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 .
1. The Election filed March 23, 2026, in response to the Office Action of December 22, 2025, is acknowledged and has been entered. Applicants elected without traverse Group I and the species of:
A. second antibody that binds to PD-1, comprises Ly516 sequences (VH and VL SEQ ID NOs:3 and 4); and
B. antibody format comprising two polypeptides: a first antibody moiety that binds to human CD137 is a scFv; a second moiety that binds to PD-1 comprising a first polypeptide comprising an antibody heavy chain and a second polypeptide comprising an antibody light chain, and wherein the scFv is fused to either the first polypeptide or second polypeptide (claims 2-4).
Claims 1-4, 6, 8-10, 12, 13, 15, 16, 18, 19, 21, 22, 24-26, 40, 42, 44-46 are pending. Claim 26 has been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 6, 8, 13, 15, 16, 18, 19, 21, 22, 24 are withdrawn as being drawn to non-elected species. Claims 1-4, 9, 10, 12, 25, 40, 42, 44, 45, and 46 are currently under prosecution as drawn to the elected species.
It is noted that the instant specification defines the CDR, VH and VL sequences of PD-1 antibody Ly516 and CD137 antibody Ly1630 in Example 1 ([213]).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
2. Claim 42 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 42 recites “A host cell comprising the nucleic acid or nucleic acid set of claim 40”. The instant specification discloses that a “host cell” encompasses a mammalian host cell ([22]), and mammals are preferably human ([174]). Therefore, claim 42 encompasses transformed humans.
Examiner Suggestion: Amend claim 42 to recite “An isolated host cell”.
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.
3. Claims 3, 9, 11, 25, 40, 42, 44, 45 and 46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation “the other antibody moiety”. There is insufficient antecedent basis for this limitation in the claim. No previous antibody was identified as “the other antibody moiety”.
Claim 9 recites: “The bi-specific antibody of claim 1, wherein the first antibody moiety that binds human CD137 has the same heavy chain and light chain CDRs as reference antibody L1630, optionally wherein the first antibody moiety that binds human CD137 has the same VH and/or VL as reference antibody Ly1630.” A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 requires the CD137 antibody to comprise the same heavy and light chain CDRs as reference antibody Ly1630, however, the claim also recites the antibody can optionally comprise the same VH or VL as reference antibody Ly1630, which requires only one CDR set from the heavy or light chain of reference antibody Ly1630, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. It is unclear what CDRs are required in the CD137 antibody claimed.
Claim 11 recites the limitation: “the bi-specific antibody of claim 11”. Claim 11 is canceled, therefore there is insufficient antecedent basis for this limitation in the claim.
Claim 25 recites “The antibody of claim 1, which is any of the bi-specific antibodies set forth in any one of Examples 1-5”. There is insufficient antecedent basis for this limitation in the claim because it is unclear what Examples and antibodies the claim is referring to.
Claim 40 recites: “A nucleic acid or a nucleic acid set, which collectively encodes an antibody of claim 1”. The claim is unclear with regards to what “an antibody” is being referenced because claim 1 recites a bi-specific antibody, a first antibody moiety, and a second antibody moiety. Clarification is required. Claims 42 and 44 are rejected for encompassing the rejected limitation of claim 40.
Claim 45 recites a pharmaceutical composition comprising an antibody or bispecific antibody set forth in claim 1” Claim 45 is unclear with regard to what “an antibody” is being referenced. There is insufficient antecedent basis for this limitation in the claim because claim 1 recites first and second antibody moieties. Further, claim 45 recites “or a nucleic acid(s) encoding such”. Claim 45 is unclear with regards to what “such” is that the nucleic acid(s) are encoding. There is insufficient antecedent basis for this limitation in the claim.
Claim 46 recites: “the antibody of claim 1” and “pharmaceutical composition comprising the antibody”. Claim 46 is unclear with regard to what antibody of claim 1 is being referenced. Claim 1 recites a bi-specific antibody, a first antibody moiety, and a second antibody moiety. Clarification is required. Claim 46 also recites: “a nucleic acid(s) encoding such”. Claim 46 is unclear with regards to what “such” is that the nucleic acid(s) are encoding. There is insufficient antecedent basis for this limitation in the claim.
