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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/10/2026 has been entered.
Claims 193, 199, 205, and 212 have been amended. Claims 212-214 have been added. Claim 193-195 and 199-214 are pending and under consideration.
The rejection of claim 205 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of applicant’s amendment.
The rejection of claims 193-195, 197, 199-202, and 209-212 under 35 U.S.C. 103 as being unpatentable over Romagne et al (WO2004/056392) in view of Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192, see publication data, downloaded from the web on 9/13/2025) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562) is withdrawn in light of applicant’s argument that claim 1 requires that the first polypeptide molecule comprises in the N-to-C orientation, the first cytokine molecule connected to the second immunoglobulin chain constant region. Thus, the C-terminus of the first cytokine molecule must be connected to the N-terminus of the second immunoglobulin constant region in order to satisfy the claim limitation. Kiefer and Neri teach an example wherein the N-terminus of the first cytokine is connected to the C-terminus of the second immunoglobulin molecule and fails to provide the required structure of the first polypeptide.
New Grounds of Rejection
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 193-195, 199-204, and 206-214 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.
Claims 193-195, 199-204, and 206-214 are reliant on a genus of multifunctional polypeptide molecules comprising a first antibody molecule that binds to NKp30 or NKp46 or an antigen binding fragment thereof, a first polypeptide comprising in the N-to C- orientation the first cytokine molecule connected to the second immunoglobulin chain constant region, wherein the multifunctional polypeptide comprises a dimerization module comprising a first and second immunoglobulin constant region. The claimed genus fails to describe the attachment of the first antibody molecule to the first polypeptide comprising the cytokine and the immunoglobulin chain constant region dimerized to the second immunoglobulin constant region. When given the broadest reasonable interpretation, the first antibody molecule could be attached to cysteines or lysines via bifunctional linkers to the second immunoglobulin constant region, or could be attached at either the N-terminus or the C-terminus of the second immunoglobulin constant region. The specification fails to teach a relationship between the structure of the multifunctional polypeptide and a desired function. The specification fails to teach representative examples of the alternative attachment sites of the antibody to the second immunoglobulin constant region sufficient to describe the claimed genus. Further, the specification describes only monovalent targeting antibodies (figure 7, 9A and 9B). There is no written description of any bivalent antibodies associated with the second immunoglobulin domain. Thus, the specification fails to describe a representative number of the multifunctional polypeptide molecules sufficient to describe the claimed genus, not a relationship between the structure of the targeting antibody molecules used in the multifunctional polypeptide molecule and a specific functional attribute. One of skill in the art would reasonably conclude that applicant was not in possession of the genus of multifunctional polypeptide molecules as claimed.
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 193-195, 197, 199, 205, 209- 214 under 35 U.S.C. 103 as being unpatentable over Romagne et al (WO2004/056392, cited in the previous action) in view of Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192, cited in the previous action), Amann et al (U.S. 2016/0340399, priority to EP15161880, filed 3/31/2015, see example 5, pages 98-99) and Zheng et al (Journal of Immunology, 1999, Vol. 163, pp. 4041-4048) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562, cited in the previous action).
Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2, wherein the cancer include melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma (claims 1 and 15 of ‘392) which meets the limitations of a solid tumor or a hematological cancer in claim 211, multiple myeloma, chronic and acute myeloid leukemia in claims 212(ii); lung cancer and skin cancer in claims 212(i) .
Romagne et al do not teach the delivery of the IL-2 by an antibody construct comprising a first immunoglobulin chain constant region ad a second immunoglobulin chain constant region, wherein the (1) the C-terminus of the first cytokine molecule is attached to the N-terminus of the second immunoglobulin chain constant region in a first polypeptide, and
2) a first antibody fragment that binds to NKp30 or NKp46, wherein the antibody fragment is attached to the N-terminus of the first immunoglobulin constant region in a second polypeptide.
