DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2, 6, 9-16, 18, 20-27 are pending and will be examined on the merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Note: there is one embedded hyperlink and it is found at ¶ 0155 of the instant Specification.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 6, 9-16, 18, 20-21, 23 and 26 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.
Regarding claim 2, claim 2 recites an anti-B7H4 antibody according to claim 1, wherein the antibody comprises a VH CDR2 mutation that is 2 or 1 amino acid substitutions of: 1) P at position 2 of SEQ ID NO: 15 in place of G, 2) S at position 4 of SEQ ID NO: 15 in place of G and 3) R, D, E or T at position 5 of SEQ ID NO: 15 in place of S. Claim 2 is rendered indefinite by virtue of the fact that claim 2 first states that claim 2 permits between 1 and 2 amino acid substitutions to SEQ ID NO: 15 to arrive at the variant CDR2 but also specifically requires three substitutions: one at position 2, one at position 4 and one at position 5 of SEQ ID NO: 15.
Note: for the purposes of examination, claim 2 will be interpreted as reading that the variant CDR2 comprises one or two substitutions, each independently selected from the group consisting of: G2P, S4G and S5R/D/E/T mutations, all with respect to SEQ ID NO: 15.
Regarding claims 2, 6, 10-11, 13, 16, 20, 23 and 26, each instance of the term "preferably" each independently renders its respective claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note: for the purposes of examination, all limitations indicated as “preferable” will be treated as not required limitations for their respective claims.
Regarding claims 2 and 6, each instance of the phrase "for example" independently render its respective claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note: for the purposes of examination, all limitations following the phrase “for example” will be treated as exemplary and thus not required limitations for their respective claims.
Regarding claims 2, 6, 11 and 13, each instance of the phrase "such as" independently renders its respective claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note: for the purposes of examination, all limitations following the phrase “for example” will be treated as exemplary and thus not required limitations for their respective claims.
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 1-2, 6, 9-16, 18 and 20-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the claimed antibodies
Instant claims 1-2, 6, 9-16, 18, 20-27 are directed to antibodies capable of performing the implied recited function of binding B7H4. Regarding the antibody structure required to perform this function, instant claim 1 recites that the instant claimed anti-B7H4 antibodies comprise a heavy chain variable region comprising: 1) a HCDR1 selected from the group consisting of SEQ ID NOs: 4 and 6, 2) a HCDR2 having the amino acid sequence of SEQ ID NO: 15 and 3) a HCDR3 selected from the group consisting of SEQ ID NOs: 24 and 25.
Instant claim 1 also permits the VH to comprise mutant CDRs, wherein each mutant CDR comprises between 1 and 3 amino acid substitutions, insertions or deletions relative to the parental CDR sequence. Instant claim 1 provides no guidance, limitations or restrictions on which amino acid(s) of which explicitly recited CDR sequence(s) are permitted to be selected for mutation or which specific variant amino acid(s) are permitted to be substituted in to any of the explicitly recited CDR sequence(s).
Regarding the antibody CDR mutant structure recited in the claims dependent on claim 1, only instant claim 2 provides any specific guidance, limitations or restrictions regarding which specific amino acid mutations are permitted on any of the explicitly recited CDR sequence to arrive at a permissible mutant CDR sequence. Instant claim 2, as interpreted for examination in view of the 35 USC 112(b) rejection above, is directed to mutant HCDR2 sequences, each comprising one or two amino acid substitutions, with each amino acid substitution being independently selected from the group consisting of: G2P, S4G and S5R/D/E/T mutations, all with respect to SEQ ID NO: 15. Neither instant claim 2 or any other claim subject to this rejection recites any specific guidance, limitations or restrictions regarding specific amino acid substitutions, insertions or deletions are permissible for arriving at any variant of any of the explicitly recited HCDR1 or HCDR2 sequences capable of performing the required function of binding B7H4.