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.
4. Claims 1-4, 9, 10, 25, 40, 42, 44, 45, and 46 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn a bi-specific antibody comprising:
(a) a first antibody moiety that binds to human CD137; and
(b) a second antibody moiety that binds to PD-1.
No antibody moiety sequence structure is recited for the PD-1 or CD137 binding function. The claims are drawn to a vast genus of bispecific antibodies having unknown sequences that are critical to the CD137 and PD-1 binding function.
Dependent claim 46 requires the antibody function to modulate immune responses, however, no antibody sequence structure is recited.
Dependent claim 9 recites partial sequence structure, wherein the CD137 antibody moiety can have one or both sets of CDRs or VH/VL domains from Ly1630. However, the CD137 antibody is not required to have the full set of six CDR sequences critical to the CD137-binding function. Claim 9 also does not define the sequence structure of the PD-1 antibody moiety.
Dependent claim 12 recites partial sequence structure, wherein the PD-1 antibody moiety can have one or both sets of CDRs or VH/VL domains as Ly516. However, the PD-1 antibody is not required to have the full set of six CDR sequences critical to the PD-1-binding function. Claim 12 also does not define the sequence structure of the CD137 antibody moiety.
Thus, the claims identify the bispecific antibody by function only, or by function with partial sequence, where the function is to bind PD-1 and human CD137, as well as modulate immune responses in a subject.
The instant specification discloses only CD137 antibody 1630 comprising VH and VL SEQ ID NOs:1 and 2, and PD-1 antibody Ly516 comprising VH and VL SEQ ID NOs:3 and 4 (Example 1). The instant specification discloses the anti-PD-1/CD137 bispecific antibodies utilizing the disclosed sequences successfully inhibited tumor growth between than a single anti-PD-1 antibody pembrolizumab (Example 1).
Thus, the instant specification describes a single antibody Ly1630 that binds CD137 and two anti-PD-1 antibodies Ly615 and pembrolizumab (KEYTRUDA®) that bind PD-1 as claimed. The specification fails to disclose the structural sequence required of any other anti-CD137 or anti-PD-1 antibody to function as claimed. The specification fails to disclose the structural sequence required for anti-CD137 or anti-PD-1 antibody comprising only one set of three defined CDRs from either the heavy or light chain to function as claimed.
To provide adequate written description and evidence of possession of the claimed bispecific antibody genus and methods, the instant specification can structurally describe representative bispecific antibodies that function to bind CD137 and PD-1, as well as modulate immune responses in a subject, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the bispecific antibody function: binds human CD137, binds PD-1, modulates immune responses in a subject. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only one bispecific antibody species comprising the VH and VL sequences from both Ly1630 and Ly516 that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for Ly1630 and Ly516, the specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequences for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
With regards to partial sequence structure, the specification does not disclose any exemplary alternative CDR or VH or VL sequence variants that function in concert with each other to bind CD137 and PD-1, other than SEQ ID NOs:1 with 2 for anti-CD137, SEQ ID NOs:3 with 4 for anti-PD-1. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain CD137 and PD-1 binding function and modulate immune responses as required by the claims. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single anti-CD137 antibody Ly1630 and single anti-PD-1 antibody Ly516 to the structure of any and all anti-CD137 and anti-PD-1 antibodies, as broadly claimed. Therefore, one could not readily envision members of the broadly claimed bispecific antibody genus and those required to practice the claimed invention.
Although Applicants may argue that it is possible to screen for antibodies that bind human CD137 and PD-1 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The human CD137 and PD-1 antigens provide no information about the structure of an antibody that binds to them.
