DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed March 27, 2026 is pending.
Claims 2-7 are canceled.
Claims 1 and 8-20 are pending.
Election/Restriction
Applicant’s election of Group I (claims 1 and 8-13, drawn to a multispecific antibody and pharmaceutical composition); and the species of Clec9a as the dendritic cell (DC) marker and SEQ ID NOs: 15 and 16 in the reply filed on September 30, 2025 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In view of the amendment of claim 8 which now depends on claim 1, claims 8-13 are rejoined as they are now drawn to the elected invention.
Claims 14-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1 and 8-13 are currently under consideration as they read on the elected invention.
The declaration under 37 CFR 1.132 filed 03/27/2026 is insufficient to overcome the rejection of claims 1, 8-11, and 13 based upon the invention being obvious over Ravetch in view of Dahan as applied under 35 U.S.C. 103 and set forth in the last Office action because any differences between the claimed invention and the prior art do not result in some differences in properties and therefore do not lead to unexpected results. See MPEP 716.02.
Specifically, the Applicant’s data in the Declaration illustrating a decreased toxicity by CD40/DC bsAbs compared to the parental CD40 mAb and by CD40/DC bsAbs compared to CD40/CD11c and CD40/DEC205 bsAbs were expected results in view of the prior art. Given that the CD40 binding arm of the anti-CD40/Clec9a, Fc-modified bispecific antibody taught by Ravetch and Dahan in view of Park et al. is meant to act as an adjuvant (Ravetch and Dahan also teach that their anti-CD40, Fc-modified antibody can be used as an adjuvant), adjuvants are known to have side effects related generalized innate immune system activation, and simultaneous targeting of the antigen and the DC-activating agent (adjuvant) to the cDC1 by subset Clec9a targeting is a possible future strategy for reducing these known side effects (Park et al.); a skilled artisan would have reasonably expected that a CD40/Clec9a bsAb would have reduced toxicity compared to a monospecific CD40 antibody and CD40/CD11c and CD40/DEC205 bispecific antibodies because these antibodies would not be expected to bind the cDC1 subset. cDC1 targeting is associated with reduced adjuvant-dependent side effects, such as those caused by CD40 binding, related generalized innate immune system activation (Park et al.).
Therefore, the results presented by the Applicant in the Declaration filed 03/27/2026 are not unexpected. Thus, in view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
In view of the Applicant’s response filed March 27, 2026, the previous rejections under 35 U.S.C. 112(a), 103, and nonstatutory double patenting as set forth in the Office Action mailed October 27, 2025 are maintained for the reasons set forth below.
Priority
The present application is a CON of PCT/IL2021/050064 filed on 01/21/2021 and claims foreign priority to IL272194 filed on 01/22/2020.
Certified copies of PCT/IL2021/050064 and IL272194 have not been filed as required by 37 CFR 1.55.
Claim Objections
This is a New Ground of Objection necessitated by the Applicant's amendment. Claims 1, 8, and 11 are objected to because of the following informalities:
Claim 1 recites “a third moiety comprising a modified Fc region of said multi specific antibody which comprises a mutation S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11"), and/or E233D/G237D/P238D /H268D/P271G/A330R ("V12") corresponding to human IgG1 sequence (positions corresponding to SEQ ID NO: 1)” where it should recite “a third moiety comprising a modified Fc region, wherein the modified Fc region comprises one or more of the mutations selected from the group consisting of S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11"), and E233D/G237D/P238D /H268D/P271G/A330R ("V12"), wherein the mutations correspond to the positions according to SEQ ID NO: 1” in lines 3-8.
Claim 8 recites “wherein said first moiety comprises complementary determining regions as set forth in SEQ ID NOs: 19-21 in a heavy chain with an N to C orientation and complementary determining regions as set forth in SEQ ID NOs: 22 and 24 in a light chain with an N to C orientation, wherein CDR-L2 consists of the amino acid sequence Thr-Ala-Ser” where it should recite “wherein said first moiety comprises heavy chain complementary determining regions 1-3 as set forth in SEQ ID NOs: 19-21, respectively, and light chain complementary determining regions 1-3 as set forth in SEQ ID NO: 22, Thr-Ala-Ser, and SEQ ID NO: 24, respectively” in lines 2-6.
Claim 11 recites “wherein said mutations are in a CH3 domain of a first antibody of said bispecific antibody comprising Y349C/T366S/L368A/Y407V and in a CH3 domain of a second antibody of said multispecific antibody comprising S354C/T366W” where it should recite “wherein said mutations are Y349C/T366S/L368A/Y407V mutations in a CH3 domain of a first heavy chain of said bispecific antibody and S354C/T366W mutations in a CH3 domain of a second heavy chain of said multispecific antibody” in lines 1-4.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 10-12 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.
Claim 10 recites “The multispecific antibody of claim 1, comprising knobs-into-holes mutations” in lines 1 and 2. It is unclear if the knobs-into-holes mutations are in addition to the mutations already recited in claim 1 or if they are the mutations recited in claim 1. Furthermore, it is unclear which moiety is meant to comprise the knobs-into-holes mutations. Therefore, claim 10 is rendered indefinite.
Amending claim 10 to recite “The multispecific antibody of claim 1, wherein the modified Fc region further comprises knobs-into-holes mutations” would obviate this part of the rejection.
