DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 09/10/2026, is acknowledged.
3. Claims 1-6, 8, 10-15, 43, 46, 49, 53-54, and 59 are pending.
4. Applicant’s election without traverse of Group I, claims 1-6, 8, 10-15, 43, 46, 49 and 53-54 directed to multispecific antibody, comprising: an anti-CD3 unit comprising an anti-CD3 antibody or antigen-binding fragment having binding specificity to the human CD3 complex; and an anti-4-1BB unit comprising an anti-4-1BB antibody or antigen-binding fragment having binding specificity to the human 4-1BB protein and the following species (a) anti-4-1BB unit is a nanobody, (b) the anti-4-1BB unit binds to CRD4, (c) TAA-dependent T cell activation activity, (d) anti-CD3 unit comprising 6 CDRs of SEQ ID NOS: 13-15 and 16, 11 and 17, VH of SEQ ID NO: 37 and VL of SEQ ID NO: 46, ( e) anti-4-1BB unit comprising 3CDRs of SEQ ID NO: 111-113, filed on 09/10/2026, is acknowledged.
5. Claims 10, 12-13, 46, 53 and 59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-6, 8, 11, 14-15, 43, 49 and 54 are under examination as they read on a multispecific antibody, comprising: an anti-CD3 unit comprising an anti-CD3 antibody or antigen-binding fragment having binding specificity to the human CD3 complex; and an anti-4-1BB unit comprising an anti-4-1BB antibody or antigen-binding fragment having binding specificity to the human 4-1BB protein and the following species (a) anti-4-1BB unit is a nanobody, (b) the anti-4-1BB unit binds to CRD4, (c) TAA-dependent T cell activation activity, (d) anti-CD3 unit comprising 6 CDRs of SEQ ID NOS: 13-15 and 16, 11 and 17, VH of SEQ ID NO: 37 and VL of SEQ ID NO: 46, ( e) anti-4-1BB unit comprising 3CDRs of SEQ ID NO: 111-113.
7. Applicant’s IDS, filed 04/10/2024 and 09/10/2026, is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
9. Claim 11 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(A) Claim 1 is indefinite in the recitation of "SP34 antibody" because its characteristics are not known. The use of "SP34" monoclonal antibody as the sole means of identifying the claimed antibody and hybridoma renders the claim indefinite because "SP34" is merely a laboratory designation which does not clearly define the claimed product, since different laboratories may use the same laboratory designation s to define completely distinct hybridomas.
10. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
11. Claims 11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the hybridoma that produce the SP34 antibody is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the hybridoma, which produces this antibody, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit(s) was/were made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridoma described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
12. Claims 1-6, 8, 11, 14-15, 43, 49 and 54 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 encompasses a broad genus of anti-CD3 antibodies having a TAA-dependent T cell activation activity greater than the TAA-free T cell activation activity of the SP34 antibody and a broad genus of anti-4-1BB antibodies having a TAA-dependent agonist antibody or antigen-binding fragment.
Claim 2 encompasses broad genus of anti-tumor-associated antigen (TAA) unit.
Claim 5 encompasses a genus of anti-4-1BB nanobodies or scFv.
Claim 8 encompasses a genus of anti-4-1BB antibody that binds to CRD3 or CRD4 of the extracellular domain.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of treating cancer. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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.
The specification at [0144] discloses that another surprising discovery is that when both an anti-CD3 unit and an anti-4-1BB unit are included in a multispecific antibody, they are preferably located “away” from each other. For instance, in either the 1+1 format or the 2+Lc2 format as illustrated in FIG. 9A, the anti-CD3 unit and the anti-4-1BB unit are preferably separated by an Fc fragment, rather than located at the same end of the Fc fragment. By contrast, when an anti-TAA unit is also included, the anti-CD3 unit and the anti-TAA unit are preferably located on the same side (e.g., N-terminal) of the Fc fragment.
The specification at [0145] discloses that bispecific antibodies (CTM01-01A which did not target 4-1BB, and CTM01-01B which did not target CD3) that targeted only TAA and either CD3 or 4-1BB had suboptimal efficacies. The trispecific antibody (CTM01-01) that targeted all of TAA, CD3 and 4-1BB had far superior efficacy. This example, therefore, demonstrates the unexpectedly magnificent efficacy of targeting both CD3 and 4-1BB, in fashions as disclosed herein, in treating cold tumors.
