite “wherein the CAR”. As such, the objection to claim 27 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 17-36 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, specifically regarding the recitation of “Ab” in independent claims 17 and 33, which was not explicitly defined, and for the recitation of methods of “diagnosing and/or treating” in claims 32 and 36 wherein the only active step recited was :administering the contrast agent or drug agent”. Applicant has amended independent claims 17 and 33 such that “Ab” is now explicitly defined as an antibody. Applicant has cancelled claims 32 and 36. As such, the rejection of claims 17-36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claims 32 and 36 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement. Applicant has cancelled claims 32 and 36, rendering the rejection moot. As such, the rejection of claims 32 and 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 32 and 36 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Dennler et. al. (Bioconjugate Chemistry, 2014, 25, 569-578; reference A09 on IDS submitted 08/10/2022; herein after referred to as "Dennler") in view of non-patent literature by Morias and Ma (Drug Discovery Today: Technologies, 2018, 30, 91-104; previously cited on PTO-892; herein after referred to as "Morias"), WO 2019/057772 A1 (previously cited on PTO-892; herein after referred to as "Spycher"), and non-patent literature by Tanaka et. al. (FEBS Letters, 2005, 579, 2092-2096; previously cited on PTO-892; herein after referred to as "Tanaka").
Applicant has cancelled claims 32 and 36, rendering their rejection moot. As such, the rejection of claims 32 and 36 under 35 U.S.C. 103, as recited above, is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained/Updated
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 (i.e., changing from AIA to pre-AIA ) 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 17-23, 25-27, 29, 30-31, 33-34, and 35 stand as rejected, and new claims 37-48 are newly rejected, under 35 U.S.C. 103 as being unpatentable over non-patent literature by Dennler et. al. (Bioconjugate Chemistry, 2014, 25, 569-578; reference A09 on IDS submitted 08/10/2022; herein after referred to as "Dennler") in view of non-patent literature by Morias and Ma (Drug Discovery Today: Technologies, 2018, 30, 91-104; previously cited on PTO-892; herein after referred to as "Morias"), WO 2019/057772 A1 (previously cited on PTO-892; herein after referred to as "Spycher"), and non-patent literature by Tanaka et. al. (FEBS Letters, 2005, 579, 2092-2096; previously cited on PTO-892; herein after referred to as "Tanaka").
With regard to new claims 37, 39, and 45-48, it is noted that claims 17, 31, 33, and 35 are rendered obvious by Dennler, Morias, Spycher, and Tanaka for reasons already of record. Furthermore, it is noted that Dennler discloses a transglutaminase-based chemo-enzymatic conjugation approach to produce ADCs wherein the antibody of said ADCs is trastuzumab (see, for example, Abstract and Pages 575-576), which targets cancer antigen HER2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to new claims 38 and 40-42, it is noted that claims 35, 37, and 39 are rendered obvious by Dennler, Morias, Spycher, and Tanaka for reasons already of record and for those discussed above. Furthermore, it is noted that Morias teaches that antibodies and their derivatives radiolabeled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo wherein chelators that are covalently attached to antibodies allow radiolabeling with metallic PET and SPECT radioisotopes (Abstract). The reaction of either anti-L1-CAM chCE7 antibody or rituximab antibody (Fig. 6b), firstly with PNGaseF to remove N297 glycans, and secondly, with bifunctional chelators attached to 5-aminopentyl groups in the presence of BTG, results in IgG mAbs bearing only two chelators per antibody, attached at position Q295; radionuclide imaging and biodistribution studies in tumour-bearing mice (i.e., antibodies were administered to mice) showed that this site-specific conjugation strategy led to radiolabeled antibodies that provided higher tumour to non-target organ contrast, compared to antibodies radiolabeled using conventional, non-specific methods (i.e., the antibodies are utilized as contrast agents in PET and SPECT) (Page 99). Morais further teaches site-specifically radiolabeled antibody-based radiopharmaceuticals can deliver new clinically-useful contrast agents for molecular PET/SPECT imaging, by (i) providing clinicians with better molecular imaging tools to predict whether a patient will respond to a particular treatment or intervention (Page 100). Additionally, Morias indicates that In-capromab pendetide (comprises DPTA chelator conjugated to deglycosylated antibody) has been fundamentally important in the development of radionuclide molecular PET and SPECT imaging of its target, PSMA; several PSMA-targeted PET and SPECT imaging agents are currently being clinically developed, after showing high diagnostic utility in prostate cancer management (Page 97; emphasis added). Thus, Morias teaches/suggests the use of radiolabeled/chelator-conjugated antibodies in diagnostic methods and/or treatment methods wherein the methods comprise administering the radiolabeled/chelator-conjugated antibody to a patient, wherein said antibodies are specific to cancer antigens (e.g., PSMA). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to new claim 43, Dennler teaches a chemo-enzymatic approach using