Given the lack of representative examples to support the full scope of the claimed bispecific antibodies, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs that provide CD137 or PD-1 binding function and modulate immune responses, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of bispecific antibodies that bind human CD137 and PD-1 that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 1 to recite and require, at minimum, the six heavy and light chain CDR sequences of both the first anti-CD137 antibody moiety and the second anti-PD-1 antibody moiety that are critical to performing the claimed functions.
Claim Rejections - 35 USC § 102
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.
5. Claim(s) 1, 40, 42, and 44-46 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/229844, Enever et al, claiming priority to May 2019.
Enever teaches a bispecific antibody comprising:
(a) a first antibody moiety that binds to human CD137 and is an agonist; and
(b) a second antibody moiety that binds to PD-1 and is inhibitory (see entire document; p. 6, lines 5-9; p. 11, lines 29-35; p. 19, lines 1-5; claims).
Enever further teaches a nucleic acid encoding the bispecific antibody (p. 6, lines 17-18);
a host cell comprising the nucleic acid (p. 6, lines 20-21; claims);
a method for producing the antibody by culturing the host cell to express the antibody and harvesting the antibody (p. 6, lines 22-24; Examples; claims);
pharmaceutical compositions comprising the bispecific antibody and a pharmaceutically acceptable carrier (p. 6, lines 10-11; p. 83, line 23 to p. 84; claims); and
methods for modulating immune responses comprising administering the bispecific antibody to a subject in need thereof and treating cancer (p. 6, lines 12-16; p. 20, line 13 to p. 21, line 9; p. 86-89; claims)
Enever teaches the advantage of targeting both CD137 and PD-1 is to target tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, in order to simultaneously and independently lead to CD137 agonism or PD-1 downstream signaling inhibition, and induce T lymphocyte activation and/or proliferation (p. 18, lines 21-30; p. 20, line 13 to p. 21, line 9; p. 89, lines 1-13; p. 90, lines 1-23).
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.
6. Claim(s) 1-4, 40, 42, 44, 45, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2023/0124669, Luo et al, claiming priority to January 23, 2020; in view of WO 2017/136820, Wu, published August 2017; and WO 2020/229844, Enever et al, claiming priority to May 2019.
Luo suggests a bispecific antibody comprising:
(a) a first target binding moiety (TBM) binding to immune checkpoint molecule PD-1 that is inhibitory ([215-216]); and
(b) a second TBM antibody that binds to immune checkpoint molecule human CD137 (4-1BB) that is an agonist ([197]; [215-216]; Table C; Figure 2; [223]).
Luo teaches the bispecific antibody can comprise an IgG-scFv format, wherein the first TBM antibody is a full-length IgG antibody comprising first and second light chains and heavy chains ([18-22]; [217]; [219-220]), and the second TBM antibody is an scFv fused to the C-terminus of the first antibody first and/or second heavy chains (see Figure 2 below).
Luo further teaches the CD137 antibody is an scFv and provides exemplary scFv sequences (Table C; Figure 2; [223]). Luo exemplifies making an IgG-scFv comprising PD-L1xCD137 bispecific antibody (Table C; Example 5; Figure 2). Figure 2:
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Luo further teaches nucleic acids encoding the bispecific antibody ([50]; [441-444]);
a host cell comprising the nucleic acid ([50]; [112-113]; [441-448]);
a method for producing the antibody by culturing the host cell to express the antibody and harvesting the antibody ([50]; [441-448]);
pharmaceutical compositions comprising the bispecific antibody and a pharmaceutically acceptable carrier ([51]; [451-456]); and
methods for modulating immune responses comprising administering the bispecific antibody to a subject in need thereof and treating cancer ([52]; [458-466]).
Luo teaches the antibody functions to enhance immune responses of T lymphocytes ([462]).
Luo suggests making a bispecific antibody utilizing TBMs binding immune checkpoint molecules including PD-1 and CD137, but does not teach specifically selecting PD-1 and CD137 to produce the bispecific antibody.
Wu teaches making bispecific antibodies that target immune checkpoint molecules (Figures 1 and 2; [16-18]); and specifically suggests the antibodies target the pair CD137 and PD-1 ([28]).