[0331] In addition to the 155-8 based trispecific antibody (CTM01-01), control treatments included two mutants of CTM01-01. One of the mutants, CTM01-01A included an inactivating mutation in the anti-4-1BB antibody, and the other, CTM01-01B, included an inactivating mutation in the anti-CD3 antibody.
[0332] B16F10 tumor is a well-known PD-1 non-response and resistant model, widely considered one of the most difficult-to-treat tumors. The results are shown in FIG. 15. The mouse anti-PD-1 therapy had no efficacy in this model. The treatment with CTM01-01 (wild-type trispecific antibody targeting CD3, 4-1BB and human 5T4 as the TAA) resulted in dramatic tumor reduction. By contrast, the treatment with CTM01-01B, in which the anti-CD3 portion was inactivated, did not have a significant effect, and the treatment with CTM01-01A, in which the anti-4-1BB portion was inactivated, had only suboptimal efficacy. These results, therefore, demonstrate the exceptional in vivo efficacy of the anti-CD3/4-1BB/h5T4 trispecific antibodies.
[0336] This example developed a trispecific anti-5T4/CD3/4-1BB antibody using the 1+1 format as illustrated in FIG. 11A, which included two copies of an anti-4-1BB non-agonist antibody. The VH and VL sequences of anti-5T4 antibody naptumomab was used, in the TriAb 1+1 format, as a reference (“Naptu-tris”). Trispecific antibodies with the sequences of 14G12 and 393E9 (bin A), 159D5 (bin B), and 286B4 (bin D) were likewise constructed.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of the TAA/CD3/4-1BB in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, one or more functions recited in the claims, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-TAA/CD3/4-1BB antibodies to demonstrate possession.
Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the anti- TAA/CD3/4-1BB antibodies are required to practice the invention. The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely rely on the identification of TAA/CD3/4-1BB as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of anti-TAA/CD3/4-1BB antibodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-TAA/CD3/4-1BB antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
Given the claimed broadly class of antibodies and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of antibodies to TAA/CD3/4-1BB, including the claimed functional characteristics set forth in the claims, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims
AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163
The specification at best describes plan for making antibodies that bind TAA/CD3/4-1BB antibodies and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient.
Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification only discloses one single trispecific antibody (CTM01-01) that targeted all of TAA, CD3 and 4-1BB, within the claimed genus of TAA, CD3 and 4-1BB biAbs and TriAbs. With respect to representative number of species,
see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014)
Also, see MPEP 2163 II(A)(3)(a))(ii):
A representative number of species means that the species which 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. A "representative number of species" means that the species which 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
13. Claims 1-6, 8, 11, 14-15, 43, 49 and 54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1 encompasses a broad genus of anti-CD3 antibodies having a TAA-dependent T cell activation activity greater than the TAA-free T cell activation activity of the SP34 antibody and a broad genus of anti-4-1BB antibodies having a TAA-dependent agonist antibody or antigen-binding fragment.
Claim 2 encompasses broad genus of anti-tumor-associated antigen (TAA) unit.
Claim 5 encompasses a genus of anti-4-1BB nanobodies or scFv.
Claim 8 encompasses a genus of anti-4-1BB antibody that binds to CRD3 or CRD4 of the extracellular domain.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claims are directed to a broad class of bi- and tri-antibodies wherein the class was defined by its function—the ability to bind to TAA/CD3/4-1BB and treat cancer. However, the specification did not give the skilled in the art enough information to choose candidate antibodies from the millions of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses only one species of trispecific antibody (CTM01-01) that binds TAA/CD3/4-1BB; while the claims are directed to a genus of millions of bi-and tri-anti-CD3/4-1BB antibodies.
In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).