Description of Claimed Antibodies in specification
The instant Specification a total of 10 antibodies comprising a distinct combination of three heavy chain CDRs according instant claim 1, or mutants thereof, and are capable of performing the required function of binding B7H4, which are disclosed in Table 1-5, which is found at ¶ 0157 of the instant Specification and is reproduced below:
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The instant Specification also discloses that the anti-B7H4 antibodies of the present invention were produced via B7H4 immunization of transgenic Harbour HCAb transgenic mice, which are produce fully human “heavy chain only” antibodies, capable of binding their respective antigen without light chain sequences (Specification, ¶ 0122-0135) and, as such, one of ordinary skill in the art would reasonably expect that all of the HCDR1-3 combinations recited in Table 1-5 would be capable of forming a functional antibody capable of performing the required function of binding B7H4 without requiring pairing with a VL comprising VL CDR1-3s because the HCAb transgenic mouse system produces fully human “heavy chain only” antibodies capable of binding their respective antigen with only HCDR1-3.
Additionally, the Table 1-5 of the instant Specification shows that a total of seven mutant HCDR2s, each derived from instant SEQ ID NO: 15 according to the mutations permissible according to instant claim 2 that were capable of performing the required function of binding B7H4. The instant Specification does not, however, contain any examples of antibodies comprising up to three insertions, substitutions or deletions in either of the recited HCDR1 sequences (SEQ ID NOs: 4 and 5) and/or the recited HCDR3 sequences (SEQ ID NOs: 24 and 25) capable of performing the required function of binding B7H4. The instant Specification also does not provide any examples of antibodies comprising up to three insertions, substitutions or deletions in the recited HCDR2 of SEQ ID NO: 15 other than the specific mutations permitted as per instant claim 2 capable of performing the required function of binding B7H4.
State of the Relevant Art
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. Sela-Culang (Sela-Culang, et al., Front in Immunol. 2013; Vol. 4; Article 302) teaches on the subject of the structural basis of antibody-antigen recognition (Sela-Culang, Abstract). Sela-Culang teaches that there is a lack of intrinsic properties linking epitopic vs non-epitopic residues based on features present in said residues suggests that epitopes depend, to a great extent, on the antibody that recognizes them (Sela-Culang, p 2, ¶ 7). Sela-Culang teaches that antibodies fold in such a manner such that six hypervariable loops of the light and heavy domains of an antibody (three loops on the HC and three on the LC) are folded together and form the antigen binding site (Sela-Culang, p 3, ¶ 2). Sela-Culang teaches that the complimentary determining regions (CDRs) are amino acid sequences within this hypervariable region and that amino acids that define the CDR regions are typically defined based on numbering schemes (e.g., Kabat, Chothia, IMGT) derived from empirical studies of the boundaries between the framework and binding residues of the antibodies (Sela-Culang), p 3, ¶ 3). Sela-Culang teaches that identification of paratopes (the portion of an antibody which binds an antigen) is done through the identification of CDRs but CDRs, as identified by methods such as Kabat, Chothia and IMGT may miss ~20% of antigen binding residues (Sela-Culang, 4, ¶ 1-2). Sela-Culang teaches that each CDR has its own unique amino acid composition (i.e., different from the other CDRs) and each CDR has a unique set of contact preferences (Sela-Culang, p 5, ¶ 1).
Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict what an antibody with a particular set of functional properties would look like structurally. As discussed above, neither an epitope nor a paratope can be calculated a priori based on properties of the component amino acids. Furthermore, each and every CDR sequence is unique and distinct and, as such, a CDR sequence cannot be predicted, either from the epitope sequence of from the CDR sequences of the antibody, if known.
In addition to the importance of the CDR regions, Sela-Culang also teaches that framework residues are also play an important role in antigen binding (Sela-Culang, P 7, ¶ 3). These framework residues can be divided into two types. The first are framework residues that actually contact the antigen and therefore are part of the binding site (Sela-Culang, p 7 ¶ 4). The second type of framework residues that affect antigen binding are framework residues that do not directly contact the antigen but affect binding indirectly (Sela-Culang, p 7, ¶ 5). Some of the framework residues are in close proximity to the CDR regions of the parental antibody, with these FR residues providing structural support that permits the CDRs to adopt the right conformation to form the antigen binding.