Claim 11 recites “wherein said mutations” in lines 1 and 2. Claim 11 is dependent on claim 10 which is dependent on claim 1. Both claims 1 and 10 recite different mutations. Therefore, it is unclear which mutations claim 10 is referring to and therefore the limitation of “said mutations” in claim 10 lacks antecedent basis and renders the claim indefinite.
Amending claim 11 to recite “wherein said knobs-into-holes mutations” would obviate this part of the rejection.
Claim 11 also recites “said bispecific antibody” in line 2. Claim 11 is dependent on claim 10 which is dependent on claim 1. Neither claim 1 or 10 recite a “bispecific antibody”. Therefore, the limitation of “said bispecific antibody” in claim 10 lacks antecedent basis and renders the claim indefinite.
Amending claim 11 to recite “said multispecific antibody” would obviate this part of the rejection.
Claim 12 recites “The multispecific antibody of claim 11, comprising SEQ ID NOs: 5 and 6 and SEQ ID NOs: 15 and 16” in lines 1-3. It is noted that SEQ ID NOs: 5 and 6 are the heavy and light chain amino acid sequences, respectively, for the anti-CD40 antibody 2141 and SEQ ID NOs: 15 and 16 are the VH and VL amino acid sequences for the anti-Clec9a antibody 10B4. It is unclear is the recited SEQ ID NOs are in addition to the moieties already recited in the claims from which claim 12 depends or if these SEQ ID NOs are meant to be comprises in one of these previously recited moieties. Therefore, claim 12 is rendered indefinite.
Amending claim 12 to recite “The multispecific antibody of claim 11, wherein the first moiety comprises SEQ ID NOs: 5 and 6 and the second moiety comprises SEQ ID NOs: 15 and 16” would obviate this part of the rejection.
Written Description
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, 8-13 stand 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 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.
The instant claims are drawn to a multispecific antibody comprising a first moiety, which binds CD40, a second moiety, which specifically binds Clec9a, and a third moiety comprising a modified Fc region of said multispecific antibody which comprises a mutation S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11") and/or E233D/G237D/P238D /H268D/P271G/A330R ("V12") corresponding to human IgG1 sequence (positions corresponding to SEQ ID NO: 1).
To support such multispecific antibodies, the Applicant discloses that the variable region sequences of the parental Ab anti-human CD40 antibody 2141 can be used in combination with the variable region sequences of the parental Ab anti-Clec9a antibody 10B4 which are disclosed in US20130273150A (e.g. see page 11, lines 1-9).
The Applicant has also disclosed the anti-CD40 antibodies 12D6 and 5F11 (WO2017025365), APX005M (Johnson et al. 2017. J. ImmunoTher. Cancer 5(Suppl. 3):8.), SGN-40 (Law et al. Cancer Res., vol. 65, no. 18, pp. 8331-8338), SEA-CD40 (DOI: 10.1200/JCO.2018.36.15_suppl.3093 Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 3093-3093).
The Applicant also disclosed the anti-Clec9a antibodies 1F6, 397, and 7H11 which are described in D. Sancho et al., "Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin," J. Clin. Invest., vol. 118, no. 6, pp. 2098-2110, 2008 (e.g. see page 15, lines 1-3).
It is noted that the VH and VL of the 2141 antibody comprise SEQ ID NOs: 64 and 65, respectively, and the VH and VL of the 10B4 antibody comprise SEQ ID NOs: 15 and 16, respectively (e.g. see page 5, line 32 – page 6, line 5; and Figure 1A). The CDRs of the 2141 antibodies are SEQ ID NOs 19-22, TAS, and SEQ ID NO: 23.
When given the broadest reasonable interpretation in light of specification, the multispecific antibodies of the instant invention are defined broadly to be any multispecific antibody that binds to CD40 and Clec9a, and comprises a modified Fc region of said multispecific antibody which comprises a mutation S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11") and/or E233D/G237D/P238D /H268D/P271G/A330R ("V12") corresponding to human IgG1 sequence (positions corresponding to SEQ ID NO: 1).
It is noted that the broadest claim (claim 1) does not indicate any specific structure for the genus of multispecific antibodies claimed.
Dependent claim 8 recites sufficient structure for the CD40 binding moiety but does not recite sufficient structure for the Clec9a binding moiety.
Dependent claim 12 appears to recite sufficient structure for both the CD40 and Clec9a binding moieties but, as noted in the rejection under 35 U.S.C. 112(b) above, it is unclear which moieties the recited SEQ ID NOs correspond to.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Artisans are well aware that knowledge of a given antigen (for instance CD40 and Clec9a) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118, a reference of record) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection, a reference of record). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of multispecific antibodies that bind to CD40 and Clec9a.
As noted above, the Applicant has disclosed six anti-CD40 antibodies and four anti-Clec9 antibodies, the CDRs and VH and VL amino acid sequences of which that can be used to construct the respective antigen binding moieties of the instantly claimed multispecific antibody. Such a disclosure does not serve to provide sufficient written description of the claimed genus of multispecific antibodies.
