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 .
Priority
Acknowledgement is made of the applicant’s claim for foreign priority based on the application filed on 12 March 2021. The effective filing date is 12 March 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01 May 2024 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-39 are the original claims filed on 11 September 2023. In the preliminary amendment of 01 May 2024, claims 7, 8, 10, 14, 15, 23, 35, 36, 38, and 39 were cancelled and claims 1, 3-6, 9, 11, 13, 16-18, 24-34, and 37 were amended. Claims 1-6, 9, 11-13, 16-22, 24-34, and 37 are pending and the subject of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 16, 29, and 37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims include preferred limitations regarding the nature of amino acid substitutions. As written, it is unclear if the preferred limitations, regarding the amino acid substitutions within the Fc region, are requirements of the claim, see MPEP 2173.05(h).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-5, 9, 11-13, 17, and 29-34 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by US20170073421 A1 (herein Kjaergaard).
In regard to claims 1, 4-5, 9, 11, 12, and 13, Kjaergaard teaches IgG1 C5aR antibodies, comprising amino acid substitutions at positions 234, 235, 236, 237, 297, 328, 330, and/or 331, which do not induce phagocytosis, ADCC, or CDC ([0013], and claim 13). As defined by Kjaergaard, the term “antibody” includes whole antibodies, antigen binding fragments, or single-chains thereof ([0061]). It is further taught that a “full-length” antibody contains two heavy chains and two light chains interconnected by disulfide bonds, with each chain comprising a variable region (relevant to instant claims 9, 11, 12, 13) ([0061]). Additionally, it is taught that heavy chain constant regions comprise CH1, CH2, and CH3 domains (relevant to claim 5). It should be noted that the antibodies were developed in transgenic mice including the human immunoglobulin germ line loci ([0101]). One disclosed embodiment is an anti-C5aR antibody comprising amino acid substitutions, L234A, L235E, and G236R within human IgG1 (relevant to instant claims 1, 4, and 13) ([0187]). In addition to the mutations included in this embodiment, reference claim 13 also teaches various other amino acid modifications, which may be included in potential embodiments (relevant to instant claim 16).
In regard to claims 29, 30, 31, Kjaergaard teaches a host cell comprising one or more polynucleotide encoding one or more of the antibodies taught in the disclosure ([0230]).
In regard to claim 32, Kjaergaard teaches a pharmaceutical composition comprising an antibody in combination with a pharmaceutically acceptable carrier ([0211).
In regard to claim 33 and 34, Kjaergaard teaches a method for treating or preventing a disorder in a subject comprising the administration of the antibody, described above, in which the antibody is suitable for the disease or disorder ([0214]). The scope of possible diseases includes numerous autoimmune diseases such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), among others ([0216]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over US20170073421 A1 (herein Kjaergaard) in view of Rowley TF, et al. (2018) Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions. Commun Biol. 2018 Sep 14;1:146 (herein Rowley).
As discussed in the 102 rejections of claims 1, 3-6, 9, 11-13, 17, and 29-34, Kjaergaard teaches C5aR antibodies comprising amino acid substitutions, L234A, L235E, and G236R, within human IgG1 ([0187]). In regard to the nature of these amino acid substitutions, Kjaergaard teaches an embodiment comprising L234A, L235E, and G236R substitutions ([0192]).
Kjaergaard does not teach the use of a triple mutant comprising a L324F mutation. Although, it should be noted that the two mutants (L234A and L234F) appear to be functionally equivalent, based on the prior art. This deficiency is taught by Rowley.