The other type of framework residues that indirectly affect antigen binding are further from the CDR regions and affect the relative orientation of the VH and VL regions, and thus the orientation of the CDRs relative to each other (Sela-Culang, p 7, ¶ 6). Sela-Culang also teaches that the effect of framework residues on antigen binding is impossible to predict a priori. For example, Sela-Culang teaches that positions in FR-3 of the heavy chain affects the orientation of CDRH1 relative to CDRH2, however this is not always the case, as it has been shown that mutating a Lys in this region for either a Val, Ala or Arg resulted in affinity differences but no structural changes (Sela-Culang, p 7, ¶ 5).
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species that are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
As stated and articulated above, the instant disclosure does antibodies species comprising all of the combinations of explicitly recited HCDR1-3s recited in instant claim 1 (i.e., HCDR1-3 of: 1) SEQ ID NOs: 4, 15 and 24, 2) SEQ ID NOs: 4, 15 and 25, 3) SEQ ID NOs: 5, 15 and 24 and 4) SEQ ID NOs: 5, 15 and 25), all possessing the required function of binding B7H4. Additionally, the instant disclosure does recite sufficient species of functional anti-B7H4 antibodies comprising mutant HCDR2 sequences derived from SEQ ID NO: 15 as per instant claim 2 to be representative of genus of HCDR2s encompassed by instant claim 2.
However, as stated and articulated above, the instant Specification does not disclose any examples of anti-B7H4 antibodies comprising HCDR1s comprising up to 3 insertions, deletions or substitutions to either of SEQ ID NOs: 4 or 5 capable of performing the required function of binding B7H4. The instant Specification does not disclose any examples of anti-B7H4 antibodies comprising HCDR3s comprising up to 3 insertions, deletions or substitutions to either of SEQ ID NOs: 24 or 25 capable of performing the required function of binding B7H4. The instant specification also does not disclose any examples of anti-B7H4 antibodies comprising HCDR2s comprising up to three insertions, deletions or substitutions to SEQ ID NO: 15 other than the mutations of claim 2 capable of performing the required function of binding B7H4. As such, the disclosed species cannot be considered to be representative of the claimed genus of antibodies comprising mutant CDRs according to claim 1 because the disclosed species do not reflect variation of the claimed genus with respect to permissible mutant HCDR1 sequences, permissible mutant HCDR3 sequences or permissible mutant HCDR2 sequences other than the specific mutations encompassed by instant claim 2.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 claimed genus.
As noted above, the art generally accepted that the combination of the CDRs of an antibody was the minimum structure essential for binding specificity and the framework residues also play a role in antigen binding and a disclosure of an antigen or epitope does not permit a skilled artisan to envision the structure an antibody would need to have to bind that antigen or epitope, even if the amino acid sequence of that epitope is known.
The teachings of Sela-Culang make very clear that a structure-function relationship between an antibody’s CDRs and the epitope it binds is not understood well enough to permit a skilled artisan to analyze an epitopic sequence and envision, a priori, the required CDR structure required to form a functional antibody capable of binding that epitope. Sela-Culang teaches that CDRs are independent structurally and each possess independent binding preferences. There is nothing in the present disclosure nor the prior art that would lead one of skill in the art to believe that the disclosure contains any new discoveries that would supplant these notions. The lack of known structure/function correlation between any given antibody’s CDR structure and that antibody’s ability to bind its respective antigen means that it is highly unlikely that a skilled artisan would be able to start with the HCDR1-3 amino acid sequences of claims 1 and envision, a priori which, if any, of the mutant HCDRs encompassed by the instant claims are capable of forming a function antibody capable of performing the required function of binding B7H4.