MTGase as a strategy to form ADCs with a defined DAR of 2 (Abstract). Enzymatic modification of antibodies and other proteins represents an alternative approach to chemical modification strategies (e.g., targeting carbohydrate moieties); transglutaminases (TGase) are a family of enzymes (EC 2.3.2.13) that catalyze the formation of a covalent bond between the γ-carbonyl amide group of glutamines and the primary amine of lysines (Figure 1), and some TGases also accept substrates other than lysine as the amine donor and have been used to modify proteins (Page 570, Column 1 Paragraph 3). The author’s teach direct enzymatic coupling of a toxin to an antibody as well as a novel chemo-enzymatic approach whereby a small linker with a synthetic functional group was first attached to the antibody by MTGase (Page 570, Column 2, Paragraph 1). For antibody deglycosylation, antibody in phosphate buffered saline (PBS) was incubated with 6 U/mg protein of N-glycosidase F (PNGase F) from Flavobacterium meningosepticum overnight at 37 °C after which the enzyme was then removed by centrifugation-dialysis (Page 572, Deglycosylation of Antibodies). For enzymatic modification, deglycosylated antibody in PBS was incubated with 80 mol equiv. (40 mol equiv. per conjugation site) of the corresponding amine-functionalized chemical entity and 6 U/mL microbial transglutaminase (MTGase) overnight (16 h) at 37 °C after which excess substrate and the MTGase were removed by centrifugation-dialysis or by size exclusion chromatography (Page 572, Enzymatic Modification of Antibodies). Thus, Dennler teaches a process for preparing site-specific bioconjugated antibodies comprising (i) enzymatic deglycosylation of the antibodies by PNGase F; (ii) enzymatic modification (i.e., reactive linker attachment to the antibody) by microbial transglutaminase; and (iii) conjugation of a toxin to the antibody via the linker. However, Dennler does not disclose conjugates comprising a chelator, an oligopeptide linker, nor coupling a Linker-Chelator construct to a degylcosylated antibody. These deficiencies are remedied by Morias, Spycher, and Tanaka.
With regard to chelator conjugation, Morias teaches that antibodies and their derivatives radiolabeled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo wherein chelators that are covalently attached to antibodies allow radiolabeling with metallic PET and SPECT radioisotopes (Abstract). Recent advances in bioconjugation technology enable site-specific modification to generate well-defined constructs with superior properties; the authors survey
existing site-specific chelator-protein conjugation methods including chelator attachment to
cysteines/disulfide bonds or the glycan region of the antibody, enzyme-mediated chelator conjugation, and incorporation of sequences of amino acids that chelate the radiometal (Id.). Metallic radioisotopes are incorporated into an antibody via a chelator, and recent efforts have resulted in new site-selective conjugation methods for attaching chelators and other cargoes (fluorescent molecules, small molecular weight drugs) to antibodies wherein such an approach (often described as orthogonal) uses complementary pairs of functional groups that react chemoselectively with each other; this involves appending one functional group to the chelator, and the other to the protein, followed by reaction between the two motifs (Page 93). IgG proteins contain two conserved post-translational modification glycosylation sites (Fig. 1) that can be chemically modified to enable site-selective attachment of chelators (Page 96, Column 2, Last Paragraph) and recently protein technology has been developed to enable enzyme-mediated, site-specific conjugation of a cargo to target antibodies and proteins (Page 99, Column 1, Paragraph 1). Bacterial transglutaminase (BTG) enzyme catalyzes the formation of a new amide bond between the primary amine of a lysine side chain and the γ-carboxamide group of a glutamine
side chain, but BTG is only reactive towards glutamine side chains located in flexible regions of proteins/biomolecules and glutamine side chains of IgG antibodies are thus normally unreactive to BTG; removal of glycans from position N297 of an IgG antibody, using the enzyme N-glycosidase F (PNGaseF), results in increased flexibility of this antibody region which gives rise to the increased BTG-catalyzed reactivity of a glutamine residue, Q295, in close proximity to N297, and chelators bearing 5-aminopentyl groups can be site-selectively introduced into this
position in the presence of BTG (Page 99). Reaction of either anti-L1-CAM chCE7 antibody or rituximab antibody (Fig. 6b), firstly with PNGaseF to remove N297 glycans, and secondly,
with bifunctional chelators attached to 5-aminopentyl groups in the presence of BTG, results in IgG mAbs bearing only two chelators per antibody, attached at position Q295; this site-specific conjugation strategy led to radiolabeled antibodies that provided higher tumour to non-target organ contrast, compared to antibodies radiolabeled using conventional, non-specific methods (e.g., lysine modification) (Id.).
