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 3-12, 22, and 24 have been cancelled and claims 1, 21, 23, and 29 have been amended, as requested in the amendment filed on 11/14/2025. Following the amendment, claims 1-2, 13-21, 23, and 25-30 are pending in the instant application.
Claims 25-28 and 30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions in the Response filed 05/21/2024, there being no allowable generic or linking claim.
Claims 1-2, 13-21, 23, and 29 are under examination in the instant office action.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1-2, 13-14, 17, 19-20, and 29 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/002362 A1 (previously provided on PTO-892; herein after referred to as “Mimoto”), U.S. Patent 9,850,320 B2 (herein after referred to as “Bernett”), non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; herein after referred to as “Shields”), and non-patent literature by Liu et. al. (Frontiers in Immunology, 2017, 8(38), 1-15; previously provided on PTO-892; herein after referred to as “Liu”).
Claims 15-16 were rejected under 35 U.S.C. 103 as being unpatentable over Mimoto, Bernett, Shields, and Liu as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of Yang and Ambrogelly (Current Opinion in Biotechnology, 2014, 30, 225-229; previously presented on PTO-892; herein after referred to as “Yang”).
Claim 18 was rejected under 35 U.S.C. 103 as being unpatentable over Mimoto, Bernett, Shields, and Liu as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of WO 2008/090959 A1 (previously presented on PTO-892; herein after referred to as "Shitara").
Claims 21 and 23 were rejected under 35 U.S.C. 103 as being unpatentable over Mimoto, Bernett, Shields, and Liu as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of non-patent literature by Makaraviciute et. al. published in 2016 (herein after referred to as " Makaraviciute ").
Double Patenting - Withdrawn
Claims 1-2, 13-15, 17-21, 23, and 29 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-10, and 14 of copending Application No. 17/916,275 (herein after referred to as "'275") in view of Bernett and Shields.
Claim 16 was provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-10, and 14 of ‘275, Bernett, and Shields, as applied to instant claims 1-2, 13-15, 17-21, 23, and 29 above, and in further view of non-patent literature by Yang and Ambrogelly (Current Opinion in Biotechnology, 2014, 30, 225-229; previously presented on PTO-892; herein after referred to as “Yang”).
Response to Arguments
Applicant’s arguments, see Pages 14-19 of Remarks, filed 11/14/2025, with respect to the rejection(s) of claim(s) 1-2, 13-21, 23, and 29 under 35 U.S.C. 103 and nonstatutory double patenting (as listed above) have been fully considered and are persuasive, specifically with regard to the combination of references not teaching the combinations of mutations recited in amended claim 1(x1)-(x10). Therefore, the rejection(s) have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of US 2014/0105889 A1 (herein after referred to as "Igawa") as discussed below.
Claim Rejections - 35 USC § 103 - New
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 1-2, 13-14, 17, 19-20, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/002362 A1 (previously cited on PTO-892; herein after referred to as “Mimoto”), US 2014/0105889 A1 (herein after referred to as “Igawa”), non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”), and non-patent literature by Liu et. al. (Frontiers in Immunology, 2017, 8(38), 1-15; previously cited on PTO-892; herein after referred to as “Liu”).
With regard to claim 1, Mimoto teaches a heterodimerized polypeptide having an Fc region that comprises two polypeptides having different amino acid sequences from each other (i.e., a first polypeptide and a second polypeptide), and succeeded in the production of a heterodimerized polypeptide containing an Fc region having an improved function compared with that of a homodimer having an Fc region composed only of the first polypeptide or a homodimer having an Fc region composed of the second polypeptide which are produced by conventional techniques (Abstract). Additionally, a preferred polypeptide of the invention is an antibody which can include natural IgG molecules including natural human IgG1, IgG2, IgG3, IgG4 and naturally occurring variants of the like (Paragraph 0021). Thus, in an embodiment wherein the heterodimerized polypeptide is an antibody, the first and second polypeptides comprising the antibody are antibody half-molecules which comprise a light and heavy chain, light and heavy chain variable regions, CH1, CH2, and CH3 domains, and an Fc domain. Additionally, the polypeptide of the invention can also be a bispecific antibody (Paragraph 0075), and thus the “first polypeptide” and “second polypeptide” would bind different antigens/different antigen epitopes. The "first polypeptide" and the "second polypeptide" mean a polypeptide constituting an Fc region of the antibody; the "first polypeptide" and the "second polypeptide" means that the sequences are different from each other, and it means that the arrangement of at least the CH2 region is preferably different (Paragraph 0017). According to the invention, the first and/or second polypeptide have at least one amino acid mutation in the Fc region, the Fc region binds to the Fc gamma receptor Fc gamma RIIIa (i.e., CD16a), and the mutation in the Fc region increases selectivity/binding activity to the Fc gamma receptor including mutations at amino acid positions (according to EU numbering) 238, 265, and 267 (i.e., amino acid positions of the “first CD16a binding region” of the instant application) and positions 326, 328, and 329 (i.e., amino acid positions of the “second CD16a binding region” of the instant application) (Paragraphs 0020-0024; Table 6). Mimoto further teaches that the balance of the binding activity of the antibody to each of the activated receptor comprising Fc gamma RIa, FcγRIIa, FcγRIIIa, FcγRIIIb, and the inhibitory receptor comprising Fc gamma RIIb is an important element for optimizing the effector function of the antibody; enhancing the binding activity to the activated receptor and using the Fc region in which the binding activity is reduced with respect to the inhibitory receptor, it is possible to impart an optimal effector function to the antibody whereas the binding activity to the activated receptor is maintained or reduced, and the Fc region with enhanced binding activity to the inhibitory receptor may be used to impart the immunosuppressive effect to the antibody (Paragraph 0005). Thus, Mimoto suggests various mutations within the Fc region that alter binding properties.