The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. In the instant case, the specification discloses only one species that performed the claimed function by their amino acid sequences, with the claimed genus of millions different bi- and tri-anti-TAA/CD3/4-1BB antibodies. The instant claims are directed to a class of anti- TAA/CD3/4-1BB antibodies that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
The scope of the instant claims encompassed millions of antibodies and that it was necessary to first generate and then screen each candidate to determine whether it met the functional limitations. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the two antibodies they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
14. 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(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.
15. Claims 1-2, 6, 11, 14-15 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Liu et al. (Cancer Research, (July 2019) Vol. 79, No. 13, Supp. Abstract Number: 554).
Liu et al teach tumor-antigen 5T4-dependent activation of the CD137 costimulatory pathway by bispecific 5T4 x CD137 x CD137 TRIDENT® molecules. Liu et al teaches trophoblast glycoprotein 5T4 (i.e., TAA) is expressed on the cell surface of multiple cancers yet sparingly on normal adult tissues. CD137 (4-1BB) is a co-stimulatory molecule expressed by activated T and NK cells that support cell activation, proliferation and survival. Liu et al identified a bispecific TRIDENT format (comprising Fc region) bearing bivalent CD137 and monovalent tumor antigen engagement that provides maximal CD137 activation in a tumor antigen anchored manner. Liu et al generate a 5T4 x CD137 x CD137 TRIDENT molecule that promotes CD137 activation in proximity to 5T4-expressing tumor cells leading to enhanced T-cell co-stimulation, proliferation and tumor cell killing activity when combined with CD3- engaging tumor-targeting bispecific DART molecules. Liu et al shows that the 5T4 x CD137 x CD137 TRIDENT molecule induces CD137 signaling in a reporter cell line and promotes cytokine release in primary human & cynomolgus monkey T-cell assays in the presence of 5T4+ tumor cells. In the absence of 5T4+ tumor cells, the TRIDENT molecule lacks agonistic activity. Furthermore, 5T4 x CD137 x CD137 TRIDENT molecule enhances T-cell proliferation and tumor cell cytolysis induced by CD3-targeted DART molecules. Consistent with preferential induction of CD137 by CD8 T-cells, 5T4 x CD137 x CD137 TRIDENT increases the fraction of CD8+ central memory and effector memory T cells in the presence 5T4+ tumor cells. Liu et al concluded that 5T4 x CD137 x CD137 TRIDENT molecule promotes T-cell co-stimulation in a tumor antigen-dependent manner offering an opportunity to target CD137 immunostimulation, while potentially limiting non-specific systemic T-cell activation and related side effects. The TRIDENT molecules were constructed comprising bivalent CD137 binding and monovalent 5T4 binding (see abstract).
The claimed functional properties recited in claims 11, 14-15 are considered inherent properties.
The reference teachings anticipate the claimed invention.
16. Claims 1-2, and 6 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20210388087.
The `087 publication teaches and claims antigen-binding molecules comprising:
an antibody variable region that is capable of binding to CD3 and CD137 (i.e., 4-1bb), but does not bind to CD3 and CD137 at the same time, wherein the antigen-binding molecule has an agonistic activity against CD137, which further comprises an antibody variable region that is capable of binding to a third antigen different from CD3 and CD137, wherein the third antigen is a molecule specifically expressed in a cancer tissue, further comprising an antibody Fc region.
The reference teachings anticipate the claimed invention.
17. Claims 1-4, 6, 11, 14-15 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by US 20210024630 A.
The `630 publication teaches a tetra-specific (multispecific) GNC antibody with an EGFRvIII (TAA) (SI-39E18), ROR1 AgBD (SI-35E20); and CD19 AgBD (SI-38E17); (see Figs. 1-2). The two tetra-specific GNC antibodies, SI-39E18 and SI-39E29, were the most efficacious at stimulating CD8 T cell proliferation in the presence of target cells (FIG. 14). These two molecules are composed of adjacent binding domains for CD3 and tumor antigen (TABLE 5) [0084]. SI-39E18 comprises D1(scFv x D2 (FAB)-Fc-D3 (scFv) x D4 (scFv) of αCD3 x αTAA(806)-Fc-αPD-L1 x α4-1BB. See Table 6 and Fig. 2A.
The `630 publication teaches that 41BB, which is a co-stimulation factor exerting agonist activity [0067] [0068].