Romagne et al do not teach the replacement of one or more residues that make up the CH3-CH3 interface with a charged amino acid such that the interaction between like chains becomes electrostatically unfavorable in order to discourage the homodimer formation to provide the bispecific antibody.
Amann et al teach antibody constructs comprising first polypeptide comprising a cytokine which interacts with a TNF receptor, wherein the C-terminus of the ligand is attached to the N-terminus of an immunoglobulin constant region, and a second polypeptide comprising a targeting Fab, wherein the C-terminus of the Fab is attached to the N-terminus of an immunoglobulin constant region (Figures 3A, 3B, 4A and 4B). The configuration of the antibody constructs in Figures 3A, 3B, 4A and 4B meet the limitations for the configuration of the multifunctional polypeptide of the instant claims.. Amann et al teach that there is a need for antigen-binding molecules that combine a moiety capable of preferred binding to tumor specific or tumor associated Amann et al teach that the Fc domain comprises a first and second subunit is capable of stable association between the binding moiety that binds the target cell and the cytokine (page 3, paragraph [0029], section c). Amann et al teach that the Fc domain confers favorable pharmacokinetic properties to the antigen binding molecules of the invention, including a long serum half-life which contributes to good accumulation in the target tissue and a favorable tissue-blood distribution ratio. The Fc domain thus favorably contributes to the pharmacokinetic parameters (PK data) of the antigen binding molecules, such as clearance, volume of distribution or elimination half-time (t.sub.1/2). Amann et al teach that the Fc receptor may lead to undesirable targeting of the antibody construct of the invention to cells expressing Fc receptors rather than to the preferred antigen-bearing cells and that in order to counter this undesirable effect, the Fc domain exhibits reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a native IgG1 Fc domain. (paragraph [0221]).
Amann et al teach an embodiment wherein the Fc domain of the antibody constructs of the invention comprises one or more amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor and/or effector function. Typically, the same one or more amino acid mutation is present in each of the two subunits of the Fc domain, such as an amino acid substitution at a position of E233, L234, L235, N297, P331 and P329 (EU numbering) (paragraph [0224)).
Amman et al teach an embodiment wherein 0235] In a specific aspect, said modification is a so-called “knob-into-hole” modification, comprising a “knob” modification in one of the two subunits of the Fc domain and a “hole” modification in the other one of the two subunits of the Fc domain. allowing a heterodimerization of the two Fc chains comprising the first Fc chain fused to the targeting moiety and a second Fc fused to the cytokine, wherein the first dimerization module comprises knobs and the second dimerization module comprises holes according to the knob into hole technology (paragraph [0235]) and meets the limitations of claim 195..
Amann et al teach that the cytokine can be fused to the Fc or attached via a linker (paragraph [0018], section c) which meets the limitations of claims 199, 213 and 214.
Amann et al teach that target cell antigens include FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 (paragraph [0036]) and that the targeting moiety formats include antibody fragment selected from the group consisting of a Fab molecule, a crossover Fab molecule, a single chain Fab molecule, a Fv molecule, a scFv molecule, a single domain antibody, and a VH (paragraph [0032])..
Kiefer and Neri teach immunocytokines, wherein cytokine payloads which can be efficiently delivered to the tumor site include Il-2 (page 180, second column, number 1). Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass antigens.(page 182, first column, lines 182, lines 1-6 of the second full paragraph). Because Il-2 is a ligand of the Il-2 receptor, it therefore comprises a receptor dimerizing domain as required in claim 197.
Kiefer and Neri teach that in most applications of bispecific antibodies, one antibody moiety was specific for a tumor specific antigen and the other antibody moiety was specific for a leukocyte antigen (page 185, lines 1-5 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that in most of the applications CD3 was used to recruit T cells, but other molecular targets such as CD16 on NK cells have been contemplated (page 185, lines 6-8 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action (page 188, first column, lines 8-11 of the first full paragraph).
