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 .
Claims 2-5 and 20-33 have been cancelled. Claim 34 has been newly added.
Applicant's arguments filed 3/5/2026 have been fully considered but they are not persuasive.
The certified translations of Korean priority documents 10-2020-0110439 and 10-2021-0075180 are acknowledged. Kim et al. (WO 2022/005100) was published 6 January 2022 and filed 24 June 2021 remains valid prior art as these priority documents do not provide support for all of the instant claims. At least for example, there is no basis for hexameric antibodies that bind antigens other than VEGF. See instant claim 1.
The rejection of claims 1-4 and 15-17 under 35 U.S.C. 102(a)(1) as being anticipated by Tsurushita et al. (U.S. Patent Application Publication 2014/0037621) is withdrawn in view of the claim amendments.
Specification
The substitute specification filed 3/5/2026 has been entered.
The replacement drawings for Figures 1-2 and 9A were received on 3/5/2026. These drawings are acceptable. However, applicant is reminded that they should have included marked-up copies of each sheet including annotations indicating the changes made to the previous version. See 37 CFR 1.121(d)(1).
The replacement sequence listing submitted 3/5/2026 and adding SEQ ID NOS: 77-81 is acknowledged. These sequences are disclosed and the sequence identifiers referenced in replacement Figures 1-2.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 8-11, 15-19, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been substantively amended. The claim no longer requires that the antibody monomers bind specifically to a vascular endothelial growth factor (VEGF). Original claim 1 required VEGF antigen binding. The hexameric antibody of claim 1 as amended is not required to bind any particular antigen. No basis has been pointed to for this broader claim and none is apparent.
Only claim 6 recites that the antibody monomers bind specifically to a vascular endothelial growth factor (VEGF). See also dependent claim 7.
The hexameric antibody of claims 12-14 implicitly must specifically to a vascular endothelial growth factor (VEGF) in view of the VH/VL and heavy chain/light chain sequences required by these claims.
In particular, no basis has been pointed to for antibodies having CDRs that bind antigens other than VEGF in the context of the framework regions of claims 8-10.
In particular, no basis has been pointed to for antibodies having light chains with CDRs that bind antigens other than VEGF in combination with the heavy chains recited in claim 19. Again, claim 19 defines only the heavy chain but not the light chain of the antibody.
The claims constitute new matter.
With respect to claim 8, the claim recites multiple heavy chain frameworks in the alternative for HFR1, HFR2, and HFR3 and recites multiple light chain frameworks in the alternative for LFR2. The claim encompasses mixing frameworks from the antibody Hz2 having the frameworks of SEQ ID NOS: 37-44 (see claim 9) with frameworks from the antibody Lu007 having the frameworks of SEQ ID NOS: 51-53, 40-41, 54, and 44 (see claim 10). With respect to claim 11, the claim recites multiple heavy and light chain CDRs in the alternative. The claim encompasses mixing CDRs from antibody Hz2 having the CDRs of SEQ ID NOS: 45-50 (present in the VH/VL of claim 12) with CDRs from antibody Lu007 having the CDRs of SEQ ID NOS: 55-60 (present in the VH/VL of claim 13). There is no disclosure that CDRs for different anti-VEGF antibodies could be combined and result in an antibody that binds VEGF or any other antigen, particularly in the context of any framework regions. The disclosure does not support this genus of antibodies. See at least section 2.3 of Lee et al. which discloses that combining CDRs from one antibody with the framework regions from a different antibody did not necessarily result in a functional antibody. See also Figure 2 and Table 2. The specification exemplifies the Hz2 and Lu007 anti-VEGF having particular framework region sequences and CDR sequences but the structural variability of the claims is large with only partial structures being required. No reasonable structure-function correlation has been established that is commensurate in scope with the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 18-19 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 depends upon claim 1. Claim 19 depends upon claim 18. Claim 1 requires the mutation E430H. SEQ ID NO: 75 in claim 18 and SEQ ID NO: 71 in claim 19 do not contain this mutation. As such, claims 18-19 are not properly dependent. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 depends upon claim 10. Claim 10 requires the presence of the HFR1 of SEQ ID NO: 51 and the HFR3 of SEQ ID NO: 53 and . None of SEQ ID NOS: 35 or 36 in claim 14 contain the sequence of SEQ ID NO: 51. None of SEQ ID NOS: 34, 35, or 36 in claim 14 contain the sequence of SEQ ID NO: 53. As such, claim 14 is not properly dependent upon claim 10. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 34 depends upon claim 1 and is directed to a pharmaceutical composition. However, the composition requires nothing more than the hexameric antibody of claim 1. Claim 34 does not further limit the subject matter of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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, 6, 11, 15-17, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Tsurushita et al. (U.S. Patent Application Publication 2014/0037621, of record) in view of Spirig et al. (U.S. Patent Application Publication 2019/0119377, of record), Lazar et al. (U.S. Patent Application Publication 2018/0022813), and Harding et al. (U.S. Patent Application Publication 2010/0322931, of record)
Tsurushita et al. (U.S. Patent Application Publication 2014/0037621) discloses hexameric antibodies multimerized through cysteine mutations and a mu tailpiece. An L309C mutation is a preferred cysteine mutation. (See instant claim 1.) The antibody monomers can be identical. VEGF is a target of interest. Anti-VEGF antibodies such as bevacizumab are disclosed. (See instant claims 1 and 6.) Heavy chain CH2 and CH3 IgG regions are present where disulfide bonds in the CH2 and CH3 region link the monomers. (See instant claim 1). The constructs can have mutations that reduce effector function. Substitutions of positions 234, 235, 236 and/or 237 reduce affinity for Fc gamma receptors. Positions 234, 236, and or 237 can be substituted with alanine. (See instant claims 15-17). Pharmaceutical compositions are disclosed. (See instant claim 34.) See at least abstract; Figures 7 and 8C; and paragraphs [0009-0010, 0016-0022, 0042, 0082-0090, 0120-0121, 0135-0136]. Tsurushita et al. does not disclose the mutations H310L and E430H as recited in instant claim 1. Tsurushita et al. does not disclose the anti-VEGF sequences for antibodies Hz2 and Lu007 as disclosed in the instant specification and where the CDR and framework sequences are recited in the instant claims.
Spirig et al. (U.S. Patent Application Publication 2019/0119377). discloses IgG Fc hexameric multimers. Use of the combined mutations of L309C and H310L is disclosed to mimic the sequence of IgM. The Fc domain of SEQ ID NO: 2 having the L309C mutation is disclosed. The reference indicates that further mutations can be made to the Fc domain. See at least abstract; Figure 1A; and paragraph [0010 and 0019].
Lazar et al. (U.S. Patent Application Publication 2018/0022813) discloses hexameric antibodies that can have Fc domain mutations including E430H. (See instant claim 1.) Additional modifications for attenuating effector function such as L234A and L235A are disclosed. (See instant claims 15-17.) See at least abstract; claims 1-3, 25, and 32-34, and paragraphs [0006, 0025, 0104, 0202].
Harding et al. (U.S. Patent Application Publication 2010/0322931) discloses the anti-VEGF antibody bevacizumab (Avastin) VH (SEQ ID NO: 1) and VL (SEQ ID NO: 2) and their CDRs in Figures 1A-B and the anti-VEGF antibody ranibizumab (Lucentis) VH (SEQ ID NO: 9) and VL (SEQ ID NO: 10) and their CDRs in Figures 1C-D. See also paragraph [0012].
With respect to instant claim 6, SEQ ID NOS: 1 and 9 have Kabat amino acids 13Q, 74S, 77T, 105Q. See amino acids 13, 75, 78, and 115, respectively
With respect to instant claim 6, SEQ ID NO: 2 and 10 have Kabat amino acids 22T, 43A, 83F, and 100Q. See amino acids 22, 43, 83, and 100, respectively.
With respect to claim 11, ranibizumab (Lucentis) HCDR1 of SEQ ID NO:11 contains instant SEQ ID NO: 55. Ranibizumab (Lucentis) HCDR2 of SEQ ID NO: 4, HCDR3 of SEQ ID NO: 12, LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8 correspond to instant SEQ ID NOS: 56-60, respectively.
It would have been obvious to produce the anti-VEGF hexameric antibodies of Tsurushita et al. using the sequences for the anti-VEGF antibody ranibizumab (Lucentis) or the anti-VEGF antibody bevacizumab (Avastin) taught by Harding et al. with the L309C mutation suggested by both Tsurushita et al. and Spirig et al. and the H310L mutation suggested by Spirig et al. and the E430H mutation suggested by Lazar et al. One would have been motivated to do so as the anti-VEGF ranibizumab (Lucentis) antibody and the anti-VEGF antibody bevacizumab (Avastin) would have been well known anti-VEGF antibodies. Tsurushita et al. specifically suggests using bevacizumab. One would have been motivated to make the H310L and E430H mutations for the reasons set forth by Spirig et al. and Lazar et al. to modulate functional properties of the antibodies. With respect to claim 34, the intended use limitation “for preventing or treating angiogenic disease” is given no patentable weight as it does not further define the structure of the claimed hexameric antibody.