However, while Mimoto teaches modifications in the Fc domain, Mimoto does not specifically teach any Fc mutations that attenuate CD16a binding activity. This deficiency is remedied by Igawa.
The invention of Igawa is directed to modifications of the Fc region of an antigen-binding molecule to improve pharmacokinetics of the antigen-binding molecule and reduce the immune response to the antigen-binding molecule (Abstract). Igawa discloses the production and evaluation of various Fc mutants, wherein amino acids and their surrounding amino acids thought to be involved in FcγR binding (positions 234-239, 265-271, 295, 296, 298, 300, and 324-327) were respectively substituted with 18 types of amino acids, excluding original amino acids and cysteine, and the binding strength of said Fc mutant was evaluated by analyzing the interaction with each FcγR; The value of the amount of antibody derived from each B3 variant bound to FcγR was divided by the value of the amount of comparative antibody in which mutations were not introduced into B3 (antibody having the sequence of naturally-occurring human IgG1 at position 234 to position 239, position 265 to position 271, position 295, position 296, position 298, position 300 and position 324 to position 337, indicated by EU numbering) bound to FcγR, and hat value was then further multiplied by 100, and the resulting value was used as an indicator of relative binding activity to each FcγR (Paragraphs 0697-0700). Table 20 lists the 236 modifications that reduced binding to at least one FcγR among the analyzed variants; it is specifically noted that Table 20 indicates that L235R, P238A, S239R, D265N, D265A, S267K, E269P, Y296P, A327I, L328R, P329K, P329W, P329Y, and A330P all reduced binding to FcγRIIIaF (see Pages 75-77; Table 20). Igawa further discloses that there are no particular limitations on the amino acid modifications introduced to decrease binding activity to each type of human FcγR in comparison with the binding activity of a native FcγR binding domain, and it was shown to be possible to achieve this by introducing the amino acid modifications shown in Table 20 into at least one location; in addition, the amino acid modifications introduced as described by the invention may be at one location or a combination of multiple locations (Paragraph 0700). As such, Igawa reads on the instantly claimed modification combinations of claim 1(x1)-(x2), (x4)-(x7), and (x10).
Shields further supports the notion that different Fc mutations have different impacts on the different Fcγ receptors. For example, Table 1 of Shields lists various point mutations introduced into the binding site of Human IgG1 for Fc receptors; each class of mutations has different effects across the different Fcγ receptors (Page 6595). Shields further discloses methods utilized to evaluate the binding of IgG to Fcγ receptors (Page 6592, Experimental Procedures: IgG Immune Complexes and IgG Binding to FcγR). Thus, both Igawa and Shield teach Fc (i.e., CD16a) variants that impact Fcγ receptor binding, wherein Igawa discloses specific mutations that attenuate Fcγ receptor binding, and suggests their combination, and Shields teaches differential Fcγ receptor binding across different mutations and how such binding is evaluated. Thus, as evidenced by the reference, it is noted that attenuation of Fcγ receptor binding via point mutations is recognized as an antibody/Fc engineering variable which achieves a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of Fc variants with regard to attenuating Fcγ receptor binding would be seen as routine optimization.
It is noted that none of Mimoto, Igawa, nor Shields specifically teach altered hinge domains wherein an inter-heavy chain disulfide bond is not formed between IgG half-molecules. This deficiency is remedied by Liu.