Zheng et al teach that a Il-2/Fc fusion protein retains specific and high affinity binding to Il-2 receptor and exhibits an extended half-life of 25 hrs. after system administration (abstract and Figure 1)
It would have been prima facie obvious at the time prior to the effective filing date to substitute an anti-NKp30 Fab or an anti-NKp46 Fab for the anti- FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 targeting moieties of the antibody construct of Aman et al and to replace the cytokine binding to TNFR with Il-2 in the antibody construct of Aman et al. One of skill in the art would have been motivated to do so in order to obtain a stable targeted construct that targeted Il-2 to NK cells via binding to Nkp30 or NKp46. One of skill in the art would have been motivated to do so by the teachings of Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2 and the teachings of Amann et al that an antibody construct comprising a targeting moiety and a cytokine allows delivery of the cytokine to the desired cell and avoids side effects of the untargeted administration of a cytokine, and the further teachings of Amann et al that attachment of the cytokine to the N-terminus of an Fc provides for a stable association between the polypeptide comprising targeting moiety attached to the N-terminus of an Fc and also provides for enhanced serum half-life of the construct. The teachings of Zheng et al provide a reasonable expectation that the Il-2 attached to the N terminus of the Fc will be able to binds to the Il-2 receptor.
One of skill in the art would have been motivated to combine the resulting bispecific immunocytokine with a pharmaceutically acceptable carrier for the admisntration to a subject with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma. One of skill in the art would have been motivated to do so by the teachings of Romagne et al on the administration of anti-NKp30 or anti-NKp46 in combination with Il-2 for the treatment of melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma and the teachings of Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action. One of skill in the art would understand that providing the Il-2 with the anti-NKp30 or NKp46 bispecific antibody would provide NK cells at the site of action in the tumor mass because Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass. Thus, one of skill in the art would understand that the massive infiltration of NK cells were the accessory lymphocytes needed at the site of action for the bispecific antibodies targeting tumor antigen and NKp30 or NKp46.
The administration of the bispecific immuocytokine to patients taught by Romagne et al to be treatable with anti-NKp30 or anti-NKp46 are patients with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma which meets the limitations of claim 210 and a solid tumor and a hematological cancer in claim 211, lung cancer, skin cancer and liver cancer in claim 212(i) and chronic myeloid leukemia and multiple myeloma in claims 212ii). The resulting antibody construct based on the format of 3A , 3B, 4A and 4B of Amann et al wherein the antigen binding specificity for a leukocyte was either anti-NKp30 or anti-NKp46 meets the limitations of claim 193 wherein the multifunctional polypeptide further comprises a dimerization module comprising a first Ig constant region and a second Ig constant region, wherein the anti-NKp30 or the anti-NKp46 and the Il-2 is linked to the Ig constant region as in immunocytokine. The resulting construct meets the limitation of claim 194 for having a first and second Fc region; the knobs -in-hole format meets the limitation of claim 195. Il-2 attached to the N-terminus of the Fc for the first polypeptide meets the limitation of claims 197 as evidenced by Boger and Goldberg who teach that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Therefore, because Il-2 is a ligand of the Il-2 receptor, it comprises a receptor dimerizing domain required in claim 197.
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 193-195, 197, 199, 205, 209- 214 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 21-23 of U.S. Patent No.12,384,842, in view of Romagne et al (WO2004/056392), Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192), Amann et al (U.S. 2016/0340399, priority to EP15161880) and Zheng et al (Journal of Immunology, 1999, Vol. 163, pp. 4041-4048) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims are obvious over the ‘842 claims.