Because the species disclosed are insufficient to be considered representative of either the unfathomably large number of possible variations to the binding-critical CDR regions, coupled with the lack of established structure/function correlation, the claims lack written description and Applicant was not in possession of the invention as claimed.
Claims 21 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating a tumor comprising administration either the anti-B7H4 antibody of claim 1 or the bispecific antibody of claim 6, does not reasonably provide enablement for methods of preventing a tumor comprising administration either the anti-B7H4 antibody of claim 1 or the bispecific antibody of claim 6. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The instant claims are drawn to methods of treatment and/or prevention of a tumor, said methods comprising administering to said subject a composition comprising the anti-B7-H3 antibodies of instant claim 1 (the method of claim 21) or a composition comprising the bispecific antibodies of instant claim 6 (the method of claim 27).
When given the broadest reasonable interpretation, “a subject in need thereof” includes humans and non-experimental animals.
The Merriam-Webster definition of the word “prevent”—“to keep from happening or existing”. Thus, the broadest reasonable interpretation of the claim is that the methods comprising the administration of the instant claimed composition comprising the anti-B7-H3 antibodies of instant claim 1 or the bispecific antibody of instant claim 6 described in the preceding paragraph prophylactically prevents cancer from occurring by killing every cancer cell present or stopping every healthy cell from becoming cancerous.
The skilled artisan recognized that before any method of preventing a particular cancer could be practiced with any level of predictability, some method of identifying subjects predisposed to the particular cancer must be available. While the art has advanced in recent years, it is still highly unpredictable not only which individuals will develop a particular cancer, but also when a “preventative” therapy will be helpful.
Breast cancer illustrates the difficulties associated with detecting and preventing cancer. The skilled artisan generally recognized symptoms of breast cancer to include changes in the breast such as the presence of a lump, nipple discharge, or other changes in the shape or texture of the breast. However, such symptoms are non-specific and have multiple other potential causes. Even detection of a breast mass by mammography is only an early step in the diagnosis of breast cancer. As noted in a 2014 article in the World Journal of Clinical Oncology, following an abnormal mammographic finding exam, biopsy is required for a diagnosis (cancer vs. benign lesion) and staging is required to determine appropriate treatment (Shah, et al. World J Clin Oncol 2014 August 10; 5(3): 283-298, Table 1).
Further, even in individuals judged to have a twofold increased risk of developing breast cancer, prevention with tamoxifen was incomplete. Briefly, high risk women were given either tamoxifen or a placebo and the occurrence of breast cancer was monitored for 20 years. The placebo group had a breast cancer rate of 12.3% and the treatment group had a breast cancer rate of 7.8 %. (Cuzick, et al Lancet Oncol 2015 Jan; 16(1) 67-75, Results, page 4). While tamoxifen did reduce the risk of the occurrence of breast cancer, it did not completely prevent it. It should be noted that the Specification is not enabling for any methods of preventing any type of tumor, said methods comprising administering the anti-B7H4 antibody of claim 1 or the bispecific antibody of instant claim 6.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 6, 9-11, 14, 16, 18, 21-23 and 26-27 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Wu (Wu, et al., US 2025/0326843 A1; Published 10/23/2025; Priority to 6/18/2021 via CN202110678326.X)
Wu teaches SEQ ID NO 110 of Wu, which is an anti-B7H4 VH sequence (Wu, p 63), with a pairwise alignment of SEQ ID NO: 110 of Wu with instant claimed CDRs 4, 15 and 25 (in that order) being depicted below:
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Please note that SEQ ID NO: 110 of Wu reads on all of the CDR limitations of instant claims 1 and 2 because SEQ ID NO: 110 comprises HCDR1 that is a 100% match for SEQ ID NO: 4, a HCDR3 that is a 100% match for SEQ ID NO: 24 and an HCDR2 that is the same as instant SEQ ID NO: 15 with a S5R mutation (permissible under instant claim 2). Please also note that that Wu’s numbering for the VH CDRs of Wu’s SEQ ID NO: 110 are VHCDR1-3 of Wu’s SEQ ID NOs: 97, 103 and 99, respectively (Wu, Table 2, ¶ 0134).