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of CD40 and Clec9a binding. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited anti-CD40/Clec9a multispecific antibodies which gives rise to their functional activity. Ultimately, identifying an antibody simply on the basis of binding to CD40 and Clec9a rather than by identifying the sequence/structure, namely a complete set of six CDRs for each binding moiety, of the anti-CD40/Clec9a multispecific antibody in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of anti-CD40/Clec9a multispecific antibodies which are functionally defined by their ability to bind to CD40 and Clec9a without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure. Thus, there is insufficient written description for the breadth of anti-CD40/Clec9a multispecific antibodies as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to CD40 and Clec9a.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-CD40/Clec9a multispecific antibodies as encompassed by the claims at the time the instant application was filed.
Applicant's arguments filed March 27, 2026 have been fully considered but they are not persuasive.
The Applicant argues that amended claim 1 now fully complies with the written description requirement of 35 U.S.C. 112(a). The Applicant asserts that as amended, claim 1 is expressly limited to a multi-specific antibody comprising (i) a CD40-binding first moiety, (ii) a Clec9a-binding second moiety, and (iii) a modified Fc region comprising mutations S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11") and/or E233D/G237D/P238D/H268D/P271G/A330R ("V12").
The Applicant further asserts that the specification repeatedly and expressly describes multi-specific antibodies comprising these exact elements in combination, including antibodies comprising a CD40-binding moiety, a Clec9a-binding moiety, and Fc-engineered variants designed to enhance FeyRIIB binding. The Applicant further asserts that the specification further provides specific sequence information, representative constructs, and experimental data demonstrating the structure and function of such antibodies, including Clec9a-binding embodiments and Fc-modified variants.
The Applicant argues that claim 1 is limited to a concrete, structurally characterized embodiment that the inventors actually possessed. The Applicant further argues that accordingly, the specification clearly conveys to a person of ordinary skill in the art that the inventors were in possession of the presently claimed subject matter as of the filing date. The Applicant further argues the amended claim is limited to a specifically disclosed and exemplified species, and therefore satisfies the written description requirement.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that amended claim 1 now fully complies with the written description requirement of 35 U.S.C. 112(a) because it is limited to a concrete, structurally characterized embodiment that the inventors actually possessed and that the specification clearly conveys to a person of ordinary skill in the art that the inventors were in possession of the presently claimed subject matter as of the filing date; it is noted that the claims are not limited to the species disclosed in the specification.
When given the broadest reasonable interpretation in light of specification, the multispecific antibodies of the instant invention are defined broadly to be any multispecific antibody that binds to CD40 and Clec9a, and comprises a modified Fc region of said multispecific antibody which comprises a mutation S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11") and/or E233D/G237D/P238D /H268D/P271G/A330R ("V12") corresponding to human IgG1 sequence (positions corresponding to SEQ ID NO: 1).
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). See MPEP 2161.01.I.
Ultimately, identifying an antibody simply on the basis of binding to CD40 and Clec9a rather than by identifying the sequence/structure, namely a complete set of six CDRs for each binding moiety, of the anti-CD40/Clec9a multispecific antibody in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of anti-CD40/Clec9a multispecific antibodies which are functionally defined by their ability to bind to CD40 and Clec9a without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure. Thus, there is insufficient written description for the breadth of anti-CD40/Clec9a multispecific antibodies as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to CD40 and Clec9a.
Regarding the Applicant’s arguments that the specification repeatedly and expressly describes multi-specific antibodies comprising these exact elements in combination, including antibodies comprising a CD40-binding moiety, a Clec9a-binding moiety, and Fc-engineered variants designed to enhance FcyRIIB binding and the specification further provides specific sequence information, representative constructs, and experimental data demonstrating the structure and function of such antibodies, including Clec9a-binding embodiments and Fc-modified variants; it is noted, again, that the claims are not limited to the species disclosed in the specification.
While the Applicant has disclosed six anti-CD40 antibodies and four anti-Clec9 antibodies, the CDRs and VH and VL amino acid sequences of which that can be used to construct the respective antigen binding moieties of the instantly claimed multispecific antibody, such a disclosure does not serve to provide sufficient written description of the claimed genus of multispecific antibodies. The disclosure does not identify sufficient structural features or combination of features which give rise to the function of CD40 and Clec9a binding. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited anti-CD40/Clec9a multispecific antibodies which gives rise to their functional activity.
Ultimately and as stated above, identifying an antibody simply on the basis of binding to CD40 and Clec9a rather than by identifying the sequence/structure, namely a complete set of six CDRs for each binding moiety, of the anti-CD40/Clec9a multispecific antibody in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of anti-CD40/Clec9a multispecific antibodies which are functionally defined by their ability to bind to CD40 and Clec9a without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure. Thus, there is insufficient written description for the breadth of anti-CD40/Clec9a multispecific antibodies as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to CD40 and Clec9a.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-CD40/Clec9a multispecific antibodies as encompassed by the claims at the time the instant application was filed.
Amending the claim 1 to recite the amino acid sequences of a full set of six CDRs for both the Cd40 and Clec9a binding moieties, as is done in claim 12, would obviate this part of the rejection.
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.
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, 8, 9, 12, and 13 stand rejected under 35 U.S.C. 103 as being unpatentable over Ravetch and Dahan 2017 (US20170253659A1, an IDS reference filed 09/08/2022) in view of Park et al. 2017 (npj Vaccines. 2(31); 1-11, a reference of record).