Claim 9 of the ‘842 patent teaches a multispecific molecule comprising the antigen or antigen-binding portion thereof of claim 2 which is an antibody or antigen-binding portion thereof which binds to NKp30. Claim 10 teaches that the multispecific molecule of claim 9 further comprises, in part,, a cytokine molecule, Claim 13 teaches that the antibody or antigen-binding portion thereof of claim 47 comprises an immunoglobulin chain constant region, which meets the limitation of “the first antibody molecule binds to NKp30 or antigen binding fragment thereof is linked to dimerization module which is an immunoglobulin constant region in claim 193 and the first Fc in claim 194. Claim 12(a) teaches that the multispecific molecule comprises a linker between the targeting moiety and the immunoglobulin chain constant region of instant claims 199 requiring, in part, a linker between the first antibody molecule and the first immunoglobulin chain constant region. Claim 21 teaches the pharmaceutical composition comprising the antibody of claim 2; claim 22 and 23 are drawn in part to a method of treating a disease or condition which is cancer by administering the antibody of claim 2, all of which render obvious a pharmaceutical composition comprising the multispecific molecule comprising the antibody of claim 2; and a method of treating a disease or condition which is cancer by administering the comprising the multispecific molecule comprising antibody of claim 2 comprising a tumor targeting antibody which fulfils the limitations of claim 209 and 210,
The claims of the application do not teach that the multispecific molecule includes the attachment of the first antibody molecule to the N-terminus of the first immunoglobulin constant region; the dimerization between the first immunoglobulin constant region and the second immunoglobulin constant region and the particular cytokine of Il-2 or the particular tumor-targeted antigens or the particular cancers treated by administration of the multispecific molecule of claim 2 comprising a tumor targeting moiety.
Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2, wherein the cancer include melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma (claims 1 and 15 of ‘392) which meets the limitations of a solid tumor or a hematological cancer in claim 211, multiple myeloma, chronic and acute myeloid leukemia in claims 212(ii); lung cancer and skin cancer in claims 212(i)
Romagne et al do not teach the delivery of the IL-2 by an antibody construct comprising a first immunoglobulin chain constant region ad a second immunoglobulin chain constant region, wherein the (1) the C-terminus of the first cytokine molecule is attached to the N-terminus of the second immunoglobulin chain constant region in a first polypeptide, and
2) a first antibody fragment that binds to NKp30 or NKp46, wherein the antibody fragment is attached to the N-terminus of the first immunoglobulin constant region in a second polypeptide.
Romagne et al do not teach the replacement of one or more residues that make up the CH3-CH3 interface with a charged amino acid such that the interaction between like chains becomes electrostatically unfavorable in order to discourage the homodimer formation to provide the bispecific antibody.
Amann et al teach antibody constructs comprising first polypeptide comprising a cytokine which interacts with a TNF receptor, wherein the C-terminus of the ligand is attached to the N-terminus of an immunoglobulin constant region, and a second polypeptide comprising a targeting Fab, wherein the C-terminus of the Fab is attached to the N-terminus of an immunoglobulin constant region (Figures 3A, 3B, 4A and 4B). The configuration of the antibody constructs in Figures 3A, 3B, 4A and 4B meet the limitations for the configuration of the multifunctional polypeptide of the instant claims.. Amann et al teach that there is a need for antigen-binding molecules that combine a moiety capable of preferred binding to tumor specific or tumor associated Amann et al teach that the Fc domain comprises a first and second subunit is capable of stable association between the binding moiety that binds the target cell and the cytokine (page 3, paragraph [0029], section c). Amann et al teach that the Fc domain confers favorable pharmacokinetic properties to the antigen binding molecules of the invention, including a long serum half-life which contributes to good accumulation in the target tissue and a favorable tissue-blood distribution ratio. The Fc domain thus favorably contributes to the pharmacokinetic parameters (PK data) of the antigen binding molecules, such as clearance, volume of distribution or elimination half-time (t.sub.1/2). Amann et al teach that the Fc receptor may lead to undesirable targeting of the antibody construct of the invention to cells expressing Fc receptors rather than to the preferred antigen-bearing cells and that in order to counter this undesirable effect, the Fc domain exhibits reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a native IgG1 Fc domain. (paragraph [0221]).
Amann et al teach an embodiment wherein the Fc domain of the antibody constructs of the invention comprises one or more amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor and/or effector function. Typically, the same one or more amino acid mutation is present in each of the two subunits of the Fc domain, such as an amino acid substitution at a position of E233, L234, L235, N297, P331 and P329 (EU numbering) (paragraph [0224)).