Regarding claim 6, Wu teaches of a bispecific antibody comprising a B7H4 targeting domain and a CD3 targeting domain (Wu, claim 1), wherein the B7H4 targeting domain comprises HCDR1-3 of Wu’s SEQ ID NOs: 97, 103 and 99, respectively (Wu, claim 3). Regarding instant claims 9-11 and 22-23, Wu teaches nucleic acids encoding the bispecific anti-B7H3 antibodies of Wu (Wu, claim 7) that are contained within a recombinant expression vector (Wu, claim 8) as well as transformants comprising recombinant expression vectors comprising nucleic acids encoding the bispecific antibodies of Wu (Wu, claim 9). Regarding instant claims 16 and 26, Wu teaches pharmaceutical compositions comprising the bispecific antibodies of Wu (Wu, claims 10, 19). Regarding instant claim 14, Wu teaches that the anti-B7H4 bifunctional antibodies of Wu were produced using transformants that comprising mammalian expression vectors encoding the anti-B7H4 bifunctional antibodies of Wu (Wu, ¶ 0125). Regarding instant claim 18, Wu teaches kits comprising the bispecific anti-B7H4 antibodies of Wu (Wu, claim 17). Regarding instant claim 21, Wu teaches methods of treating a tumor, comprising administering to a subject in need the bispecific anti-B7H4 antibody of Wu (Wu, claims 15, 20).
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(s) 1-2, 6, 9-14, 16, 18, 21-24 and 26-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu, et al., US 2025/0326843 A1; Published 10/23/2025; Priority to 6/18/2021 via CN202110678326.X) as applied to claims 1-2, 6, 9-11, 14, 16, 18, 21-23 and 26-27 above and in further consideration of the Wu reference.
The teachings of Wu are discussed above.
Wu does not teach a chimeric antigen receptor comprising the bispecific, anti-B7H4-targeting antibody of Wu. Wu does not teach genetically modified cells comprising such CARs.
In addition to the teachings of Wu discussed above, Wu also teaches that bispecific antibodies binding CD3 molecules on T cells and tumor associated antigens (TAAs) on tumor cells mediate the formation of immune synapses between the cells, activating the CD3 on T cells and, as such, causing the T-cell based killing of the tumor cells (Wu, ¶ 0003) and that B7H4 is a TAA abundantly expressed on tumor cells, making B7H4 a TAA suitable for such purposes (Wu, ¶ 0005). Wu also teaches that such CD3 comprising bispecific molecules are integrated with intracellular 4-1BB CAR segments of CAR-T cells can significantly promote T cell activation and reduce T cell depletion, thereby improving therapeutic efficacy (Wu, ¶ 0004).
It would be prima facie obvious to incorporate the anti-CD3/anti-B7H4 of Wu into a CAR comprising a 4-1BB intracellular domain to form a CAR and expressing the resultant CAR in CAR-T cells in view of the teachings of Wu. One of ordinary skill in the art would be motivated to do this in order to better treat B7H4-associated cancers. One of ordinary skill in the art incorporating the anti-CD3/anti-B7H4 of Wu into a CAR comprising a 4-1BB intracellular domain to form a CAR and expressing the resultant CAR in CAR-T cells in view of the teachings of Wu because: 1) Wu teaches that anti-CD3/anti-B7H4 antibodies are suitable for use in CD3/TAA bispecific T cell engager antibodies and 2) Wu also teaches that therapeutic efficacy of CD3-targeting bispecific antibodies can be improved by integration with of the CD3-targeting bispecific antibody with an intracellular 4-1BB element to form a CAR expressed on CAR-T cells.
Claim(s) 1-2, 6, 9-11, 14-16, 18, 21-23 and 25-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu, et al., US 2025/0326843 A1; Published 10/23/2025; Priority to 6/18/2021 via CN202110678326.X) as applied to claims 1-2, 6, 9-11, 14, 16, 18, 21-23 and 26-27 above and in further view of Kim (Kim, et al., Biomol Ther (2015) 23(6):493).