Applicant’s arguments are unpersuasive. Spirig et al specifically discloses making the L309C and H310L mutations together. Lazar et al. discloses the advantages of the E430H mutation. In addition, those of ordinary skill in the art would have routinely made Fc mutations individually and in combination with an expectation of success of producing a functional antibody as evidenced by the prior art. No undue experimentation would have been required. Applicant is advised that this argument undermines the enablement of their claims. To the degree that applicant is arguing some unexpected result, no unexpected results have been shown, particularly commensurate in scope to the claims. Only claims 15-16 require particular properties and these properties are suggested by the prior art applied.
Claims 1, 6-7, 11, 15-17, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Tsurushita et al. (U.S. Patent Application Publication 2014/0037621, of record) in view of Spirig et al. (U.S. Patent Application Publication 2019/0119377, of record), Lazar et al. (U.S. Patent Application Publication 2018/0022813), and Harding et al. (U.S. Patent Application Publication 2010/0322931, of record) as applied to claims 1, 6, 11, 15-17, and 34 above, and further in view of Adams et al. (U.S. Patent Application Publication 2019/0144565) or Wu et al. (U.S. Patent Application Publication 2012/0144512).
Tsurushita et al., Spirig et al., Lazar et al., and Harding et al. are applied as above. The references do not disclose the limitations of instant claim 7.
Adams et al. discloses a heavy chain framework 2 (FR2) antibody sequence of SEQ ID NO: 15 that is identical to instant SEQ ID NO: 38. See at least paragraphs [0038 and 0065]. This sequence has 37I and 49A. See instant claims 6-7.
Wu et al. discloses a heavy chain framework 3 (FR3) antibody sequence of SEQ ID NO: 57 that is identical to instant SEQ ID NO: 38. See at least paragraph [0105]. This sequence has 73D, 74S, and 77T. See instant claims 6-7.
It would have been obvious to produce the anti-VEGF hexameric antibodies suggested by the combination of Tsurushita et al., Spirig et al., Lazar et al., and Harding et al. as set forth above. It would have been further obvious to use the heavy chain FR2 framework sequence of Adams et al. and/or the heavy chain FR3 sequence of Wu et al. as these would have been known framework regions present in antibodies. One would have been motivated to do to provide variants of the hexameric antibodies.
Claims 1, 15-17, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Tsurushita et al. (U.S. Patent Application Publication 2014/0037621) in view of Kim et al. (WO 2022/005100, Spirig et al. (U.S. Patent Application Publication 2019/0119377, of record), and Lazar et al. (U.S. Patent Application Publication 2018/0022813).
Tsurushita et al., Spirig et al., and Lazar et al. are applied as above.
Kim et al. (WO 2022/005100) was published 6 January 2022 and filed 24 June 2021. The inventors on this document are Keun Soo Kim, Seung Chul Jun, Dong Hyan An, and Hee Jung Kim. This differs from the inventors of the instant application (Seungchul Jun, Keunsoo Kim, Dong Hyun An, Devi Bahadur Basent, and Saeng Myung Han). It is by other. This document is valid prior art under 35 USC 102(a)(2). Kim et al. remains valid prior art as the foreign priority documents do not provide support for instant claims 1, 15-17, and 34. At least for example, there is no basis for hexameric antibodies that bind antigens other than VEGF.
Kim et al. discloses anti-VEGF antibodies Lucentis, Hz2, and Lu007 as in the instant application. See at least Figures 1-2. The VH sequences of SEQ ID NOS: 35, 36, and 37, and the VL sequence of SEQ ID NO: 34 (corresponding to instant SEQ ID NOS: 34, 35, 36, and 33, respectively) are also disclosed.
It would have been obvious to produce the anti-VEGF hexameric antibodies of Tsurushita et al. using the CDR and framework sequences disclosed by Kim et al. with the L309C mutation suggested by both Tsurushita et al. and Spirig et al. and the H310L mutation suggested by Spirig et al. and the E430H mutation suggested by Lazar et al. Tsurushita et al. discloses substituting positions 234, 236, and or 237 with alanine meeting the limitations of instant claims 15-17. One would have been motivated to do so Kim et al. discloses suitable anti-VEGF antibodies. One would have been motivated to make the H310L and E430H mutations for the reasons set forth by Spirig et al. and Lazar et al. to modulate functional properties of the antibodies. With respect to claim 34, the intended use limitation “for preventing or treating angiogenic disease” is given no patentable weight as it does not further define the structure of the claimed hexameric antibody.
Claims 12-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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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/Marianne P Allen/Primary Examiner, Art Unit 1647
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