The teachings of Rowley are related to design of recombinant molecules with enhanced Fc avidity (Abstact). The authors investigate the cause of the differences in safety and potency between IgG1 and IgG4 Fc hexamers by interconverting the seven FcγR-contacting CH2 domain residues that differ between IgG1 and IgG4 (Figure 4 and Results section 4). It is shown that the inclusion of the L234F mutation onto a IgG1 hexamer had a major inhibitory effect on cytokine release platelet activation, and IFN-γ release (Figure 4b-d). Additionally, it was shown that IgG1 hexamers containing the L234F mutation showed decreased binding to neutrophils and platelets (Figure 7 and Results section 5). These observations led the author to hypothesis that this mutation led to a reduction in affinity towards FcγRIIIb and FcγRIIa, which was then confirmed by surface plasmon resonance analysis for IgG1 L234F binding to FcγRIIIb and FcγRIIa (Results section 5 and Figure 7). Overall, it is shown that L234F mutation in the CH2 domain of IgG1 antibodies results in inhibited transduction of FcγRIIIb and FcγRIIa-associated activating signaling.
It would have been obvious to one skilled in the art to combine the teachings of Kjaergaard (non-activating anti-C5aR antibodies comprising L234A, L235E, and G236R amino acid substitutions) with the L234F mutation taught by Rowley. Rowley, is the first to evaluate the effect of the L234F mutation individually (i.e. not in the context of additional mutations), and provides a clearly defined mechanism for the mutation’s inhibitory effect on antibody-associated activation. One of ordinary skill in the art at the time of filing would have been motivated to incorporate the L234F mutation, taught by Rowley, with triple Fc mutant taught by Kjaergaard, as there exists proven efficacy of the individual mutation outside of context in which multiple mutation exist. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claims 3, 6, 18-22, 25-28, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over US20170073421 A1 (herein Kjaergaard) in view of Rowley TF, et al. (2018) Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions. Commun Biol. 2018 Sep 14;1:146 (herein Rowley), Husain B, Ellerman D. (2018) Expanding the Boundaries of Biotherapeutics with Bispecific Antibodies. BioDrugs. 2018 Oct;32(5):441-464 (Husain), and WO2016110576 A1 (herein Engelberts).
In regard to claims 6, 18-22, and 37, as discussed in the 103 rejection of claim 2, Kjaergaard and Rowley teach antibodies comprising IgG1 heavy chains comprising amino acid substitutions, L234F, L235E, and G236R.
Kjaergaard and Rowley do not teach that the antibodies are bispecific in nature, or that there are differences between the CH2 and CH3 regions of the two heavy chains. Engelberts and Husain teach these deficiencies.
Husain provides a review of the state of bispecific antibody therapeutics at around the effective filing date of the current disclosure. In this review the various formats of bispecific antibodies are discussed and the numerous clinical trials utilizing this technology are listed and discussed (Sections 4-6). Of relevance to this office action, the authors discuss the unique functional capabilities of these therapeutics, which are lacking in monoclonal antibody therapeutics (Section 7). It is taught that bispecific antibodies enable mechanisms of action, not enabled by monoclonal antibodies, such as recruitment of effector cells, simultaneous blocking of multiple pathways, crossing of the blood-brain barrier, receptor internalization, induction of protein-protein interactions, and cell-specific targeting (Figure 4). Thus Husain, provides motivation for the use of bispecific antibodies.
Engelberts teaches a method for producing bispecific antibodies (Example 2 from page 105 paragraph 3-page 106 paragraph 2). Briefly, two mixed mono-specific antibodies undergo a treatment, involving the introduction of mildly reducing conditions, resulting in disulfide-bond isomerization, which allows for the exchange of “Fab-arms” between the two antibodies. The controlled isomerization is enabled by the presence of a F405L mutation in the CH3 domain of one of the antibodies and the presence of a K409R mutation in the CH3 domain of the other antibody, which under certain conditions promoted the formation of heterodimers.