With regard to payload-linker constructs and oligopeptide linkers, Spycher teaches an antibody-payload conjugate comprising (i) one or more linker-payload constructs according to the above description, and (ii) an antibody comprising at least one Gln residue in the heavy or light chain, wherein, in said conjugate, the linker-payload constructs and/or the antibody have optionally been chemically modified during conjugation to allow covalent or non-covalent conjugation, to form said conjugate (Page 35). An exemplary linker for generating an antibody-payload conjugate by means of a microbial transglutaminase (MTG) is shown below in the
PNG
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N [Wingdings font/0xE0] C direction (Page 14).
As defined by the invention, m, n, and o are integers between 0 and 12, Aax can be any naturally or non-naturally occurring L- or D-amino acid, or amino acid derivative or mimetic (Page 14; emphasis added), the Aax-NH2 moiety is an amino acid, amino acid derivative or amino acid mimetic comprising a side chain having a primary amine group (e.g., lysine) (Page 15; emphasis added), and B can be a linking moiety, like e.g. a bio-orthogonal group ( e.g., an azide/N3-group) that is suitable for strain-promoted alkyne-azide cycloaddition (SPAAC) click-chemistry reaction to a DBCO-containing payload (e.g. a toxin or a fluorescent dye or a metal chelator, like DOTA or NODA-GA) or a payload such as a toxin (Page 4). It is noted that Spycher provides some exemplary linkers, such as linkers comprising three amino acid residues, as shown in Table 5 (see Pages 39-40). It is noted that some of these linkers include (from N- to C-terminus): KGH, KHG, KSG, KGS, KAG, etc. wherein it is noted that the N-terminal Lys comprises the primary amine group necessary for MTG conjugation. Thus, Spycher suggests small oligopeptide linkers comprising an N-terminal Lys for conjugation, wherein an exemplary secondary residue in the linker can include Gly; thus one of ordinary skill in the art would recognize that possible oligopeptide linkers envisioned by Spycher include those comprising the formula reproduced above, wherein m = 0, o = 0, (Aax)-NH2 = Lys, and (Aax)n may be Gly-Gly when Aax = Gly and n = 2. The microbial transglutaminase is derived from Streptomyces mobaraensis, preferentially with a sequence identity of 80% to the native enzyme (Page 24). Spycher further teaches embodiments wherein the linker may have two or more linking moieties B such that an antibody-payload conjugate can be created with, for example, an antibody to payload ratio of 2, with two payloads conjugated to each Q295 residue (Page 30). Thus, Spycher suggests linker-payload (e.g., linker-chelator) constructs that can be conjugated to an antibody by MTG.