Amman et al teach an embodiment wherein 0235] In a specific aspect, said modification is a so-called “knob-into-hole” modification, comprising a “knob” modification in one of the two subunits of the Fc domain and a “hole” modification in the other one of the two subunits of the Fc domain. allowing a heterodimerization of the two Fc chains comprising the first Fc chain fused to the targeting moiety and a second Fc fused to the cytokine, wherein the first dimerization module comprises knobs and the second dimerization module comprises holes according to the knob into hole technology (paragraph [0235]) and meets the limitations of claim 195..
Amann et al teach that the cytokine can be fused to the Fc or attached via a linker (paragraph [0018], section c) which meets the limitations of claims 199, 213 and 214.
Amann et al teach that target cell antigens include FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 (paragraph [0036]) and that the targeting moiety formats include antibody fragment selected from the group consisting of a Fab molecule, a crossover Fab molecule, a single chain Fab molecule, a Fv molecule, a scFv molecule, a single domain antibody, and a VH (paragraph [0032])..
Kiefer and Neri teach immunocytokines, wherein cytokine payloads which can be efficiently delivered to the tumor site include Il-2 (page 180, second column, number 1). Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass antigens.(page 182, first column, lines 182, lines 1-6 of the second full paragraph). Because Il-2 is a ligand of the Il-2 receptor, it therefore comprises a receptor dimerizing domain as required in claim 197.
Kiefer and Neri teach that in most applications of bispecific antibodies, one antibody moiety was specific for a tumor specific antigen and the other antibody moiety was specific for a leukocyte antigen (page 185, lines 1-5 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that in most of the applications CD3 was used to recruit T cells, but other molecular targets such as CD16 on NK cells have been contemplated (page 185, lines 6-8 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action (page 188, first column, lines 8-11 of the first full paragraph).
Zheng et al teach that a Il-2/Fc fusion protein retains specific and high affinity binding to Il-2 receptor and exhibits an extended half-life of 25 hrs. after system administration (abstract and Figure 1)
It would have been prima facie obvious at the time prior to the effective filing date to substitute an anti-NKp30 Fab or an anti-NKp46 Fab for the anti- FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 targeting moieties of the antibody construct of Aman et al and to replace the cytokine binding to TNFR with Il-2 in the antibody construct of Aman et al. One of skill in the art would have been motivated to do so in order to obtain a stable targeted construct that targeted Il-2 to NK cells via binding to Nkp30 or NKp46. One of skill in the art would have been motivated to do so by the teachings of Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2 and the teachings of Amann et al that an antibody construct comprising a targeting moiety and a cytokine allows delivery of the cytokine to the desired cell and avoids side effects of the untargeted administration of a cytokine, and the further teachings of Amann et al that attachment of the cytokine to the N-terminus of an Fc provides for a stable association between the polypeptide comprising targeting moiety attached to the N-terminus of an Fc and also provides for enhanced serum half-life of the construct. The teachings of Zheng et al provide a reasonable expectation that the Il-2 attached to the N terminus of the Fc will be able to binds to the Il-2 receptor.
One of skill in the art would have been motivated to combine the resulting bispecific immunocytokine with a pharmaceutically acceptable carrier for the admisntration to a subject with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma. One of skill in the art would have been motivated to do so by the teachings of Romagne et al on the administration of anti-NKp30 or anti-NKp46 in combination with Il-2 for the treatment of melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma and the teachings of Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action. One of skill in the art would understand that providing the Il-2 with the anti-NKp30 or NKp46 bispecific antibody would provide NK cells at the site of action in the tumor mass because Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass. Thus, one of skill in the art would understand that the massive infiltration of NK cells were the accessory lymphocytes needed at the site of action for the bispecific antibodies targeting tumor antigen and NKp30 or NKp46.
