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 July 22, 2022 is pending.
Claims 1-20 are pending.
Election/Restriction
Applicant’s election of Group I (claims 1-13, 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)).
Claims 4, 5, and 7-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions. It is noted that claims 4, 5, and 7-13 are drawn to non-elected species.
Claims 1-3 and 6 are currently under consideration as they read on the elected invention and the species of Clec9a.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
It is noted that there was no amino acid sequence found under “SEQ ID NO: 23” in the sequence listing XML. However, “SEQ ID NO: 23” is recited in claim 8, line 3. Appropriate correction is required.
If the amino acid sequence that is meant to be “SEQ ID NO: 23” is less than four amino acids in length, the Applicant may amend claim 8 to recite “SEQ ID NO: 22, XXX, and SEQ ID NO: 24” instead of “SEQ ID NOs: 22-24” in line 8, where “XXX” is the intended amino acid sequence.
If the amino acid sequence that is meant to be “SEQ ID NO: 23” is four or more amino acids in length, the Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
It is also noted that amino acid sequences appearing in Figure 1A are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
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 1-3 and 6 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 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 and activates CD40, a second moiety, which specifically binds a dendritic cell (DC) and a third moiety comprising a modified Fc region of said multispecific antibody for enhancing specificity and affinity of binding to FcyRIIb.
To support such multispecific antibodies, the Applicant discloses species that comprise variable region sequences of the parental Ab anti-human CD40 antibody 2141 in combination with anti-human/mouse DEC-205 antibody (clone HD-109) or anti-mouse CD11c antibody (clone N148) (e.g. see page 43, line 19 – page 44, line 23). The variable region sequences of the parental Ab were inserted into mammalian expression vectors with bi-specific vectors previously described (Merchant et al., 1998; Ridgway et al., 1996; Schaefer et al., 2011). For the generation of Fc-domain variants of human IgG1 with enhanced Fc
γ
RIIB engagement, the V11 point mutations (G237D/P238D/H268D/P271G/A330R) were made.
The Applicant also discloses that the variable domains of anti-human CD40 antibody 2141 were cloned from the previously generated monospecific 2141 Ab into additional bispecific Ab constructs (e.g. see page 11, lines 1-9). The variable domains of anti-DEC-205 (HD-109), CD11c (N418), Clec9a (10B4), and XRC1 (MARX10) Abs (antibodies targeting DC markers) were sequenced and cloned from the HD-109 (C. G. Park et al., J. Immunol. Methods. 2012. 3779(1-2): 15-22) and N418 (C. Demangel et al. Mol. Immunol. 2005. 42(8): 979-985) hybridomas, respectively. The variable domains of anti-Clec9a (10B4), and XRC1 (MARX10) were synthesized based on their sequences described in Patent Application Nos. US20130273150A and EP2641915A1, respectively. The amino acid sequences of the VH and VL domains and heavy and light chains of all of the antibodies above can be found in Figure 1A-B. The bispecific Abs were constructed with the "V11" Fc scaffold (noted above) to preserve the optimal high-order cross-linking by FcyRIIb that is necessary for in vivo CD40 activation (e.g. see page 11, lines 1-9).
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 and activates CD40 and a DC, and comprises any modified Fc region with enhanced specificity and affinity for FcyRIIb.
It is noted that the broadest claim (claim 1) does not indicate any specific structure for the genus of multispecific antibodies claimed.
Dependent claims 3 and 6 are drawn to a subgenera of multispecific antibodies that bind and activate CD40 and Clec9a, but still fail to recite any specific structure as is required for sufficient written description.
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 an effector cell antigen, such as CD3; a tumor cell antigen) 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) 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). 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.