With further regard to oligopeptide linkers, as recited in instant claim 1, Tanaka teaches that the N-terminal glycine (Gly) residue of a target protein can be a candidate primary amine for site-specific protein conjugation catalyzed by microbial transglutaminase (MTG) from Streptomyces mobaraensis (Abstract). The reactivities of additional peptidyl linkers were investigated and the results obtained suggested that at least three additional Gly residues at the N-terminus were required to yield the EGFP–DHFR heterodimeric form and site-directed mutagenesis analysis revealed marked preference of MTG for amino acids adjacent to the N-terminal Gly residue involved in the protein conjugation; in addition, peptide–protein conjugation was demonstrated by MTG-catalyzed N-terminal Gly-specific modification of a target protein with the myc epitope peptide (Id.). Wild-type EGFP does not contain any reactive Lys or Gln residues for MTG, which makes it suitable for characterization of MTG-mediated protein cross-linking through a specific peptide genetically fused to target proteins (Page 2093, Column 2, Last Paragraph). EGFPs possessing one, three or five Gly residues at the N-terminus were prepared, and results indicate that the presence of three Gly residues at the N-terminus resulted in a 10- fold enhancement compared with that of a single Gly residue and a slight increase in the reactivity was observed when the linker length was further increased to five Gly residues (Gly5-EGFP) (Page 2094, Column 2, Paragraph 1; Figure 3). The authors suggest that a spacer region is required to separate the N-terminal Gly from the original sequence of the target protein; the cross-linking efficiency of GMVGG-EGFP was very low despite the five additional residues at its N-terminus, which implies that the type of amino acid next to the N-terminal
Gly residue has a dominant effect on the N-terminal protein conjugation (Page 2095, Column 1, Paragraph 1). Basic (Arg), acidic (Glu) and bulky (Phe) residues were introduced as the second amino acid from the N-terminus of Gly5-EGFP (Fig. 1) wherein substitution of the second amino acid produced a substantial decrease in the efficiency of protein cross-linking: (i) when Glu was introduced, the corresponding peptidyl linker exhibited the lowest reactivity and was comparable to Gly1-EGFP, despite the fact that it had five additional residues at the N-terminus; and (ii) substitution with a basic amino acid increased the reactivity of GRG3-EGFP compared to GEG3-EGFP and GFG3-EGFP wherein said results suggests that substrate preference of MTG is suggested by tertiary structure (Page 2095, Column 1, Paragraph 2). The authors developed N-temrinal Gly specific protein modification by MTG wherein at least three additional Gly residues appeared to be necessary to ensure good reactivity for the N-terminal protein conjugation; wherein three Gly residues is the shortest peptidyl tag reported for TG-mediated protein modification (Page 2095, Column 2, Paragraph 2).
Dennler, Morias, Spycher, and Tanaka are considered to be analogous to the present invention as they are all in the same field of antibody/protein conjugation and/or transglutaminase-mediated conjugation. Thus, it would have been obvious to one of ordinary skill in the art that the method for making ADCs taught by Dennler could be modified such that the method could be for preparing a site-specific bioconjugated antibody of the formula Ab-(Linker-Chelator)n wherein the linker is an oligopeptide (as suggested by Spycher and Tanaka), the chelator is a metal chelator (as suggested by Morias and Spycher), and 0<n≤2 (as suggested by Dennler, Morias, and Spycher), wherein the method comprises: (i) enzymatic deglycosylation of an antibody (as suggested by Dennler and Morias); (ii) coupling the deglycosylated antibody with a Linker-Chelator compound (as suggested by Spycher) in the presence of transglutaminase (as suggested by Dennler, Morias, Spycher, and Tanaka) such that the linker comprises a sequence of (*K-G-G) (as suggested by Spycher and Tanaka), wherein * designates the N-terminal end of the linker that is covalently attached to the antibody, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success because all of the references teach successful bioconjugation of drug/chelator moieties to antibodies using transglutaminase, wherein the teachings of Dennler and Morias support first deglycosylating an antibody, Spycher and Tanaka further suggest the use of oligopeptide linkers, and Spycher specifically teaches the use of Linker-Chelator compounds in the bioconjugation. Particularly with regard to oligopeptide linkers, Spycher suggests linkers comprising as few as three amino acid residues, wherein the N-terminal residue may be a lysine in order to provide a reactive amine for antibody conjugation. Spycher also indicates that Gly residues may be present in said linkers, which is further supported by the teachings of Tanaka wherein additional N-terminal Gly residues promoted TG-mediated protein modification. Thus, when an N-terminal lysine residue provides a primary amine for reaction, as suggested by Spycher, the inclusion of additional Gly residues would be expected to still promote good reactivity based on the flexibility of said Gly residues and the absence of sterically bulky groups, as suggested by Tanaka. With regard to obviousness of step order, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). Therefore, the selection/order of Applicant’s steps, which provides expected results, is obvious.
With regard to new claim 44, it is noted that claim 43 is rendered obvious by Dennler, Morias, Spycher, and Tanaka as discussed above. Furthermore, it is noted that Dennler discloses a transglutaminase-based chemo-enzymatic conjugation approach to produce ADCs wherein the antibody of said ADCs is trastuzumab (see, for example, Abstract and Pages 575-576), which targets cancer antigen HER2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim 24 stands as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Dennler et. al. (Bioconjugate Chemistry, 2014, 25, 569-578; reference A09 on IDS submitted 08/10/2022; herein after referred to as "Dennler"), non-patent literature by Morias and Ma (Drug Discovery Today: Technologies, 2018, 30, 91-104; previously cited on PTO-892; herein after referred to as "Morias"), and non-patent literature by Tanaka et. al. (FEBS Letters, 2005, 579, 2092-2096; previously cited on PTO-892; herein after referred to as "Tanaka") as applied to claims 17-23, 25-27, 29, 31-33, and 35-36 above, and further in view of non-patent literature by Okoye et. al. (Radiochim. Acta, 2019, 107(9-11), 1087-1120; previously cited on PTO-892; herein after referred to as "Okoye").