It would have been obvious to one skilled in the art to combine the teachings of Kjaergaard and Rowley (non-activating antibodies comprising heavy chains comprising L234F, L235E, and G236R amino acid substitutions) with the teachings of Husain (the use of bispecific antibodies) and Engelberts’ method for producing bispecific antibodies, using a “Fab-arm” exchange. One skilled in the art would have recognized the well-known advantages of using bispecific antibodies for the treatment of various forms of disease, which is reinforced by the teachings of Husain. Husain provides clear motivation for the use of bispecific antibodies (i.e. the enablement of more complex mechanisms of action). Furthermore, Husain establishes that there is high indication of success, as shown by the rapidly increasing market for bispecific antibodies, as well as the rising level of clinical trials and approvals of bispecific antibody therapeutics (Section 9). Additionally, the use of the teachings of Engelberts method for producing bispecific antibodies would have been obvious to one skilled in the art, due to its shown effectiveness in producing IgG-like bispecific antibodies, which provides ample motivation for the selection of this technique (Example 2 found on pages 105-106).
In regard to claim 3, Kjaergaard, Rowley, Husain, and Engeleberts teach non-activating bispecific antibodies in which the one or more of the CH2 domains of the heavy chains comprise L234F, L235E, and G236R amino acid substitutions, as discussed above.
Engelberts further teaches bispecific antibodies in which one or more IgG1 heavy chain is comprised of amino acids at positions 234, 235, 265, 297, and 331 that are not L, L, D, N, or P, respectively (page 61 paragraph 3).
In regard to claim 26-28, Kjaergaard, Rowley, Husain, and Engeleberts teach non-activating bispecific antibodies in which the one or more of the CH2 domains of the heavy chains comprise L234F, L235E, and G236R amino acid substitutions, as discussed above.
Both Kjaergaard and Engeleberts teach binding regions that target cancer antigens C5aR (Abstract) and CD20 (Abstract), respectively (relevant to claim 26). Engelberts teaches a bispecific antibody comprising a CD3 binding region and a CD20 binding regions, which is relevant to claims 27 and 28 (Abstract).
In regard to claim 24, Kjaergaard, Rowley, Husain, and Engeleberts teach non-activating bispecific antibodies in which the one or more of the CH2 domains of the heavy chains comprise L234F, L235E, and G236R amino acid substitutions, as discussed above.
Kjaergaard teaches an antibody comprising an IgG1 Fc region comprising an amino acid sequence, SEQ ID NO: 33, which shares 100% sequence identity with the amino acid sequence referenced in instant claim 24. Kjaergaard also teaches an Fc region comprising an amino acid sequence, derived from SEQ ID NO:33, in which amino acid at positions corresponding to L234, L235, and G236 are substituted (Claim 13 and [0192]).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over US20170073421 A1 (herein Kjaergaard) in view of Rowley TF, et al. (2018) Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions. Commun Biol. 2018 Sep 14;1:146 (herein Rowley), Husain B, Ellerman D. (2018) Expanding the Boundaries of Biotherapeutics with Bispecific Antibodies. BioDrugs. 2018 Oct;32(5):441-464 (Husain), WO2016110576 A1 (herein Engelberts), and Jiang G, et al. (2016) Evaluation of Heavy-Chain C-Terminal Deletion on Product Quality and Pharmacokinetics of Monoclonal Antibodies. J Pharm Sci. 2016 Jul;105(7):2066-72 (herein Jiang).
Kjaergaard, Rowley, Husain, and Engeleberts teach non-activating bispecific antibodies in which the one or more of the CH2 domains of the heavy chains comprise L234F, L235E, and G236R amino acid substitutions, as discussed above. It is also taught that the Fc region is comprised of an amino acid sequence derived from SEQ ID NO:33 of Kjaergaard (corresponding to SEQ ID NO:1 from the current disclosure). These sequences contain a C-terminal lysine, and Kjaergaard, Rowley, Husain, and Engeleberts do not teach an amino acid sequence that is lacking a C-terminal lysine. This deficiency is taught by Jiang.
Jiang teaches that IgG1 antibodies are typically expressed with C-terminal PGK residues on their heavy chains, which are removed by carboxypeptidases while the antibody is circulating (Introduction paragraph 3). This processing results in various antibody isoforms with multiple charge variants, thus increasing the heterogeneity of the antibody population. This charge heterogeneity is taught to be an undesirable in the manufacturing of therapeutic antibodies (Discussion paragraph 1). The authors show that by removing the terminal lysine (or lysine and glycine), the resulting mutants shared similar structural stability and functional characteristics to the wild-type form, but were more homogeneous in nature (Results sections 1-5, Figures 1 and 2, and Table 4). The authors go onto to suggest that the genetic deletion of the terminal lysine would increase antibody homogeneity without altering structural stability or in vivo characteristics (Discussion paragraph 4).