As noted above, the specification only discloses five species of the instantly claimed multispecific antibodies which comprise the variable domains of the anti-human CD40 antibody 2141 and the variable domains of an anti-DEC-205 (HD-109), CD11c (N418), Clec9a (10B4), or XRC1 (MARX10) antibody, and further comprise the "V11" Fc scaffold (point mutations: G237D/P238D/H268D/P271G/A330R). Such a disclosure does not serve to provide sufficient written description of the claimed genus of multispecific antibodies. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to CD40 and a DC and having enhanced FcyRIIb in the modified Fc region. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited multispecific antibodies which gives rise to their functional activity. As such, the instant specification appears to disclose applicant’s wish for multispecific antibodies that bind to and activate CD40 and a DC and have enhanced FcyRIIb in the modified Fc region without informing artisans what such multispecific antibodies actually are.
Ultimately, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide written description of the antibody in question.
It is noted that the claims are drawn to a genus of multispecific antibodies which not only bind but also activate CD40. As such, the claims are drawn to CD40 agonists and exclude any anti-CD40 antibodies with antagonistic activity. Nonetheless, there is still insufficient written description for these CD40 agonists.
Regarding the lack of written description for the modified Fc region having enhanced specificity and affinity for FcyRIIb, the same logic above applies: structure does not necessarily correlate with function.
Teige et al. 2019 (Front Immunol. 10(481); 1-14) teach that since FcyRIIb may promote anti-tumor activity by facilitating extrinsic signaling of certain co-stimulatory receptors expressed on tumor or immune cells, a possible strategy to enhance therapeutic activity of antibodies would therefore be to enhance their affinity for FcyRIIb (e.g. see paragraph spanning pages 10 and 11). In fact, antibodies carrying the S267E (“SE”) mutation increase human IgG1 affinity for FcyRIIb several hundred-fold and show improved tumor regression in mouse models humanized for FcyRIIb. Similarly, human IgG2 antibodies equipped with SE or SE/LF mutated backbones (the latter further increases affinity for FcyRIIb) show enhanced CD8+ T cell activation, and improved ability to clear tumors, in mice humanized for FcγRs. Nonetheless, Fc-engineering for enhanced FcyRIIb affinity or selectivity needs close consideration of antibody (Fv-) targeted receptor's cellular distribution and function(s) (e.g. see paragraph spanning pages 10 and 11).
Together, the art suggests that identifying modified Fc regions with enhanced FcyRIIb affinity is unpredictable and requires close consideration of the specific antibody and its specific receptor target on a case-by-case basis.
Ultimately, there is insufficient written description for the breadth of multispecific antibodies as currently claimed. One of ordinary skill in the art cannot envision from the disclosed species provided, the entire genus of multispecific antibodies of the instant invention.
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 multispecific antibodies encompassed by the claims at the time the instant application was filed.
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.
Claim 1-3 and 6 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).
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 binding affinity and selectivity of human IgGs to hFcγRIIB was increased by mutagenesis of their Fc domain (e.g. see [0273]). 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]).
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 cite the 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 fail to teach that their Fc-modified bispecific antibodies, which bind CD40 with one arm, also bind to a DC with the other arm, and specifically bind the DC marker Clec9a.
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 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).
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. note 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).
Thus, 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 a DC with the other arm, and specifically bind the DC marker Clec9a.
It is well known that binding and activating both CD40 and DCs enhances immune responses (Ravetch and Dahan and Park et al). This property can be further enhanced for the agonistic anti-CD40 antibodies by modifying their Fc region for improved specificity and affinity for the inhibitory FcγRIIb (Ravetch and Dahan). Similarly, targeting DCs with antibodies also serves as a method of modulating immune response and targeting a specific subtype of DCs may prove to further tailor the immune response (Park et al.). For example, Clec9a is specifically expressed by the cDC1 subtype which is especially efficient at taking up and processing antigens from dead cells, and cross-presenting these antigens on major histocompatibility complex class I (Park et al.). Clec9a targeting has considerable promise for generation of protective Ab responses to infectious diseases, as well as for CTL responses against tumors (Park et al.). However, it is likely that a DC-activating adjuvant would need to be a component of a Clec9A-targeted vaccine (Park et al.).