Claims 11 and 14-15 are included because the claimed functional properties of the multispecific antibody is considered inherent property of the referenced multispecific antibody in the absence of evidence to the contrary.
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Fig. 2A shows that both the αCD3 and αEGFRvII are located N-terminal to the Fc fragment and α4-1BB located to the C-terminal of the Fc fragment. It is noted that both αCD3 and αTAA (EGFRvIII) are located on the same side of the Fc region (CH2) (i.e., at the N-terminus) and the α4-1BB is on the other side of the Fc region (CH3) (i.e., at the C-terminus).
The reference teachings anticipate the claimed invention.
18. Claims 1-6, 11, 14-15 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by US 20200048350.
The `350 publication teaches and claims the multispecific constructs were generated as shown in FIG. 31A, to contain a heterodimeric Fc region of an immunoglobulin coupled by a linker (e.g. a non-cleavable linker) to the CD3 binding region, a 4-1BB antigen binding domain (e.g. sdAb) as a CRBR positioned carboxy-terminally relative to the CD3 binding region, and dual antigen binding domains that bind the B7H3 tumor associated antigen (TAA) positioned amino-terminally relative to the Fc region and carboxy-terminally relative to the CD3 binding region of the multispecific polypeptide construct (see [0861-[0863], [0097], [0098] and published claims). See Fig. 31A below. Further, the `350 publication teaches a representative DLL3-targeted constrained CD3 engagers without a 41BB binding domain, cx5499 (FIG. 32A), and with a 41BB binding domain, cx5352 (FIG. 32B). cx5499 and cx5352 have a DLL3-targeting sdAb positioned at the N-terminus of one chain of the heterodimer and at the C-terminus of the same chain of the heterodimer [0099] FIG. 32, [0873] .
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FIG . 6A - 6C depicts the capacity to mediate target antigen specific agonism of a costimulatory receptor ( 41BB or OX40 ) by representative B7H3 - targeted constrained CD3 engaging constructs [0068].
The reference teachings anticipate the claimed invention.
19. Claims 1-4, 6, 11, 14-15 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by US 20210301016
The `016 publication provides multispecific antigen-binding molecules capable of binding to CD3 and CD137 (4-1BB) but not binding to CD3 and CD137 at the same time, and capable of binding to DLL3. The antigen-binding molecules of the present invention exhibit enhanced T-cell dependent cytotoxity activity in a DLL3-dependent manner through binding to the CD3/CD137 and DLL3 [0030] [0509], [0622] [0870].
The `016 publication provides multispecific antigen binding molecule which is a trispecific antigen binding molecule, i.e. it is capable of specifically binding to three different antigens—capable of binding to either one of CD3 or CD137 but does not bind to both antigens simultaneously, and is capable of specifically binding to DLL3 [0579].
The `016 publication teaches the new antibody format is a trivalent tri-specific antibody with “1+2” format which comprises two monovalent Dual-Fabs each capable of binding to one CD3 or CD137 but not simultaneously (FvB and FvC of FIG. 1a ), and one monovalent DLL3-binding arm (FvA of FIG. 1a ), wherein one disulfide bond (“LINC”) is introduced/engineered between the two Dual-Fabs by introducing a cysteine substitution e.g. at the 191 position (S191C with Kabat numbering) of the CH1 domain of each of the two Dual-Fabs (FIG. 1(a) and Table 10-1) [0859].
The reference teachings anticipate the instant claims.
20. No claim is allowed.
21. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) US 20250011427 discloses the claimed anti-5T4/CD3/4-1BB antibody, CTM01-01.
(ii) Dahlman et al. Preclinical safety and efficacy of a tumor-directed T cell activating 4-1BB x 5T4 ADAPTIR™ bispecific antibody. Cancer Res (2019) 79 (13_Supplement): 2380. Abstract 2380.
(iii) Liu et al. Tumor-antigen 5T4-dependent Activation of the CD137 Costimulatory Pathway by Bispecific 5T4 x CD137 TRIDENT™ Molecules. Presented at the American Association for Cancer Research Annual Meeting 2019, March 29–April 3, 2019, Atlanta, GA.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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October 8, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