Independent claim 1 is drawn to a multispecific antibody comprising a first moiety, which binds CD40, a second moiety, which specifically binds Clec9a, and a third moiety comprising a modified Fc region of said multi specific antibody which comprises a mutation S267E ("SE"), S267E/L382F ("SELF"), G237D/P238D/P271G/A330R ("V9"), G237D/P238D/H268D/P271G/A330R ("V11"), and/or E233D/G237D/P238D /H268D/P271G/A330R ("V12") corresponding to human IgG1 sequence (positions corresponding to SEQ ID NO: 1).
Dependent claim 8 limits the first moiety to that which comprises complementary determining regions as set forth in SEQ ID NOs: 19-21 in a heavy chain with an N to C orientation and complementary determining regions as set forth in SEQ ID NOs: 22 and 24 in a light chain with an N to C orientation, wherein CDR-L2 consists of the amino acid sequence Thr-Ala-Ser.
Dependent claim 9 limits the modified Fc region to that which comprises mutations as in SEQ ID NO: 2.
Dependent claim 12 limits the multispecific antibody to that which comprises SEQ ID NOs: 5 and 6 and SEQ ID NOs: 15 and 16.
Dependent claim 13 is drawn to a pharmaceutical composition comprising the multispecific antibody of claim 1.
Ravetch and Dahan teach agonistic antibodies, or antigen binding portions thereof, that bind to human CD40 which may comprise Fc regions with enhanced specificity for FcyRIIb (e.g. see Abstract). The anti-huCD40 antibodies have numerous in vitro and in vivo utilities involving, for example, enhancement of immune response by agonizing CD40 signaling (e.g. see [0212]). Ravetch and Dahan also teach that CD40 is expressed on dendritic cells (e.g. see Figure 1A).
The binding affinity and selectivity of human IgGs to hFcγRIIB was increased by mutagenesis of their Fc domain (e.g. see [0273]). Ravetch and Dahan teach that the mutant Fc region with enhanced specificity for FcyRIIb may comprise one or more mutations selected from the group consisting of S267E (“SE”), S267E/L382F (“SELF”), G237D/P238D/P271G/A330R (“V9”), or G237D/P238D/H268D/P271G/A330R (“V11”) (e.g. see [0004] and [0274]).
Ravetch and Dahan also teach that their anti-huCD40 antibodies may be used to form bispecific antibodies that bind to at least two different binding sites or target molecules (e.g. see [0179]). The bispecific molecules may comprise at least one first binding specificity for CD40 and a second binding specificity for a second target epitope (e.g. see [0180]).
Ravetch and Dahan also teach that recent research has revealed that human cancers and chronic infections may be treated with agents that modulate the patient's immune response to malignant or infected cells (e.g. see [0002]). Agonistic anti-CD40 antibodies, have been applied for treating cancer based on the belief that they may enhance such an immune response, and experiments in mice have revealed that anti-CD40 antibodies, with enhanced specificity for the inhibitory Fc receptor FcγRIIb, have increased anti-tumor efficacy (e.g. see [0002]). Ravetch and Dahan also teach that there is a need for improved agonistic anti-human CD40 antibodies for treatment of cancer and chronic infections in human subjects which have enhanced specificity for the inhibitory Fc receptor FcγRIIb as compared to activating Fc receptors, and exhibit enhanced anti-tumor and/or anti-infective activity (e.g. see [0003]).
Ravetch and Dahan also teach that anti-CD40 antibodies are able to substitute effectively for T cell helper activity (e.g. see [0231]). anti-huCD40 antibodies enhance co-stimulation of T cell responses, e.g., antigen-specific T cell responses (e.g. see [0215]). Their anti-huCD40 antibodies are meant to stimulate, enhance or upregulate antigen-specific T cell responses, e.g., anti-tumor T cell responses (e.g. see [0215]). CD40 agonists can be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins (e.g. see [0255]). As a method of vaccination, DC immunization can be effectively combined with CD40 agonism to activate (unleash) more potent anti-tumor responses (e.g. see [0227]).
Ravetch and Dahan also teach that similar to its application to tumors as discussed above, antibody-mediated CD40 agonism can be used alone, or as an adjuvant, in combination with vaccines, to enhance the immune response to pathogens, toxins, and self-antigens (e.g. see [0234]). CD40 agonism is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human CD40 antibody administration, thus provoking a strong T cell response (e.g. see [0234]). Anti-huCD40 antibodies can be used to enhance antigen-specific immune responses by co-administration of an anti-huCD40 antibody with an antigen of interest, e.g., a vaccine (e.g. see [0240]).
Regarding claims 8 and 12, Ravetch and Dahan also teach that the variable regions of anti-CD40 clone 2141 (CP-870,893) were cloned into Fc-modified Abs (e.g. see [0270]). It is noted that the variable regions of the 2141 antibody comprises heavy chain complementary determining regions 1-3 as set forth in SEQ ID NOs: 19-21, respectively, and light chain complementary determining regions 1-3 as set forth in SEQ ID NO: 22, Thr-Ala-Ser, and SEQ ID NO: 24, respectively, and the HC and LC as set forth in instant SEQ ID NOs: 5 and 6, respectively (e.g. see instant specification page 12, lines 6-13).
Regarding claim 9, instant SEQ ID NO: 2 corresponds to an Fc region comprising the G237D/P238D/H268D/P271G/A330R ("V11") mutations (e.g. see instant specification page 25, line 7) which is taught by Ravetch and Dahan (e.g. see [0004] and [0274]).