Thus, given the considerable promise of Clec9a targeting in stimulating an immune response against a desired target, but their possible requirement of a DC-activating adjuvant to be most efficacious; and that Fc-modified anti-CD40 antibodies with enhanced specificity and affinity for the inhibitory FcγRIIb, which can be extrapolated to bispecific antibodies, also have DC-dependent immune enhancing properties; it would have been to a skilled artisan, with the aim of designing a molecule that stimulates a significant DC-dependent immune response, to experiment with engineering a bispecific antibody from the Fc-modified anti-CD40 antibodies taught by Ravetch and Dahan that simultaneously targets Clec9a on cDC1 so as to further enhance the immune response toward an intended target with a reasonable expectation of success. Without evidence to the contrary, a skilled artisan would have reasonably expected that the simultaneous targeting of CD40 and Clec9a by an Fc-modified bispecific antibody would synergize the immune enhancing properties of the individual monospecific antibodies because the individual binding arms would ultimately function as adjuvants for one another.
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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 6 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).
The instant claims are drawn to a multispecific antibody comprising a first moiety, which binds and activates CD40, a second moiety, which specifically binds a DC and a third moiety comprising a modified Fc region of said multispecific antibody for enhancing specificity and affinity of binding to FcyRIIb.
The claims in the ‘835 Patent are drawn to an isolated antibody, or antigen binding portion thereof, that binds to human CD40; pharmaceutical composition; and a method of stimulating an immune response in a subject in need thereof.
It is noted that the ‘835 Patent’s method of using the product would anticipate any claims to the product because one cannot practice the method without the product.
The claims in the ‘835 Patent differ from the instant invention by not teaching that the anti-CD40 antibody is a bispecific antibody that also binds to a DC or specifically binds to the DC marker Clec9a.
The teachings of Ravetch and Dahan and Park et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims of the ‘835 Patent incorporate the teachings of Ravetch and Dahan and Park et al. to include that the ‘835 Patent’s anti-CD40 antibody is a bispecific antibody that also binds to a DC or specifically binds to the DC marker Clec9a.
It is well known that binding and activating both CD40 and DCs enhances immune responses (Ravetch and Dahan and Park et al). This property can be further enhanced for the agonistic anti-CD40 antibodies by modifying their Fc region for improved specificity and affinity for the inhibitory FcγRIIb (Ravetch and Dahan). Similarly, targeting DCs with antibodies also serves as a method of modulating immune response and targeting a specific subtype of DCs may prove to further tailor the immune response (Park et al.). For example, Clec9a is specifically expressed by the cDC1 subtype which is especially efficient at taking up and processing antigens from dead cells, and cross-presenting these antigens on major histocompatibility complex class I (Park et al.). Clec9a targeting has considerable promise for generation of protective Ab responses to infectious diseases, as well as for CTL responses against tumors (Park et al.). However, it is likely that a DC-activating adjuvant would need to be a component of a Clec9A-targeted vaccine (Park et al.).
Thus, given the considerable promise of Clec9a targeting in stimulating an immune response against a desired target, but their possible requirement of a DC-activating adjuvant to be most efficacious; and that Fc-modified anti-CD40 antibodies with enhanced specificity and affinity for the inhibitory FcγRIIb which have DC-dependent immune enhancing properties can be extrapolated to the bispecific platform; it would be obvious to a skilled artisan, with the aim of designing a molecule that stimulates a significant DC-dependent immune response, to experiment with engineering a bispecific antibody from the Fc-modified anti-CD40 antibodies taught by the ‘835 Patent that simultaneously targets Clec9a on cDC1 so as to further enhance the immune response toward an intended target with a reasonable expectation of success. Without evidence to the contrary, a skilled artisan would reasonably expect that the simultaneous targeting of CD40 and Clec9a by an Fc-modified bispecific antibody would synergize the immune enhancing properties of the individual monospecific antibodies because the individual binding arms would ultimately function as adjuvants for one another.
Therefore, the claims in the ‘835 Patent would render the instant claim obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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