Liu teaches Fc engineering for the development of bispecific therapeutic antibodies wherein bispecificity by heterodimer formation was promoted via the introduction of hinge region mutations including F241R/F243S or F241S/F342R in combination with C226S and C229S mutations to avoid the covalent association of knob/knob or hole/hole monomers (i.e., prevent homodimer formation), see p. 5. In the instant case, such mutations could be applied in order to prevent disulfide bond formation between the two hinge regions of the first and second half-molecules, ultimately stabilizing the half-molecules in the instant composition and preventing homodimer formation/aggregation.
Mimoto, Igawa, Shields, and Liu are all considered to be analogous to the present invention as they are all in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, it would have been obvious to one of ordinary skill in the art to modify the first and second polypeptides (i.e., antibody half-molecules) that can bind different antigens taught by Mimoto wherein mutations to the Fc regions (i.e., first and second CD16a binding domains) attenuate Fc binding/effector functions and comprise the alterations and combinations of alterations disclosed in instant claim 1(x1)-(x2), (x4)-(x7), or (x10), as taught/suggested by Igawa and Shields, and wherein the hinge regions of the half-molecules are modified via amino acid substitution such that inter-heavy chain disulfide bonds are not formed between the half-molecules, as suggested by Liu, such that the combination of prior art elements according to known methods would be expected to yield predictable results. Mimoto teaches a heterodimerized polypeptide having an Fc region that comprises two polypeptides having different amino acid sequences from each other (i.e., a first polypeptide and a second polypeptide), and succeeded in the production of a heterodimerized polypeptide containing an Fc region having an improved function compared with that of a homodimer having an Fc region composed only of the first polypeptide or a homodimer having an Fc region composed of the second polypeptide which are produced by conventional techniques (Abstract); Mimoto generally teaches antibody half molecules that are different from each other that are capable of forming heterodimeric polypeptides (i.e., antibody molecules) that have improved function compared to homodimeric polypeptides due to Fc mutations. Igawa teaches point mutations, and suggests their combinations, within Fc regions wherein said point mutations can attenuate FcγRIIIaF binding, wherein attenuating said binding would reduce activation of said FcγR and would reduce the inflammatory immune response to the antigen binding molecule (as suggested by Igawa Paragraphs 0011-0012) wherein point mutations can include L235R, P238A, S239R, D265N, D265A, S267K, E269P, Y296P, A327I, L328R, P329K, P329W, P329Y, and/or A330P, as pertain to claim 1(x1)-(x2), (x4)-(x7), or (x10) and wherein each point mutation provided on a given monomeric polypeptide could, as taught by Shields, be evaluated for Fcγ receptor binding. One of ordinary skill in the art would recognize that evaluation of Fcγ receptor binding of point mutations that attenuate Fcγ receptor binding, as suggested by Shields, would allow for the selection of mutations that can be different from each other in the antibody half-molecules such that effector functions are different between half-molecules, which would lead to more beneficial heterodimeric antibody formats with reduced off-target effects still capable of maintaining some effector function through different CD16a interactions of each of the half-molecule Fc domains. The additional introduction of hinge region mutations including F241R/F243S or F241S/F342R in combination with C226S and C229S mutations would serve to avoid the covalent association of knob/knob or hole/hole monomers (i.e., prevent homodimer formation; see Liu p. 5) and would further promote the formation of heterodimers over homodimers wherein said heterodimers are expected to be more beneficial than homodimeric antibody formats as they have reduced off-target effects while still being capable of maintaining some effector function through different CD16a interactions of each of the half-molecule Fc domains.