Regarding claim 13, Ravetch and Dahan also teach that pharmaceutical compositions comprising anti-huCD40, Fc-modified antibodies of their invention (e.g. see [0015]).
Ravetch and Dahan fail to teach that their Fc-modified bispecific antibodies, which bind CD40 with one arm, also bind to Clec9a with the second arm.
Park et al. teach that DCs, as the key antigen-presenting cells, are a logical target for immune response modulation, including improving the response to vaccines (e.g. see page 1, left column, first paragraph). One approach to achieving this is to target the normal DC network in situ by injecting putative vaccines molecules coupled to a mAb recognizing a DC surface molecule. By choosing a DC subset-specific mAb, it is possible to restrict initial antigen presentation to a particular DC subtype and so tailor the immune response. This approach generally involves co-injection of an adjuvant or DC activation agent, to ensure the presenting DC initiates an effective immune response rather than tolerance (e.g. see page 1, left column, first paragraph).
Park et al. also teach that a promising DC surface target is the C-type lectin-like receptor Clec9a, also termed DNGR1 (e.g. see page 1, paragraph spanning left and right columns). This receptor is specifically expressed along with XCR1 by a DC subtype common to mouse and humans termed conventional DC1 (cDC1). This subtype includes the CD8+ mouse DC lineage and its migratory CD103+ equivalent, and the human CD141+ DCs. This DC subtype is especially efficient at taking up and processing antigens from dead cells, and cross-presenting these antigens on major histocompatibility complex class I. Clec9a is a receptor involved in this process, binding filamentous actin exposed when the cell membrane is damaged and facilitating the cross-presentation of dead cell-associated antigen. Thus, targeting vaccine antigens to Clec9a plugs them into a natural and efficient antigen uptake and processing system (e.g. see page 1, paragraph spanning left and right columns).
Park et al. also teach that Clec9a targeting has considerable promise for generation of protective Ab responses to infectious diseases, as well as for CTL responses against tumors (e.g. see paragraph spanning pages 1 and 2). Park et al. further note that it seems likely that a DC-activating adjuvant would need to be a component of a Clec9a-targeted vaccine (e.g. see page 7, right column, second paragraph). It is possible that the amount of adjuvant could be reduced with Clec9a targeting, and simultaneous targeting of the antigen and the DC-activating agent to the cDC1 subset is a possible future strategy for reducing the side effects of generalized innate immune system activation (e.g. see page 7, right column, second paragraph). Clec9a targeting of antigens in the presence of adjuvants is also a very effective procedure for generating CTL (e.g. see page 9, left column, second paragraph).
Park et al. also teach, in an example, that although the single injection of M2e targeted to Clec9A allowed most mice to survive a lethal dose of influenza, there was still a marked weight loss indicating incomplete protection (e.g. see page 7, right column, third paragraph). The usual solution to this problem is to give multiple injections, or at least two injections in a prime-boost sequence, to expand to level of responding B and T cells (e.g. see page 7, right column, third paragraph).
Park et al. also teach that Ab responses on targeting Clec9A were much higher than those obtained by targeting some other DC surface molecules including DEC205 (e.g. see page 1, right column, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Ravetch and Dahan to incorporate the teachings of Park et al. to include that Ravetch and Dahan’s Fc-modified bispecific antibodies, which bind CD40 with one arm, also bind to Clec9a with the second arm. This is because antibody-mediated CD40 agonism can be used alone, or as an adjuvant, in combination with vaccines, to enhance the immune response to pathogens, toxins, and self-antigens (Ravetch and Dahan) and simultaneous targeting of the antigen and the DC-activating agent (adjuvant) to the cDC1 subset by targeting Clec9a is a possible future strategy for reducing the side effects of generalized innate immune system activation known to be caused by said adjuvants (Park et al.).
Given that CD40 is expressed on dendritic cells (Ravetch and Dahan), CD40 agonism by anti-huCD40 antibodies can be used alone, or as an adjuvant to enhance antigen-specific immune responses by co-administration of an anti-huCD40 antibody with an antigen of interest (Ravetch and Dahan), the anti-CD40, Fc-modified antibodies taught by Ravetch and Dahan can be bispecific, and Clec9a-targeted vaccines have considerable promise for the generation of protective Ab responses but seem to require a DC-activating adjuvant, which are known to have unwanted side effects, and, therefore, simultaneous targeting of the antigen and the DC-activating agent to the cDC1 subset is a possible strategy for reducing the side effects of generalized innate immune system activation; it would be obvious to a skilled artisan, with the goal of enhancing the immune response to a Clec9a-targeted vaccine by using an adjuvant, to modify the anti-CD40, Fc-modified bispecific antibodies taught by Ravetch and Dahan to specifically target Clec9a with its second binding arm with a reasonable expectation of success. A skilled artisan would reasonably expect that an anti-CD40/Clec9a, Fc-modified bispecific antibody would specifically target and activate cDC1-specific immune response.