The teachings of Wu are discussed above.
Wu does not teach an antibody-drug conjugate comprising a chemotherapeutic drug linked to the bispecific, B7H4-targeting antibodies of Wu.
In addition to the teachings of Wu discussed above, Wu also teaches pharmaceutical compositions comprising the B7H4-targeting antibodies of Wu and further comprising a chemotherapeutic agent (Wu, claims 10, 17 and 19).
Kim teaches on the subject of antibody drug-conjugates as delivery vehicles for highly potent cytotoxic molecules with specificity for TAAs (Kim, Abstract). Kim teaches that most chemotherapeutic agents target both cancer and normal proliferating cells and are used near their maximum tolerated dosage to achieve therapeutic results, creating a narrow therapeutic window due to severe off-target toxicity and lack of target specificities as major drawbacks (Kim, p 494, ¶ 2). Kim also teaches that conjugation of a chemotherapeutic drug with a TAA-targeting antibody provides a means to selectively localize the chemotherapeutic drug in and around tumor cells by way of the antibody’s specificity for the TAAs, allowing for targeted delivery of the chemotherapeutics to tumors, thus improving the therapeutic efficacy when compared to systemic chemotherapeutic administration (Kim (p 494, ¶ 3- p 496, ¶ 1).
It would be prima facie obvious to one of ordinary skill in the art to conjugate the chemotherapeutic agents present in the pharmaceutical compositions of Wu to the bispecific, B7H4-targeting antibodies of Wu to form antibody-drug conjugates in view of the teachings of Kim. One of ordinary skill in the art would be motivated to do this in order improve the therapeutic window and therapeutic efficacy of the chemotherapeutic agents of Wu. One of ordinary skill in the art would have a reasonable expectation of success conjugating the chemotherapeutic agents present in the pharmaceutical compositions of Wu to the bispecific, B7H4-targeting antibodies of Wu to form antibody-drug conjugates in view of the teachings of Kim because Wu teaches pharmaceutical compositions comprising free chemotherapeutic agents as well as B7H4-targeting bispecific antibodies and Kim teaches that conjugation of chemotherapeutic agents to TAA-targeting antibodies, such as the B7H4-targeting bispecific antibodies of Wu, is a known method of reducing chemotherapeutic systemic toxicity and improving therapeutic efficacy of the chemotherapeutic agent because conjugation of the chemotherapeutic agent to a TAA-targeting antibody localizes the chemotherapeutic in and around tumors by way of the antibody’s specificity for the TAA (such as B7H4).
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.
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Claims 1-2, 6, 9-11, 16, 18, 21-23 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11, 13-15 and 17-20 of copending Application No. 18/571,174 (Published as US 20250326743A1 on 10/23/2025).
Regarding instant claims 1 and 2, a pairwise alignment of SEQ ID NO: 110 of the ‘174 Application with instant claimed CDRs 4, 15 and 25 (in that order) being depicted below:
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Please note that SEQ ID NO: 110 of the ‘174 Application reads on all CDR limitations of instant claims 1 and 2 because SEQ ID NO: 110 of the ‘174 Application comprises HCDR1 that is a 100% match for SEQ ID NO: 4, a HCDR3 that is a 100% match for SEQ ID NO: 24 and an HCDR2 that is the same as instant SEQ ID NO: 15 with a S5R mutation (permissible under instant claim 2). Please also note that that the ‘174 Application’s numbering for the VH CDRs of Wu’s SEQ ID NO: 110 are VHCDR1-3 of copending SEQ ID NOs: 97, 103 and 99, respectively (see comparative sequence results in PatentCenter).