With regard to claim 2, as mentioned above, the modification of the hinge regions of the antibody half-molecules as taught by Liu would serve to stabilize the half-molecules by preventing disulfide bond formation and ultimately preventing homodimer formation/aggregation. The half-molecules would be in close proximity on the surface of cells that co-express the antigens of each molecule, and thus only in that situation would the half-molecules be expected to associate and exhibit an effector function. Additionally, one of ordinary skill in the art would recognize that different Fc mutations at different sites (i.e., the first CD16a and second CD16a binding domains) can differently attenuate FcR binding at said sites, but overall can still yield Fc regions, for example in a heterodimer, capable of exhibiting effector function, as suggested by Mimoto, Igawa, and Shields. Furthermore, given that the instant invention and that rendered obvious by the prior art are identical, said inventions would be expected to possess similar effects (i.e., promotion of heterodimer formation wherein said heterodimers would have reduced off-target effects, but would still exhibit effector function at a target expressing both antigens targeted by each half-molecule). 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 claim 13, as detailed above, Liu teaches hinge modifications, and more specifically amino acid substitutions, at amino acid positions 226 and 229. 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 claim 14, teachings of Mimoto, Igawa, Shields, and Liu are all drawn to IgG molecules and more specifically IgG1 molecules. 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 claim 17, Mimoto and Liu specifically disclose the use of CH2 modifications, and more specifically different CH2 modifications, in antibody half-molecules in order to attenuate FcR binding at different sites (i.e., sites corresponding to the first CD16a and second CD16a binding domains). Thus, if FcR binds at the first CD16a binding site of the first half-molecule and the second CD16a binding site of the second half molecule, one of ordinary skill in the art would expect that FcR binding would still occur at the second CD16a binding site of the first half-molecule and the first CD16a binding site of the second half molecule since there are no modifications at those sites. 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 claims 19-20, according to the invention of Mimoto, the first and/or second polypeptide have at least one amino acid mutation in the Fc region, the Fc region binds to the Fc gamma receptor Fc gamma RIIIa (i.e., CD16a), and the mutation in the Fc region increases selectivity/binding activity to the Fc gamma receptor including mutations at amino acid positions (according to EU numbering) 238, 265, and 267 (i.e., amino acid positions of the “first CD16a binding region” of the instant application) and positions 326, 328, and 329 (i.e., amino acid positions of the “second CD16a binding region” of the instant application) (Paragraphs 0020-0024; Table 6). Mimoto further teaches that the balance of the binding activity of the antibody to each of the activated receptor comprising Fc gamma RIa, FcγRIIa, FcγRIIIa, FcγRIIIb, and the inhibitory receptor comprising Fc gamma RIIb is an important element for optimizing the effector function of the antibody; enhancing the binding activity to the activated receptor and using the Fc region in which the binding activity is reduced with respect to the inhibitory receptor, it is possible to impart an optimal effector function to the antibody whereas the binding activity to the activated receptor is maintained or reduced, and the Fc region with enhanced binding activity to the inhibitory receptor may be used to impart the immunosuppressive effect to the antibody (Paragraph 0005). Among the possible mutations to enhance binding to FcγRIIIa, Mimoto specifically teaches the S298A mutation (Paragraph 0251) and E333A (Table 6). 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 claim 29, the half-molecules are rendered obvious by the combination of Mimoto, Igawa, Shields, and Liu as detailed above. It is further noted that Igawa also teaches kits comprising antigen-binding molecules of the invention (Paragraph 0091). 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.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable WO 2013/002362 A1 (previously cited on PTO-892; herein after referred to as “Mimoto”), US 2014/0105889 A1 (herein after referred to as “Igawa”), non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”), and non-patent literature by Liu et. al. (Frontiers in Immunology, 2017, 8(38), 1-15; previously cited on PTO-892; herein after referred to as “Liu”), as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of Yang and Ambrogelly (Current Opinion in Biotechnology, 2014, 30, 225-229; previously cited on PTO-892; herein after referred to as “Yang”).
With regard to claim 15, the composition of claim 1 is rendered obvious by the combination of Mimoto, Igawa, Shields, and Liu as detailed above. However, none of the cited references teach/suggest that CH3 domain of the H chain in the first IgG half-molecule and the second IgG half-molecule has a weaker inter-CH3 domain interaction than a CH3 domain of the IgG1 subclass. This deficiency is remedied by Yang.
Yang teaches that IgG1 and IgG4 differ by up to seven amino acids in the CH3 domain, with only position 409 being at the known dimerization interface wherein a lysine occupies position 409 in IgG1 molecules and an arginine is present in the most common IgG4 allotypes; conversion of the IgG4 arginine 409 to a lysine stabilizes the CH3-CH3 interface and is sufficient to prevent half-molecule exchange whereas mutation of lysine 409 to arginine in an IgG1 context dramatically reduces the strength of the CH3-CH3 interaction and therefore the stability of the resulting variant molecule (Page 227, Column 2, Paragraph 1). Yang further teaches that the mutation of both proline 228 and lysine 409 to serine and arginine respectively, results in a mutant IgG1 molecule able to engage in Fab arm exchange to levels similar to those obtained with wild type IgG4 molecules (i.e., weaker CH3-CH3 interactions) (Id.). Thus, Yang teaches modifications that can weaken CH3-CH3 interactions.
Mimoto, Igawa, Shields, Liu, and Yang are all considered to be analogous to the present invention as they are all in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, it would have been obvious to further modify the composition rendered obvious by Mimoto, Igawa, Shields, and Liu such that the half molecules further comprise additional mutations to weaken CH3-CH3 interactions, as taught/suggested by Yang, wherein the combination of prior art elements according to known methods would be expected to yield predictable results; the addition of mutations to weaken CH3-CH3 interactions would be expected to better facilitate Fab arm exchange/heterodimerization as opposed to homodimerization.