It would have been obvious to one skilled in the art to combine the non-activating bispecific antibodies taught by Kjaergaard, Rowley, Husain, and Engeleberts with the terminal IgG1 heavy chain lysine deletion, taught by Jiang. Jiang provides clear motivation for the terminal truncation (i.e. reduced antibody heterogeneity). Furthermore, Jiang establishes that there is high indication of success, as shown by the near wild-type stability and functionality of the mutated antibodies compared to their wild-type counterparts (Results sections 1-5, Figures 1 and 2, and Table 4).
Double Patenting
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).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 9, 11, 13, 16-22, 26, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 177, 178, 179, 180 of U.S. Patent No. 12351650 (herein ‘650). Although the claims at issue are not identical, they are not patentably distinct from each other, because the invention disclosed in ‘650 encompasses the invention disclosed in the current application, as explained below.
Claims 177-180 of ‘650 all refer to an anti-FAPα/DR4 bispecific antibody (relevant to instant claims 6, 9, 11, 13, 17, 18, and 26) wherein at least one IgG1 heavy chain has amino acid substitutions at positions 234, 235, and 236 (relevant to instant claims 1, 2, 4, and 5). Claim 178 of ‘650 states that one of the two heavy chains may comprise L234F, L325E, and D265A amino acid substitutions (relevant to instant claim 3). Additionally, the antibody is enabled for controlled isomerization by the presence of a F405L mutation in the CH3 domain of one of the antibodies and the presence of a K409R mutation in the CH3 domain of the other antibody (relevant to instant claims 16, 19, 20, 21, 22, and 37).
Claims 1, 2, 4, 5, 9, 13 17, 29, 30-34, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 23, 27, 30-32 of U.S. Patent No. 11932693 (herein ‘693). Although the claims at issue are not identical, they are not patentably distinct from each other, because the invention disclosed in ‘693 encompasses the invention disclosed in the current application, as explained below.
Claims 1, 13, 23, 27, ‘693 all refer to either an anti-PD-1 antibody (comprising L234F, L235E, and G236R amino acid substitutions within the IgG1 CH2 domain), a nucleic acid encoding said antibody, or a pharmaceutical composition comprising the antibody or the nucleic acid (relevant to instant claims 1, 2, 4, 5, 9, 13, 17, 29, 30-34).
Claims 1-6, 9, 11, 13, 16-22, 26, 33, 34, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61, 64, 88, 92, 115, and 116 of U.S. Patent No. 12398214 (herein ‘214). Although the claims at issue are not identical, they are not patentably distinct from each other, because the invention disclosed in ‘214 encompasses the invention disclosed in the current application, as explained below.
Claims 61 and 88 of ‘214 refer to an anti-EpCAM/CD137 bispecific antibody (relevant to instant claims 6, 9, 11, 13, 17, 18, and 26) wherein at least one IgG1 heavy chain has amino acid substitutions at positions 234, 235, and 236 (relevant to instant claims 1, 2, 4, and 5). Claim 64 of ‘214 states that one of the two heavy chains may comprise L234F, L325E, and D265A amino acid substitutions (relevant to instant claim 3). Additionally, as defined in claim 92 of ‘214, the antibody is enabled for controlled isomerization by the presence of a F405L mutation in the CH3 domain of one of the antibodies and the presence of a K409R mutation in the CH3 domain of the other antibody (relevant to instant claims 16, 19, 20, 21, 22, and 37). Claims 115 and 116 of ‘214 relate to methods of using the antibody or a pharmaceutical composition comprising the antibody as treatment, which is relevant to instant claims 33 and 34.
Conclusion
No claims allowed.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647