Regarding claim 6, Wu teaches of a bispecific antibody comprising a B7H4 targeting domain and a CD3 targeting domain, wherein the B7H4 targeting domain comprises HCDR1-3 of copending SEQ ID NOs: 97, 103 and 99, respectively (Copending claim 1). Regarding instant claims 9-11 and 22-23, the ‘174 Application teaches nucleic acids encoding the bispecific anti-B7H3 antibodies of ‘174 Application (Copending claim 7) that are contained within a recombinant expression vector (Copending claim 8) as well as transformants comprising recombinant expression vectors comprising nucleic acids encoding the bispecific antibodies of the ‘174 Application (Copending claim 9). Regarding instant claims 16 and 26, the ‘174 Application teaches pharmaceutical compositions comprising the bispecific antibodies of the ‘174 Application (Copending claims 10, 19). Regarding instant claim 18, the ‘174 Application teaches kits comprising the bispecific anti-B7H4 antibodies of the ‘174 Application (copending claim 17). Regarding instant claim 21, the ‘174 Application teaches methods of treating a tumor, comprising administering to a subject in need the bispecific anti-B7H4 antibody of the ‘174 Application (copending claims 15, 20).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 6, 9-14, 16, 18, 21-24 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11, 13-15 and 17-20 of copending Application No. 18/571,174 (Published as US 20250326743A1 on 10/23/2025) as applied to claims 1-2, 6, 9-11, 16, 18, 21-23 and 26-27 above and in further view of Wu (Wu, et al., US 2025/0326843 A1; Published 10/23/2025; Priority to 6/18/2021 via CN202110678326.X).
The teachings of the ‘174 Application are discussed above.
The ‘174 Application does not teach a chimeric antigen receptor comprising the bispecific, anti-B7H4-targeting antibody of the ‘174 Application. The ‘174 Application does not teach genetically modified cells comprising such CARs. The ‘174 Application does not teach a method of producing the B7H4 targeting bispecific antibodies of the ‘174 Application, said method comprising culturing transformants comprising mammalian expression vector(s)
Wu also teaches that bispecific antibodies binding CD3 molecules on T cells and tumor associated antigens (TAAs) on tumor cells mediate the formation of immune synapses between the cells, activating the CD3 on T cells and, as such, causing the T-cell based killing of the tumor cells (Wu, ¶ 0003) and that B7H4 is a TAA abundantly expressed on tumor cells, making B7H4 a TAA suitable for such purposes (Wu, ¶ 0005). Wu also teaches that such CD3 comprising bispecific molecules are integrated with intracellular 4-1BB CAR segments of CAR-T cells can significantly promote T cell activation and reduce T cell depletion, thereby improving therapeutic efficacy (Wu, ¶ 0004). Wu teaches that the anti-B7H4 bifunctional antibodies of Wu (identical to those of the ‘174 Application) were produced using transformants that comprising mammalian expression vectors encoding the anti-B7H4 bifunctional antibodies of Wu (Wu, ¶ 0125).
It would be prima facie obvious to incorporate the anti-CD3/anti-B7H4 of the ‘174 Application into a CAR comprising a 4-1BB intracellular domain to form a CAR and expressing the resultant CAR in CAR-T cells in view of the teachings of Wu. One of ordinary skill in the art would be motivated to do this in order to better treat B7H4-associated cancers. One of ordinary skill in the art incorporating the anti-CD3/anti-B7H4 of the ‘174 Application into a CAR comprising a 4-1BB intracellular domain to form a CAR and expressing the resultant CAR in CAR-T cells in view of the teachings of Wu because: 1) Wu teaches that anti-CD3/anti-B7H4 antibodies of the ‘174 Application are suitable for use in CD3/TAA bispecific T cell engager antibodies and 2) Wu also teaches that therapeutic efficacy of CD3-targeting bispecific antibodies can be improved by integration with of the CD3-targeting bispecific antibody with an intracellular 4-1BB element to form a CAR expressed on CAR-T cells.