With regard to claim 16, Yang further suggests that the IgG4 CH3-CH3 interactions, even between wild-type IgG4, are less than that compared to IgG1 as Yang teaches that the mutation of both proline 228 and lysine 409 to serine and arginine respectively, results in a mutant IgG1 molecule able to engage in Fab arm exchange to levels similar to those obtained with wild type IgG4 molecules (Page 227, Column 2, Paragraph 1). It is further noted that Mimoto suggests that antibodies as pertain to the invention can be derived from natural human IgG4. 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 18 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/002362 A1 (previously cited on PTO-892; herein after referred to as “Mimoto”), US 2014/0105889 A1 (herein after referred to as “Igawa”), non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”), and non-patent literature by Liu et. al. (Frontiers in Immunology, 2017, 8(38), 1-15; previously cited on PTO-892; herein after referred to as “Liu”), as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of WO 2008/090959 A1 (previously cited on PTO-892; herein after referred to as "Shitara").
The antibody composition of claim 1 is rendered obvious by the combination of Mimoto, Igawa, Shields, and Liu as detailed above. However, none of the cited references explicitly teach a composition wherein a ratio of sugar chains in which fucose is not bound to N-acetylglucosamine at a reducing end of the sugar chain among the total N-glycoside-linked type sugar chains bound to an Fc region in the first IgG half-molecule and the second IgG half-molecule is 20% or more. This deficiency is remedied by Shitara.
Shitara teaches that the structure of the sugar chain added to the antibody constant region is controlled as a technique for enhancing the effector activity of the antibody wherein it is known that the ADCC activity of the human IgG antibody changes according to the structure of the N-glycoside-binding complex sugar chain added to the 297-th asparagine in the Fc region; the ADCC activity of the antibody changes depending on the amount of galactose and N-acetylglucosamine contained in the sugar chain wherein the IgG antibody having an N-glycoside-binding complex sugar chain that affects the most ADCC activity is a fucose that binds alpha 1 and 6 to the N-acetylglucosamine at the sugar chain reduction terminal, and has an N-glycoside-binding complex sugar chain in which fucose is not bonded to the N-acetylglucosamine at the sugar chain reduction terminal (Paragraph 0018). More specifically, Shitara teaches a gene recombinant antibody composition comprising a human IgG1 antibody molecule having an N-glycoside bond complex type sugar chain in Fc, wherein the ratio of sugar chains in which fucose is not bonded to N-acetylglucosamine at a sugar chain reduction terminal among all N-glycoside bond composite type sugar chains bonded to Fc contained in the composition is 20% or more (Paragraph 0022).
Mimoto, Igawa, Shields, Liu, and Shitara are all considered to be analogous to the present invention as they are all in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, it would have been obvious to further modify the composition rendered obvious by Mimoto, Igawa, Shields, and Liu such that a ratio of sugar chains in which fucose is not bound to N-acetylglucosamine at a reducing end of the sugar chain among the total N-glycoside-linked type sugar chains bound to an Fc region in the first IgG half-molecule and the second IgG half-molecule is 20% or more to effectively modulate effector function, as taught/suggested by Shitara, wherein the combination of prior art elements according to known methods would be expected to yield predictable results; increasing the ratio of sugar chains in which fucose is not bonded to N-acetylglucosamine at a sugar chain reduction terminal among all N-glycoside bond composite type sugar chains bonded to Fc is expected to enhance ADCC activity.
Claims 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/002362 A1 (previously cited on PTO-892; herein after referred to as “Mimoto”), US 2014/0105889 A1 (herein after referred to as “Igawa”), non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”), and non-patent literature by Liu et. al. (Frontiers in Immunology, 2017, 8(38), 1-15; previously cited on PTO-892; herein after referred to as “Liu”), as applied to claims 1-2, 13-14, 17, 19-20, and 29 above, and further in view of non-patent literature by Makaraviciute et. al. published in 2016 (previously cited on PTO-892; herein after referred to as " Makaraviciute ").
The first and second IgG half-molecules of claims 21 and 23, respectively, are rendered obvious by Mimoto, Igawa, Shields, and Liu as detailed above. However, none of the cited references teach or suggest isolated half-antibody molecules. This deficiency is remedied by Makaraviciute.