Furthermore, given the desire to expand the level of responding B and T cells in Clec9a-targeted vaccine platforms (Park et al.), that DC immunization can be effectively combined with CD40 agonism to activate (unleash) more potent anti-tumor responses (Ravetch and Dahan), and anti-huCD40 antibodies are meant to stimulate, enhance or upregulate antigen-specific T cell responses; it would further be obvious to modify the anti-CD40, Fc-modified bispecific antibodies taught by Ravetch and Dahan to specifically target Clec9a with its second binding arm with a reasonable expectation of success. A skilled artisan would reasonably expect that an anti-CD40/Clec9a, Fc-modified bispecific antibody, through its CD40 binding arm, to stimulate, enhance or upregulate antigen-specific T cell responses thereby unleashing a more potent immune response.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant's arguments filed March 27, 2026 have been fully considered but they are not persuasive.
The Applicant argues that while Ravetch discloses monospecific agonistic anti-CD40 antibodies having Fc regions engineered to enhance FeyRIIB engagement and teaches systemic administration of such antibodies to broadly activate CD40 on multiple immune cell populations, including B cells, monocytes, macrophages, and dendritic cells, Ravetch does not disclose or suggest any particular multi-specific format, any second targeting moiety, or any selective targeting of Clec9a-positive dendritic cells. The Applicant asserts that, rather, Ravetch relies exclusively on Fc-mediated crosslinking to enhance CD40 signaling (see paragraph 122, therein).
The Applicant further argues that while Park discloses antibodies directed to dendritic cell markers such as DEC-205, Park is limited to generating monoclonal antibodies for antigen recognition and does not disclose coupling such antibodies to CD40 agonists, engineering multi-specific constructs, combining dendritic cell targeting with Fc modifications, or addressing CD40-associated toxicity.
The Applicant further argues that neither Ravetch nor Park, alone or in combination, teaches or suggests physically linking CD40 agonism, Clec9a-mediated dendritic cell targeting, and FcyRIIB-enhancing mutations in a single multi-specific antibody, nor do they identify dendritic cells, and particularly Clec9a-positive cDCi cells, as a critical population for reducing systemic toxicity. The Applicant asserts that the Examiner's proposed combination requires selecting a specific dendritic cell subset, adding a second targeting moiety, integrating this with Fc engineering, and predicting improved safety (as shown in Example 2), none of which is suggested by the cited references. The Applicant argues that the cited art therefore fails to provide any motivation or reasonable expectation of success for arriving at the claimed invention, and the rejection relies on impermissible hindsight reconstruction based on Applicant's disclosure.
The Applicant asserts that the present inventors have found that targeting the anti CD40 antibody with the modified Fc moiety to cDC1, through the cDC1-restricted marker Clec9a is superior to targeting a range of dendritic cell subtypes through other markers such as Dec205 and CD1lc. The Applicant further asserts that this is manifested by reduced toxicity as shown in the attached Declaration.
In the Declaration the Applicant asserts that targeting the anti CD40 antibody with the modified Fc moiety to cDC1, through the cDC1-restricted marker Clec9a is superior to targeting a range of dendritic cell subtypes through other markers such as Dec205 and CD11c. The Applicant asserts that this is manifested by reduced toxicity as shown in the results below. The Applicant asserts that the figure in the Declaration, copied below, illustrates liver toxicity profile of CD40 mAb and CD40/DC bsAbs. The Applicant asserts that in plotting dose-dependent levels of in vivo T cell-related efficacy versus liver toxicity highlighted the increased therapeutic window achieved by CD40/DC bsAbs compared to the parental CD40 mAb and of CD40/Clec9a compared to CD40/CD11c and CD40/DEC205 bispecific antibodies.
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The Applicant ultimately argues that for all the above reasons, the combination of Ravetch and Dahan (2017) in view of Park (2017) does not teach or suggest the presently claimed method and does not render the claims obvious.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that (1) neither Ravetch nor Park, alone or in combination, teaches or suggests physically linking CD40 agonism, Clec9a-mediated dendritic cell targeting, and FcyRIIB-enhancing mutations in a single multi-specific antibody, (2) the Examiner's proposed combination requires selecting a specific dendritic cell subset, adding a second targeting moiety, integrating this with Fc engineering, and predicting improved safety, and (3) the cited art therefore fails to provide any motivation or reasonable expectation of success for arriving at the claimed invention, and the rejection relies on impermissible hindsight reconstruction based on Applicant's disclosure; it is noted that simultaneous targeting of the antigen and the DC-activating agent (adjuvant) to the cDC1 subset by targeting Clec9a is a possible future strategy for reducing the side effects of generalized innate immune system activation known to be caused by said adjuvants(Park et al.).
Given that CD40 is expressed on dendritic cells (Ravetch and Dahan), CD40 agonism by anti-huCD40 antibodies can be used alone, or as an adjuvant to enhance antigen-specific immune responses by co-administration of an anti-huCD40 antibody with an antigen of interest (Ravetch and Dahan), the anti-CD40, Fc-modified antibodies taught by Ravetch and Dahan can be bispecific, and Clec9a-targeted vaccines have considerable promise for the generation of protective Ab responses but seem to require a DC-activating adjuvant, which are known to have unwanted side effects, and, therefore, simultaneous targeting of the antigen and the DC-activating agent to the cDC1 subset is a possible strategy for reducing the side effects of generalized innate immune system activation; it would be obvious to a skilled artisan, with the goal of enhancing the immune response to a Clec9a-targeted vaccine by using an adjuvant, to modify the anti-CD40, Fc-modified bispecific antibodies taught by Ravetch and Dahan to specifically target Clec9a with its second binding arm with a reasonable expectation of success. A skilled artisan would reasonably expect that an anti-CD40/Clec9a, Fc-modified bispecific antibody would specifically target and activate cDC1-specific immune response.