The administration of the bispecific immuocytokine to patients taught by Romagne et al to be treatable with anti-NKp30 or anti-NKp46 are patients with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma which meets the limitations of claim 210 and a solid tumor and a hematological cancer in claim 211, lung cancer, skin cancer and liver cancer in claim 212(i) and chronic myeloid leukemia and multiple myeloma in claims 212ii). The resulting antibody construct based on the format of 3A , 3B, 4A and 4B of Amann et al wherein the antigen binding specificity for a leukocyte was either anti-NKp30 or anti-NKp46 meets the limitations of claim 193 wherein the multifunctional polypeptide further comprises a dimerization module comprising a first Ig constant region and a second Ig constant region, wherein the anti-NKp30 or the anti-NKp46 and the Il-2 is linked to the Ig constant region as in immunocytokine. The resulting construct meets the limitation of claim 194 for having a first and second Fc region; the knobs -in-hole format meets the limitation of claim 195. Il-2 attached to the N-terminus of the Fc for the first polypeptide meets the limitation of claims 197 as evidenced by Boger and Goldberg who teach that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Therefore, because Il-2 is a ligand of the Il-2 receptor, it comprises a receptor dimerizing domain required in claim 197.
Claims 193-195, 197, 200, 201, 202, 204, 208-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-69 of copending Application No. 18/172,928 in view of Romagne et al (WO2004/056392), Kiefer and Neri (Immunological Reviews, first published February 10, 2016, Vol. 270, pp. 178-192), Amann et al (U.S. 2016/0340399, priority to EP15161880) and Zheng et al (Journal of Immunology, 1999, Vol. 163, pp. 4041-4048) as evidenced by Boger and Goldberg (Bioorganic and Medicinal Chemistry, 2001, Vol. 9, pp. 557-562).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims are obvious over the ‘842 claims.
Claim 52 of the application teaches an antibody molecule which binds to NKp30, wherein the antibody is part of a multifunctional molecule . Claim 52 teaches that the antibody molecule comprises an immunoglobulin heavy chain constant region. Claim 55 teaches that the antibody molecule comprises a first immunoglobulin heavy chain constant region and a second immunoglobulin heavy chain constant region enhanced for providing paired cavity protuberance, electrostatic interaction, or strand exchange in order to provide a greater ratio of heteromultimer: homomultimer forms. Claim 57 teaches that the antibody molecule further comprises a cytokine. Claim 58 teaches that the cytokine is, in part, and Il-2. Claim 66 teaches a pharmaceutical composition comp[rising the antibody that binds to NKp30 of claim 46. Which meets the limitations of claims 209. Claim 67 teaches a method of treating a disease or disorder which is cancer comprising the administration of the antibody of claim 46 which binds to NKp30 which meets the limitations of claim 210 . Claim 68 teaches that the cancer is a solid tumor or a hematological cancer which meets the limitations of claim 211.. Claim 69 teaches that the solid tumor includes pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer or liver cancer, which meets the limitations of instant claims 212
The claims of the application do not teach that the multispecific molecule includes the attachment of the first antibody molecule to the N-terminus of the first immunoglobulin constant region; the dimerization between the first immunoglobulin constant region and the second immunoglobulin constant region.
Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2, wherein the cancer include melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma (claims 1 and 15 of ‘392) which meets the limitations of a solid tumor or a hematological cancer in claim 211, multiple myeloma, chronic and acute myeloid leukemia in claims 212(ii); lung cancer and skin cancer in claims 212(i)
Romagne et al do not teach the delivery of the IL-2 by an antibody construct comprising a first immunoglobulin chain constant region ad a second immunoglobulin chain constant region, wherein the (1) the C-terminus of the first cytokine molecule is attached to the N-terminus of the second immunoglobulin chain constant region in a first polypeptide, and
2) a first antibody fragment that binds to NKp30 or NKp46, wherein the antibody fragment is attached to the N-terminus of the first immunoglobulin constant region in a second polypeptide.