Makaraviciute teaches that half-antibody fragments are a promising reagent for biosensing, drug-delivery and labeling applications, since exposure of the free thiol group in the Fc hinge region allows oriented reaction; despite the structural variations among the molecules of different IgG subclasses and those obtained from different hosts, only generalized preferential antibody reduction protocols are currently available (Abstract). Half-antibody fragments obtained by preferential reduction of intact antibody molecules and consisting of a heavy (H) and a light (L) chain are attractive due to their higher stability and less complicated production; the half-antibody fragment consists of a heavy and a light chain joined by a disulfide bond and has a free sulfhydryl group (Page 51, Column 1, Paragraph 2). This study focused on investigating the preferential reduction of IgG obtained from two different species aiming to obtain the highest yield of half-antibody fragments and determine the parameters influencing the reaction (Page 51, Column 1, Paragraph 6) wherein results show how a significantly higher yield of half-antibody fragments can be obtained by careful manipulation of factors including antibody host, pH, reductant, and reductant concentration (Page 55, Column 2, Paragraph 1). The study looked at sheep polyclonal anti-digoxin IgG, rabbit polyclonal anti-E.coli IgG, and rabbit anti-myoglobin IgG individually under selected reducing conditions and demonstrate that antibody-half molecules can be produced (see Figures 4-5). Additionally, Makaraviciute teaches/suggests that reducing yields of other reduction products might also simplify the purification of half-antibody fragments; during the course of the reduction reaction characteristic mixtures of reduced antibody fragments are produced and, as illustrated in the study, knowing what antibody fragments are obtained at a starting point can facilitate the optimization of the reduction and to obtain the desired fragments more quickly and efficiently.
Mimoto, Igawa, Shields, Liu, and Makaraviciute are all considered to be analogous to the present invention as they are all in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, one of ordinary skill in the art would recognize that the method of Makaraviciute could be applied individually to parental antibodies (i.e., antibodies from which the first and second polypeptides/half-molecules are derived), wherein the parental antibodies are modified based on the teachings of Mimoto, Igawa, Shields, and Liu as detailed above to produce the desired half-molecules, in order to obtain isolated populations of a first half-molecule and a second half-molecule because applying a known technique would yield predictable results; parental antibodies comprising the mutations of each desired half molecule could be utilized to produce/isolate said desired half molecules according to the method of Makaraviciute.
Double Patenting - New
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
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Claims 1-2, 13-15, 17-21, 23, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-10, and 14 of copending Application No. 17/916,275 (herein after referred to as "'275") in view of US 2014/0105889 A1 (herein after referred to as “Igawa”) and non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”) as evidenced by WO 2013/002362 A1 (previously cited on PTO-892; herein after referred to as “Mimoto”).
With regard to instant claim 1, the claims of ‘275 detail a species of the antibody composition of the instant application. Specifically, ‘275 claim 1 recites an antibody composition against a first and second antigen, that are different from each other, comprising a first and second IgG half-molecule wherein: (i) each of the first IgG half-molecule and the second IgG half-molecule is composed of one immunoglobulin light chain (hereinafter abbreviated as L chain) and one immunoglobulin heavy chain (hereinafter abbreviated as H chain), and the H chain includes an H chain variable region, a hinge domain, a CHI domain, a CH2 domain, and a CH3 domain, and has a first Fcγ receptor IIIA (hereinafter CD16a)-binding domain and a second CD16a-binding domain that are different from each other in the CH2 domain, (ii) each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of C226A and C229A numbered according to the EU index, (iii) the first IgG half-molecule includes an antigen-binding domain that binds to the first antigen, and includes an amino acid residue substitution of D265A numbered according to the EU index in the first CD16a-binding domain, (iv) the second IgG half-molecule includes an antigen-binding domain that binds to the second antigen, and includes an amino acid residue substitution of P329Y numbered according to the EU index in the second CD16a-binding domain, (v) each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (a) S239D and K326T numbered according to the EU index, or each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (b) S239D, S298A, E333A, L242C, and K334C numbered according to the EU index, and (vi) at least one of the first IgG half-molecule and the second IgG half-molecule includes an amino acid residue substitution in the CH3 domain as an alteration for attenuating an inter-CH3 domain interaction as compared with an inter-CH3 domain interaction of the IgG1 subclass. However, it is noted that the amino acid modifications recited in ‘275 claim 1, and those also recited in ‘275 claim 5, enhance FcR binding, rather than attenuate binding. It is also noted that the specific alteration combinations of (x1)-(x10) are also not taught/suggested by ‘275. However, these deficiencies are remedied by Igawa and Shields.