It would be prima facie obvious to one of ordinary skill in the art to produce the B7H4-targeting bispecific antibodies of the ‘174 Application using Wu’s method of culturing transformants comprising mammalian expression vectors comprising nucleic acids encoding the B7H4-targeting bispecific antibodies of the ‘174 Application in view of the teachings of Wu. One of ordinary skill in the art would be motivated to do this in order have a method of producing the B7H4-targeting bispecific antibodies of the ‘174 Application. One of ordinary skill in the art would have a reasonable expectation of success to producing the B7H4-targeting bispecific antibodies of the ‘174 Application using Wu’s method of culturing transformants comprising mammalian expression vectors comprising nucleic acids encoding the B7H4-targeting bispecific antibodies of the ‘174 Application in view of the teachings of Wu because Wu teaches that the production method of Wu is capable of producing B7H4-targeting bispecific antibodies identical to those of the ‘174 Application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 6, 9-11, 15-16, 18, 21-23 and 25-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11, 13-15 and 17-20 of copending Application No. 18/571,174 (Published as US 20250326743A1 on 10/23/2025) as applied to claims 1-2, 6, 9-11, 16, 18, 21-23 and 26-27 above and in further view of Kim (Kim, et al., Biomol Ther (2015) 23(6):493).
The teachings of the ‘174 Application are discussed above.
The ‘174 Application does not teach an antibody-drug conjugate comprising a chemotherapeutic drug linked to the bispecific, B7H4-targeting antibodies of ‘174 Application.
In addition to the teachings of the ‘174 Application discussed above, the ‘174 Application also teaches pharmaceutical compositions comprising the B7H4-targeting antibodies of the ‘174 Application and further comprising a chemotherapeutic agent (Copending claims 10, 17 and 19).
Kim teaches on the subject of antibody drug-conjugates as delivery vehicles for highly potent cytotoxic molecules with specificity for TAAs (Kim, Abstract). Kim teaches that most chemotherapeutic agents target both cancer and normal proliferating cells and are used near their maximum tolerated dosage to achieve therapeutic results, creating a narrow therapeutic window due to severe off-target toxicity and lack of target specificities as major drawbacks (Kim, p 494, ¶ 2). Kim also teaches that conjugation of a chemotherapeutic drug with a TAA-targeting antibody provides a means to selectively localize the chemotherapeutic drug in and around tumor cells by way of the antibody’s specificity for the TAAs, allowing for targeted delivery of the chemotherapeutics to tumors, thus improving the therapeutic efficacy when compared to systemic chemotherapeutic administration (Kim (p 494, ¶ 3- p 496, ¶ 1).
It would be prima facie obvious to one of ordinary skill in the art to conjugate the chemotherapeutic agents present in the pharmaceutical compositions of ‘174 Application to the bispecific, B7H4-targeting antibodies of ‘174 Application to form antibody-drug conjugates in view of the teachings of Kim. One of ordinary skill in the art would be motivated to do this in order improve the therapeutic window and therapeutic efficacy of the chemotherapeutic agents of ‘174 Application. One of ordinary skill in the art would have a reasonable expectation of success conjugating the chemotherapeutic agents present in the pharmaceutical compositions of ‘174 Application to the bispecific, B7H4-targeting antibodies of ‘174 Application to form antibody-drug conjugates in view of the teachings of Kim because ‘174 Application teaches pharmaceutical compositions comprising free chemotherapeutic agents as well as B7H4-targeting bispecific antibodies and Kim teaches that conjugation of chemotherapeutic agents to TAA-targeting antibodies, such as the B7H4-targeting bispecific antibodies of ‘174 Application, is a known method of reducing chemotherapeutic systemic toxicity and improving therapeutic efficacy of the chemotherapeutic agent because conjugation of the chemotherapeutic agent to a TAA-targeting antibody localizes the chemotherapeutic in and around tumors by way of the antibody’s specificity for the TAA (such as B7H4).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-2, 6, 9-16, 18, 20-27 are rejected.
The Specification is objected to.
No claims are allowed.
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/SYDNEY VAN DRUFF/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643
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