Romagne et al do not teach the replacement of one or more residues that make up the CH3-CH3 interface with a charged amino acid such that the interaction between like chains becomes electrostatically unfavorable in order to discourage the homodimer formation to provide the bispecific antibody.
Amann et al teach antibody constructs comprising first polypeptide comprising a cytokine which interacts with a TNF receptor, wherein the C-terminus of the ligand is attached to the N-terminus of an immunoglobulin constant region, and a second polypeptide comprising a targeting Fab, wherein the C-terminus of the Fab is attached to the N-terminus of an immunoglobulin constant region (Figures 3A, 3B, 4A and 4B). The configuration of the antibody constructs in Figures 3A, 3B, 4A and 4B meet the limitations for the configuration of the multifunctional polypeptide of the instant claims.. Amann et al teach that there is a need for antigen-binding molecules that combine a moiety capable of preferred binding to tumor specific or tumor associated Amann et al teach that the Fc domain comprises a first and second subunit is capable of stable association between the binding moiety that binds the target cell and the cytokine (page 3, paragraph [0029], section c). Amann et al teach that the Fc domain confers favorable pharmacokinetic properties to the antigen binding molecules of the invention, including a long serum half-life which contributes to good accumulation in the target tissue and a favorable tissue-blood distribution ratio. The Fc domain thus favorably contributes to the pharmacokinetic parameters (PK data) of the antigen binding molecules, such as clearance, volume of distribution or elimination half-time (t.sub.1/2). Amann et al teach that the Fc receptor may lead to undesirable targeting of the antibody construct of the invention to cells expressing Fc receptors rather than to the preferred antigen-bearing cells and that in order to counter this undesirable effect, the Fc domain exhibits reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a native IgG1 Fc domain. (paragraph [0221]).
Amann et al teach an embodiment wherein the Fc domain of the antibody constructs of the invention comprises one or more amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor and/or effector function. Typically, the same one or more amino acid mutation is present in each of the two subunits of the Fc domain, such as an amino acid substitution at a position of E233, L234, L235, N297, P331 and P329 (EU numbering) (paragraph [0224)).
Amman et al teach an embodiment wherein 0235] In a specific aspect, said modification is a so-called “knob-into-hole” modification, comprising a “knob” modification in one of the two subunits of the Fc domain and a “hole” modification in the other one of the two subunits of the Fc domain. allowing a heterodimerization of the two Fc chains comprising the first Fc chain fused to the targeting moiety and a second Fc fused to the cytokine, wherein the first dimerization module comprises knobs and the second dimerization module comprises holes according to the knob into hole technology (paragraph [0235]) and meets the limitations of claim 195..
Amann et al teach that the cytokine can be fused to the Fc or attached via a linker (paragraph [0018], section c) which meets the limitations of claims 199, 213 and 214.
Amann et al teach that target cell antigens include FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 (paragraph [0036]) and that the targeting moiety formats include antibody fragment selected from the group consisting of a Fab molecule, a crossover Fab molecule, a single chain Fab molecule, a Fv molecule, a scFv molecule, a single domain antibody, and a VH (paragraph [0032])..
Kiefer and Neri teach immunocytokines, wherein cytokine payloads which can be efficiently delivered to the tumor site include Il-2 (page 180, second column, number 1). Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass antigens.(page 182, first column, lines 182, lines 1-6 of the second full paragraph). Because Il-2 is a ligand of the Il-2 receptor, it therefore comprises a receptor dimerizing domain as required in claim 197.
Kiefer and Neri teach that in most applications of bispecific antibodies, one antibody moiety was specific for a tumor specific antigen and the other antibody moiety was specific for a leukocyte antigen (page 185, lines 1-5 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that in most of the applications CD3 was used to recruit T cells, but other molecular targets such as CD16 on NK cells have been contemplated (page 185, lines 6-8 under the heading “Antigen-binding specificities”). Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action (page 188, first column, lines 8-11 of the first full paragraph).