The invention of Igawa is directed to modifications of the Fc region of an antigen-binding molecule to improve pharmacokinetics of the antigen-binding molecule and reduce the immune response to the antigen-binding molecule (Abstract). Igawa discloses the production and evaluation of various Fc mutants, wherein amino acids and their surrounding amino acids thought to be involved in FcγR binding (positions 234-239, 265-271, 295, 296, 298, 300, and 324-327) were respectively substituted with 18 types of amino acids, excluding original amino acids and cysteine, and the binding strength of said Fc mutant was evaluated by analyzing the interaction with each FcγR; The value of the amount of antibody derived from each B3 variant bound to FcγR was divided by the value of the amount of comparative antibody in which mutations were not introduced into B3 (antibody having the sequence of naturally-occurring human IgG1 at position 234 to position 239, position 265 to position 271, position 295, position 296, position 298, position 300 and position 324 to position 337, indicated by EU numbering) bound to FcγR, and hat value was then further multiplied by 100, and the resulting value was used as an indicator of relative binding activity to each FcγR (Paragraphs 0697-0700). Table 20 lists the 236 modifications that reduced binding to at least one FcγR among the analyzed variants; it is specifically noted that Table 20 indicates that L235R, P238A, S239R, D265N, D265A, S267K, E269P, Y296P, A327I, L328R, P329K, P329W, P329Y, and A330P all reduced binding to FcγRIIIaF (see Pages 75-77; Table 20). Igawa further discloses that there are no particular limitations on the amino acid modifications introduced to decrease binding activity to each type of human FcγR in comparison with the binding activity of a native FcγR binding domain, and it was shown to be possible to achieve this by introducing the amino acid modifications shown in Table 20 into at least one location; in addition, the amino acid modifications introduced as described by the invention may be at one location or a combination of multiple locations (Paragraph 0700). As such, Igawa reads on the instantly claimed modification combinations of claim 1(x1)-(x2), (x4)-(x7), and (x10).
Shields further supports the notion that different Fc mutations have different impacts on the different Fcγ receptors. For example, Table 1 of Shields lists various point mutations introduced into the binding site of Human IgG1 for Fc receptors; each class of mutations has different effects across the different Fcγ receptors (Page 6595). Shields further discloses methods utilized to evaluate the binding of IgG to Fcγ receptors (Page 6592, Experimental Procedures: IgG Immune Complexes and IgG Binding to FcγR). Thus, both Igawa and Shield teach Fc (i.e., CD16a) variants that impact Fcγ receptor binding, wherein Igawa discloses specific mutations that attenuate Fcγ receptor binding and Shields teaches differential Fcγ receptor binding across different mutations and how such binding is evaluated. Thus, as evidenced by the reference, it is noted that attenuation of Fcγ receptor binding via point mutations is recognized as an antibody/Fc engineering variable which achieves a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of Fc variants with regard to attenuating Fcγ receptor binding would be seen as routine optimization.
‘275, Igawa, and Shields are considered to be analogous to the present invention as they are in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, it would have been obvious to one of ordinary skill in the art to modify the half-molecules of ’275 such that the amino acid alterations include substitutions that attenuate FcR binding, including mutations that could be combined as claimed in instant claim 1(x1)-(x2), (x4)-(x7), and (x10), as suggested by Igawa and Shields, wherein the combination of known elements according to known methods would be expected to yield predictable results; Igawa teaches specific modifications that attenuate Fcγ receptor binding, and suggests they combination in heterodimeric antibody formats of the invention, wherein Shields teaches that each mutation can have different impacts on Fcγ receptor binding such that one of ordinary skill could, via routine optimization, select preferred Fc variants for use in each half molecule.
With regard to instant claim 2, claim 2 of ‘275 recites antibody composition according to claim 1, wherein the antibody composition exhibits an effector function specifically for a target cell co-expressing the first antigen and the second antigen and damages the target cell as compared with an effector function for a target cell expressing only the first antigen and a target cell expressing only the second antigen. 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 instant claim 13, ‘275 claim 1(ii) recites each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of C226A and C229A numbered according to the EU index. 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 instant claim 14, ‘275 claim 8 recites the antibody composition of claim 1 wherein the immunoglobulin subclass of the first IgG half-molecule and the second IgG half-molecule is IgG1. 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 instant claim 15, ‘275 claims 1(vi) and 3-4 recite residues for amino acid substitutions wherein said substitutions attenuate inter-CH3 domain interactions as compared with the inter-CH3 domain interactions of the IgG1 subclass. 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 instant claim 17, ‘271 claim 1, and in combination with Igawa and Shields, specifically suggests the use of CH2 modifications, and more specifically different CH2 modifications, in antibody half-molecules in order to attenuate FcR binding at different sites (i.e., sites corresponding to the first CD16a and second CD16a binding domains). Thus, if FcR binding at the first CD16a binding site of the first half-molecule and the second CD16a binding site of the second half molecule, one of ordinary skill in the art would expect that FcR binding would still occur at the second CD16a binding site of the first half-molecule and the first CD16a binding site of the second half molecule since there are no modifications at those sites. 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 instant claim 18, ‘275 claim 7 recites the antibody composition of claim 1 wherein a ratio of sugar chains in which fucose is not bound to N-acetylglucosamine at a reducing end of the sugar chain among the total N-glycoside-linked type sugar chains bound to an Fc region in the first IgG half-molecule and the second IgG half-molecule is 20% or more. 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 instant claims 19-20, ‘275 claim 1(v) recites that each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (a) S239D and K326T numbered according to the EU index, or each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (b) S239D, S298A, E333A, L242C, and K334C numbered according to the EU index. Such mutations are known to enhance effector function/FcR binding (as evidenced by Mimoto above). 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 instant claims 21 and 23, ‘275 claims 9 and 10 recite first and second IgG half molecules, respectively, with the same limitations outlined in earlier claims. ‘275 claims 9 and 10 recite amino acid modifications that enhance FcR binding, however as detailed above, Igawa in combination with Shields teach/suggest Fc mutations that attenuate FcR binding and thus it would have been obvious to one of ordinary skill in the art to modify the half-molecules of ’275 such that the amino acid alterations include mutations that could be combined as claimed in embodiments (x1)-(x2), (x4)-(x7), and (x10), wherein the combination of known elements according to known methods would be expected to yield predictable results.