Furthermore, given the desire to expand the level of responding B and T cells in Clec9a-targeted vaccine platforms (Park et al.), that DC immunization can be effectively combined with CD40 agonism to activate (unleash) more potent anti-tumor responses (Ravetch and Dahan), and anti-huCD40 antibodies are meant to stimulate, enhance or upregulate antigen-specific T cell responses; it would further be obvious to modify the anti-CD40, Fc-modified bispecific antibodies taught by Ravetch and Dahan to specifically target Clec9a with its second binding arm with a reasonable expectation of success. A skilled artisan would reasonably expect that an anti-CD40/Clec9a, Fc-modified bispecific antibody, through its CD40 binding arm, to stimulate, enhance or upregulate antigen-specific T cell responses thereby unleashing a more potent immune response.
Regarding the Applicant’s argument that Ravetch does not disclose or suggest any particular multi-specific format, any second targeting moiety, or any selective targeting of Clec9a-positive dendritic cells; it is noted that Ravetch and Dahan teach that their anti-huCD40 antibodies may be used to form bispecific antibodies that bind to at least two different binding sites or target molecules and that these bispecific molecules may comprise at least one first binding specificity for CD40 and a second binding specificity for a second target epitope (e.g. see [0170] and [0180]).
Regarding the Applicant’s argument that Ravetch relies exclusively on Fc-mediated crosslinking to enhance CD40 signaling; given that anti-CD40/Clec9a, Fc-modified bispecific antibody taught by Ravetch and Dahan in view of Park et al. would comprise the instantly claimed Fc modification; a skilled artisan would have reasonably expected that the anti-CD40/Clec9a, Fc-modified bispecific antibody would also have the Fc-mediated crosslinking-dependent enhancement of CD40 signaling.
Regarding the Applicant’s argument that Park is limited to generating monoclonal antibodies for antigen recognition and does not disclose coupling such antibodies to CD40 agonists, engineering multi-specific constructs, or combining dendritic cell targeting with Fc modifications; it is noted that Park et al. teach that while Clec9a targeting has considerable promise for generation of protective Ab responses to infectious diseases, as well as for CTL responses against tumor, it seems likely that a DC-activating adjuvant would need to be a component of a Clec9a-targeted vaccine (e.g. see paragraph spanning pages 1 and 2; and page 7, right column, second paragraph).
Regarding the Applicant’s arguments that Park does not disclose addressing CD40-associated toxicity and neither Ravetch nor Park identify dendritic cells, and particularly Clec9a-positive cDCi cells, as a critical population for reducing systemic toxicity; it is noted that while Park et al. does not explicitly teach CD40 toxicity, Park et al. does teach that adjuvants are known to have side effects related generalized innate immune system activation.
Therefore, given that the CD40 binding arm of the anti-CD40/Clec9a, Fc-modified bispecific antibody taught by Ravetch and Dahan in view of Park et al. is meant to act as an adjuvant (Ravetch and Dahan also teach that their anti-CD40, Fc-modified antibody can be used as an adjuvant), adjuvants are known to have side effects related generalized innate immune system activation, and simultaneous targeting of the antigen and the DC-activating agent (adjuvant) to the cDC1 by subset Clec9a targeting is a possible future strategy for reducing these known side effects (Park et al.); a skilled artisan would have reasonably expected that immune activation by an anti-CD40/Clec9a, Fc-modified bispecific antibody would be restricted to the cDC1 cell subset thereby reducing the side effects associated with adjuvants.
Regarding the Applicant’s arguments that the combination targeting the anti CD40 antibody with the modified Fc moiety to cDC1, through the cDC1-restricted marker Clec9a unexpectedly leads to reduced toxicity, which is supported by the attached declaration; it is noted that, similar to the rationale given above, in view of the teachings in the art, a skilled artisan would have reasonably expected that immune activation by an anti-CD40/Clec9a, Fc-modified bispecific antibody would be restricted to the cDC1 cell subset thereby reducing the side effects associated with adjuvants. This is because the CD40 binding arm of the anti-CD40/Clec9a, Fc-modified bispecific antibody taught by Ravetch and Dahan in view of Park et al. is meant to act as an adjuvant (Ravetch and Dahan also teach that their anti-CD40, Fc-modified antibody can be used as an adjuvant), adjuvants are known to have side effects related generalized innate immune system activation, and simultaneous targeting of the antigen and the DC-activating agent (adjuvant) to the cDC1 by subset Clec9a targeting is a possible future strategy for reducing these known side effects (Park et al.).
Regarding the Applicant’s data illustrating a decreased toxicity of CD40/Clec9a compared to CD40/CD11c and CD40/DEC205 bispecific antibodies, given that Clec9 is known to be specifically expressed on the cDC1 cell subset; a skilled artisan would have reasonably expected that a CD40/Clec9a bsAb would have reduced toxicity compared to CD40/CD11c and CD40/DEC205 bispecific antibodies because CD11c and DEC205 is not known to be expressed on cDC1 and cDC1 targeting is associated with reduced adjuvant-dependent side effects related generalized innate immune system activation (Park et al.).