Claim 28 stands as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Dennler et. al. (Bioconjugate Chemistry, 2014, 25, 569-578; reference A09 on IDS submitted 08/10/2022; herein after referred to as "Dennler"), non-patent literature by Morias and Ma (Drug Discovery Today: Technologies, 2018, 30, 91-104; previously cited on PTO-892; herein after referred to as "Morias"), and non-patent literature by Tanaka et. al. (FEBS Letters, 2005, 579, 2092-2096; previously cited on PTO-892; herein after referred to as "Tanaka") as applied to claims 17-23, 25-27, 29, 31-33, and 35-36 above, and further in view of non-patent literature by Phillips and Signs (Current Protocols in Protein Science, 2004, Unit 4.4, Supplement 38, 1-15; previously cited on PTO-892; herein after referred to as "Phillips") and non-patent literature by Knuckles et. al. (J. Agr. Food Chem., 1975, 23(2), 209-212; previously cited on PTO-892; herein after referred to as “Knuckles”).
Response to Arguments
With regard to the claim rejections presented above under 35 U.S.C. 103 in view of Dennler, Morias, Spycher, and Tanaka, Applicant argues the following on Pages 13-22 of Remarks (11/27/2025):
There is no suggestion in any of the cited references of using "the linker compris[ing] a sequence of (*G-G-G)" in the process for preparing a site-specific bioconjugated antibody as recited in claim 17 such that ""the Linker ... [is] bound to the Ab at its N-terminal end, and comprising a sequence chosen among (*G-G-G), (*K-G-G) and (*A-K-A), where * denotes the N-terminal end of the Linker which is covalently bound to the Ab"; Tanaka does not relate to the preparation of antibody conjugates. Rather, Tanaka relates solely to the feasibility of regioselective coupling of a protein modified by MTG with a "small organic molecule" (pp. 2092, 2094 and 2095), which does not encompass antibodies. Antibodies are composed of multi-chain proteins, not a single polypeptide chain as the alleged myc epitope peptide with amino acid sequence EQKLISEEDLGC (p. 2095) of Tanaka. Thus, Tanaka cannot cure the admitted deficiency of Dennler, Morias, and Spycher.
The G-G-G sequence in Tanaka is present in Gly5-enhanced green fluorescent protein (EGFP) (see Abstract), which is not a Linker in Tanaka and, therefore, does not read on the instantly claimed linker. the alleged "linker compris[ing] a sequence of (*G-G-G)" of Tanaka is not coupled with an antibody in Tanaka, which also differs from the instant claims. Tanaka "shows the possibility of the N-terminal-specific protein labeling with small organic molecules" (p. 2095). Tanaka does not teach or suggest the possibility of the N-terminal-specific protein labeling with antibodies, which are much larger and are composed of multi-chain proteins and very different from the single polypeptide chain of the alleged myc epitope peptide with amino acid sequence EQKLISEEDLGC of Tanaka (p. 2095). The "small organic molecules" of Tanaka (p. 2095) do not encompass antibodies.
Tanaka would have taught one of ordinary skill in the art away from coupling "the linker compris[ing] a sequence of (*G-G-G)" with a "deglycosylated antibody" because Tanaka teaches that the size of the molecule matters and is crucial for coupling feasibility and that the "small organic molecule" requirement is crucial for conjugation, wherein Tanaka emphasizes the "small" size of the molecules and avoidance of "steric hindrance".
One of ordinary skill in the art would not have reasonably considered combining the teaching of Tanaka with the teachings of Dennler, Morias and Spycher and, in fact, would have been deterred from considering Tanaka as Tanaka seeks to avoid stearic hindrance and teaches that the "small" molecule size is crucial for coupling; teaching away from coupling of large molecules.