Zheng et al teach that a Il-2/Fc fusion protein retains specific and high affinity binding to Il-2 receptor and exhibits an extended half-life of 25 hrs. after system administration (abstract and Figure 1)
It would have been prima facie obvious at the time prior to the effective filing date to substitute an anti-NKp30 Fab or an anti-NKp46 Fab for the anti- FAP, CEA, MCSP, EGFR, CD19, CD20 and CD33 targeting moieties of the antibody construct of Aman et al and to replace the cytokine binding to TNFR with Il-2 in the antibody construct of Aman et al. One of skill in the art would have been motivated to do so in order to obtain a stable targeted construct that targeted Il-2 to NK cells via binding to Nkp30 or NKp46. One of skill in the art would have been motivated to do so by the teachings of Romagne et al teach a method of treating cancers susceptible to NK cell lysis comprising administering a pharmaceutical composition comprising an anti-NKp30 or an anti-NKp46 antibody or an immunoreactive fragment thereof in combination with Il-2 and the teachings of Amann et al that an antibody construct comprising a targeting moiety and a cytokine allows delivery of the cytokine to the desired cell and avoids side effects of the untargeted administration of a cytokine, and the further teachings of Amann et al that attachment of the cytokine to the N-terminus of an Fc provides for a stable association between the polypeptide comprising targeting moiety attached to the N-terminus of an Fc and also provides for enhanced serum half-life of the construct. The teachings of Zheng et al provide a reasonable expectation that the Il-2 attached to the N terminus of the Fc will be able to binds to the Il-2 receptor.
One of skill in the art would have been motivated to combine the resulting bispecific immunocytokine with a pharmaceutically acceptable carrier for the admisntration to a subject with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma. One of skill in the art would have been motivated to do so by the teachings of Romagne et al on the administration of anti-NKp30 or anti-NKp46 in combination with Il-2 for the treatment of melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma and the teachings of Kiefer and Neri teach that bispecific antibodies are extremely efficient in mediating targeted cell killing even at low concentrations provided that the accessory lymphocytes are available at the site of action. One of skill in the art would understand that providing the Il-2 with the anti-NKp30 or NKp46 bispecific antibody would provide NK cells at the site of action in the tumor mass because Kiefer and Neri teach that Il-2 delivered to the tumor mediates a massive infiltration of T cells and NK cells into the tumor mass. Thus, one of skill in the art would understand that the massive infiltration of NK cells were the accessory lymphocytes needed at the site of action for the bispecific antibodies targeting tumor antigen and NKp30 or NKp46.
The administration of the bispecific immuocytokine to patients taught by Romagne et al to be treatable with anti-NKp30 or anti-NKp46 are patients with melanoma, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Lymphomas, Multiple Myeloma, hepatocarcinoma, lung adenocarcinoma and Neuroblastoma which meets the limitations of claim 210 and a solid tumor and a hematological cancer in claim 211, lung cancer, skin cancer and liver cancer in claim 212(i) and chronic myeloid leukemia and multiple myeloma in claims 212ii). The resulting antibody construct based on the format of 3A , 3B, 4A and 4B of Amann et al wherein the antigen binding specificity for a leukocyte was either anti-NKp30 or anti-NKp46 meets the limitations of claim 193 wherein the multifunctional polypeptide further comprises a dimerization module comprising a first Ig constant region and a second Ig constant region, wherein the anti-NKp30 or the anti-NKp46 and the Il-2 is linked to the Ig constant region as in immunocytokine. The resulting construct meets the limitation of claim 194 for having a first and second Fc region; the knobs -in-hole format meets the limitation of claim 195. Il-2 attached to the N-terminus of the Fc for the first polypeptide meets the limitation of claims 197 as evidenced by Boger and Goldberg who teach that cytokine receptors are activated by ligand-induced homodimerization (page 557, second column, lines 4-9). Therefore, because Il-2 is a ligand of the Il-2 receptor, it comprises a receptor dimerizing domain required in claim 197.
All claims are rejected.
All other rejections as set forth or maintained in the prior Office action are withdrawn.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643
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