With regard to instant claim 29, ‘275 claim 14 recites a kit comprising IgG half-molecules with limitations outlined in earlier claims. ‘275 claim 29 recites amino acid modifications that enhance FcR binding, however as detailed above, Igawa and Shields teach/suggest Fc mutations that attenuate FcR binding and thus it would have been obvious to one of ordinary skill in the art to modify the half-molecules of ’275 such that the amino acid alterations include substitutions L235R, P238A, S239R, D265N, D265A, S267K, E269P, Y296P, A327I, L328R, P329K, P329W, P329Y, and/or A330P that attenuate FcR binding, wherein the combination of known elements according to known methods would be expected to yield predictable results.
This is a provisional nonstatutory double patenting rejection.
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-10, and 14 of ‘275, US 2014/0105889 A1 (herein after referred to as “Igawa”), and non-patent literature by Shields et. al. (The Journal of Biological Chemistry, 2001, 276(9), 6591-6604; previously cited on PTO-892; herein after referred to as “Shields”), as applied to instant claims 1-2, 13-15, 17-21, 23, and 29 above, and in further view of non-patent literature by Yang and Ambrogelly (Current Opinion in Biotechnology, 2014, 30, 225-229; previously cited on PTO-892; herein after referred to as “Yang”).
The composition of instant claim 15 is rendered obvious by ’275, Igawa, and Shields. However, none of ‘275, Igawa, or Shields explicitly recite the antibody composition according to claim 15 wherein the immunoglobulin subclass of the CH3 domain of the H chain in the first IgG half- molecule and the second IgG half-molecule is IgG4. This deficiency is remedied by Yang.
Yang teaches that IgG1 and IgG4 differ by up to seven amino acids in the CH3 domain, with only position 409 being at the known dimerization interface wherein a lysine occupies position 409 in IgG1 molecules and an arginine is present in the most common IgG4 allotypes; conversion of the IgG4 arginine 409 to a lysine stabilizes the CH3-CH3 interface and is sufficient to prevent half-molecule exchange whereas mutation of lysine 409 to arginine in an IgG1 context dramatically reduces the strength of the CH3-CH3 interaction and therefore the stability of the resulting variant molecule (Page 227, Column 2, Paragraph 1). Yang further teaches that the mutation of both proline 228 and lysine 409 to serine and arginine respectively, results in a mutant IgG1 molecule able to engage in Fab arm exchange to levels similar to those obtained with wild type IgG4 molecules (i.e., weaker CH3-CH3 interactions) (Id.). Thus, Yang teaches modifications that can weaken CH3-CH3 interactions.
'275, Igawa, Shields, and Yang are all considered to be analogous to the present invention as they are all in the same field of antibodies, antibody-based products/processes, and/or antibody engineering. Thus, it would have been obvious to modify the composition rendered obvious by ‘275, Igawa, and Shields such that the half molecules comprise mutations to weaken CH3-CH3 interactions, wherein if the CH3 domains were derived from IgG4, as ‘275 does not limit the subclass to which the IgG half molecules belong and as such it assumed they can be of any subclass including IgG4, they would have weaker CH3-CH3 interactions than the IgG1 subclass, as taught/suggested by Yang, wherein the combination of prior art elements according to known methods would be expected to yield predictable results; weaker CH3-CH3 interactions would allow for better Fab exchange/heterodimerization compared to homodimerization.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-2, 13-21, 23, and 25-30 are pending. Claims 25-28 and 30 are withdrawn. Claims 1-2, 13-21, 23, and 29 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