Therefore, while the data provided in the Declaration filed 03/27/2026 clearly indicates decreased toxicity by CD40/DC bsAbs compared to the parental CD40 mAb and by CD40/DC bsAbs compared to CD40/CD11c and CD40/DEC205 bsAbs, in view of the art, this was an expected result as outlined in the above paragraphs.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ravetch and Dahan 2017 (US20170253659A1, an IDS reference filed 09/08/2022) in view of Park et al. 2017 (npj Vaccines. 2(31); 1-11, a reference of record), as applied to claim 1, and further in view of Wang et al. 2019 (Antibodies 2019, 8(3), 43, 1-30).
Dependent claim 10 limits the multispecific antibody to that which comprises knobs-into-holes mutations.
Dependent claim 11 limits the mutations to that which are in a CH3 domain of a first antibody of said bispecific antibody comprising Y349C/T366S/L368A/Y407V and in a CH3 domain of a second antibody of said multispecific antibody comprising S354C/T366W.
The combined teachings of Ravetch and Dahan in view of Park et al. pertaining to claim 1 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the multispecific antibody comprises knobs-into-holes mutations or that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3.
Wang et al. teach knobs-into-holes technology, which involves engineering CH3 domains to create either a “knob” or a “hole” in each heavy chain to promote Fc heterodimerization has been extensively applied for Fc engineering (e.g. see page 15, second paragraph). Mutation sites including S354C and T366W in a CH3 domain were found to generate knobs while Y349C, T366S, L368A, and Y407V were examined in the other CH3 domain for holes. The knobs-into-holes heterodimerization not only solves the heavy-chain problem via the correct heterodimeric pairing of bispecific antibodies but also renders them conformationally stable and allows for antibody purification by protein A (e.g. see page 15, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Ravetch and Dahan in view of Park et al., as applied to claim 1, to incorporate the teachings of Wang et al. to include that the multispecific antibody comprises knobs-into-holes mutations and that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3. This is because knobs-into-holes technology promotes proper Fc heterodimerization in the design of bispecific antibodies (Wang et al.)
Given that knobs-into-holes heterodimerization not only solves the heavy-chain problem via the correct heterodimeric pairing of bispecific antibodies but also renders them conformationally stable and allows for antibody purification by protein A and mutation sites including S354C and T366W in a CH3 domain were found to generate knobs while Y349C, T366S, L368A, and Y407V were examined in the other CH3 domain for holes; it would have been obvious to a skilled artisan to include that the multispecific antibody comprises knobs-into-holes mutations and that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3 with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
In view of the Applicant’s lack of response to the NSDP rejection set forth in the office action mailed 10/27/2025, claims 1, 8, 9, 12, and 13 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,894,835 (the ‘835 Patent) in view of Ravetch and Dahan 2017 (US20170253659A1) and Park et al. 2017 (npj Vaccines. 2(31); 1-11) for the reasons of record.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 10 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,894,835 (the ‘835 Patent) in view of Ravetch and Dahan 2017 (US20170253659A1) and Park et al. 2017 (npj Vaccines. 2(31); 1-11, a reference of record), as applied to claim 1, and further in view of Wang et al. 2019 (Antibodies 2019, 8(3), 43, 1-30).
The combined teachings of the claims in the ‘835 Patent in view of Ravetch and Dahan and Park et al. pertaining to claim 1 and the rationale for combining them is outlined in the NSDP rejection made in the office action mailed 10/27/2025.
The combined reference teachings differ from the instant invention by not teaching that the multispecific antibody comprises knobs-into-holes mutations or that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3.
Wang et al. teach knobs-into-holes technology, which involves engineering CH3 domains to create either a “knob” or a “hole” in each heavy chain to promote Fc heterodimerization has been extensively applied for Fc engineering (e.g. see page 15, second paragraph). Mutation sites including S354C and T366W in a CH3 domain were found to generate knobs while Y349C, T366S, L368A, and Y407V were examined in the other CH3 domain for holes. The knobs-into-holes heterodimerization not only solves the heavy-chain problem via the correct heterodimeric pairing of bispecific antibodies but also renders them conformationally stable and allows for antibody purification by protein A (e.g. see page 15, second paragraph).
It would be obvious to one of ordinary skill in the art to modify the combined teachings of the ‘835 Patent in view of Ravetch and Dahan and Park et al., as applied to claim 1, to incorporate the teachings of Wang et al. to include that the multispecific antibody comprises knobs-into-holes mutations and that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3. This is because knobs-into-holes technology promotes proper Fc heterodimerization in the design of bispecific antibodies (Wang et al.)
Given that knobs-into-holes heterodimerization not only solves the heavy-chain problem via the correct heterodimeric pairing of bispecific antibodies but also renders them conformationally stable and allows for antibody purification by protein A and mutation sites including S354C and T366W in a CH3 domain were found to generate knobs while Y349C, T366S, L368A, and Y407V were examined in the other CH3 domain for holes; it would be obvious to a skilled artisan to include that the multispecific antibody comprises knobs-into-holes mutations and that the knobs-into-holes mutations are Y349C/T366S/L368A/Y407V are in one CH3 and S354C/T366W in the second CH3 with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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