The deficiencies above regarding the combination of Dennler, Morias, Spycher, and Tanaka are not remedied by additional references Okoye, Phillips, and/or Knuckles.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to Applicant’s arguments against Tanaka specifically, it is noted that it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981). Specifically, it is noted that it not just the Tanka reference that is relied upon with regard to using oligomeric peptide linkers in the context of transglutaminase-mediated conjugation. It was noted in the previous Office Action that:
“it would have been obvious to one of ordinary skill in the art that the method for making ADCs taught by Dennler could be modified such that the method could be for preparing a site-specific bioconjugated antibody of the formula Ab-(Linker-Chelator)n wherein the linker is an oligopeptide (as suggested by Spycher and Tanaka), the chelator is a metal chelator (as suggested by Morias and Spycher), and 0<n≤2 (as suggested by Dennler, Morias, and Spycher), wherein the method comprises: (i) enzymatic deglycosylation of an antibody (as suggested by Dennler and Morias); (ii) coupling the deglycosylated antibody with a Linker-Chelator compound (as suggested by Spycher) in the presence of transglutaminase (as suggested by Dennler, Morias, Spycher, and Tanaka) such that the linker comprises a sequence of (*G-G-G) (as suggested by Tanaka), wherein * designates the N-terminal end of the linker that is covalently attached to the antibody, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success because all of the references teach successful bioconjugation of drug/chelator moieties to antibodies using transglutaminase, wherein the teachings of Dennler and Morias support first deglycosylating an antibody, Spycher and Tanaka further suggest the use of oligopeptide linkers, and Spycher specifically teaches the use of Linker-Chelator compounds in the bioconjugation” (emphasis added).
The teachings of Spycher suggest the use of oligomeric linkers, but does not explicitly teach linkers consisting of those recite in, for example, claim 17. Spycher discloses a general oligopeptide linker formula, wherein it is explicitly noted that such a linker must comprise a primary amine for conjugation. Tanaka is relied upon for the teachings that an N-terminal Glycine is sufficient for transglutaminase-mediated conjugation. Thus, Tanaka suggests that a lysine residue comprising a primary amine is not required for conjugation. While it is acknowledged that Tanaka focuses on conjugation of smaller molecules to avoid steric hinderance, Tanaka further discloses that flexible peptidyl linkers of suitable lengths are critical to cross linking, wherein one of ordinary skill in the art would recognize that glycine is the most flexible of the amino acids due to having a “side chain” consisting only of H. Furthermore, Tanaka indicates specifically that the alpha-amino group of an N-terminal Ala residue cannot be recognized by MTG as a substrate, suggesting the effect of steric hindrance by the side chain of the N-terminal Ala on the N-terminal protein cross-linking by MTG; it is noted that glycine is the least bulky of the amino acids as well. Furthermore, Tanaka discloses the conjugation of Gly5-EGFP to myc-DHFR (i.e., protein-protein conjugation facilitated via Gly5), not just conjugation of Gly5-EGFP to the myc epitope. Tanaka thus generally indicates that tertiary structure is critical in conjugation reactions mediated by MTG (especially in cases wherein an N-terminal primary amine is absent). Thus, the teachings of Spycher in view of Tanaka suggest the ability of glycine-based linkers to be suitable for MTG conjugation when linker length, flexibility, and steric factors are all considered. Additionally, it is noted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). While Tanaka may focus on conjugation of “smaller” molecules, it is noted that Tanaka does not explicitly discourage larger coupling reactions, especially when the teachings of Tanaka are taken in view of the teachings of Spycher which are directly pertinent to antibody conjugation (including antibody conjugation using small oligopeptide linkers; see e.g., Table 5 of Spycher). Furthermore, it is noted that metal chelators (e.g., -NH-CH2-CH2-DOTAM and -NH-TCMC as pertain to instant claim 24) would be recognized by one of ordinary skill in the art as “small” organic molecules; thus it would be expected that the teachings of Tanaka would reasonably apply to the conjugation of, for example, a small linker (e.g., 3-13 amino acid residue)-chelator to a larger protein (e.g., an antibody) and the linker-chelator would provide minimal steric hinderance compared to protein-protein conjugation. As such, the claim rejections under 35 U.S.C. 103 in view of Dennler, Morias, Spycher, and Tanaka, and the additional claim rejection in view of additional references Okoye, Phillips, and/or Knuckles, are deemed proper and are maintained.
Conclusion
Claims 17-31, 33-35, and 37-48 are pending. Claims 17-31, 33-35, and 37-48 are rejected. No claims are allowed.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642