Enever teaches making bispecific antibodies that simultaneously target immune checkpoint molecules PD-1 and CD137, wherein the PD-1 antibody is antagonistic and the CD137 antibody is agonistic, as set forth above. Enever further teaches the advantage of targeting both CD137 and PD-1 is to target activated tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, in order to simultaneously and independently lead to CD137 agonism or PD-1 downstream signaling inhibition, and induce T lymphocyte activation and/or proliferation (p. 18, lines 21-30; p. 20, line 13 to p. 21, line 9; p. 89, lines 1-13; p. 90, lines 1-23).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to formulate the bispecific antibody of Luo as a PD-1 x CD137 antibody. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Luo suggests their bispecific antibody targets two immune checkpoint molecules including PD-1 and CD137, and function to antagonize PD-1 and agonize CD137, and stimulate T lymphocytes for cancer treatment; (2) Luo demonstrates successfully making a PDL1 x CD137 IgG-scFv antibody; (3) both Wu and Enever specifically suggest pairing PD-1 and CD137 together for bispecific targeting; and (4) Enever teaches the advantage of targeting both CD137 and PD-1 is to target activated tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, in order to simultaneously and independently lead to CD137 agonism or PD-1 downstream signaling inhibition, and induce T lymphocyte activation and/or proliferation, achieving the functions taught by Luo.
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.
7. Claims 1-4, 9, 10, 12, 25, 40, 42, 44, 45, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7, 8, 12-14, 19, 21, 26, 28, 43, 53-57, 59, 61, 63, 64, and 65 of copending Application No. 18/730,415 (reference application), in view of US Patent Application Publication 2023/0124669, Luo et al, claiming priority to January 23, 2020. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application claims a multi-specific antibody that is bispecific, targeting PD-1 and CD137, rendering obvious the instantly claimed bispecific CD137 x PD-1 antibody.
With regards to rendering obvious instant claims 1, 40, 42, 44, 45, and 4, the copending application claims:
a multi-specific antibody that comprises:
(a) a first antibody moiety that binds to CD137; and
(b) a second antibody moiety that binds to PD-1;
nucleic acids encoding the multi-specific antibody;
a host cell comprising the nucleic acid;
a method for producing the antibody by culturing the host cell to express the antibody and harvesting the antibody;
pharmaceutical compositions comprising the multi-specific antibody and a pharmaceutically acceptable carrier; and
methods for modulating immune responses comprising administering the multi-specific antibody to a subject in need thereof and treating cancer.
With regards to rendering obvious instant claims 9, 10, 12, and 25 the copending application further claims the multi-specific antibody comprises sequences listed in Table 1 (claim 57). Table 1 discloses the VH and VL sequences for PD-1 antibody Ly516 (SEQ ID NOs:58 and 59) and the VH and VL sequences for CD137 antibody Ly1630 (SEQ ID NOs:54 and 55), thereby rendering obvious utilizing Ly516 and Ly1630 antibody sequences in the multi-specific antibody.
With regards to rendering obvious instant claims 2-4, the copending application does not claim an IgG-scFv format where the CD137 antibody is the scFv and the IgG is the PD-1 antibody, however, Luo remedies this deficiency.
Luo teaches and exemplifies the IgG-scFv multi-specific antibody format utilizing a CD137 scFv antibody, used for modulating immune responses in a subject, as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the bispecific IgG-scFv format of Luo for the antibody of the copending application. One would have been motivated to, and have a reasonable expectation of success to, because Luo teaches in detail how to construct an IgG-scFv utilizing anti-CD137 scFv and full-length immune checkpoint inhibitor antibody and for the same purpose claimed by the copending application to modulate immune responses in a subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
8. Conclusion: No claim is allowed. Additional prior art made of record but not currently relied upon is WO 2021/081303, Wu and Wang, claiming priority to October 23, 2020 and October 23, 2019, having a different Applicant/Assignee than the instant spplication. Wu and Wang teach a bispecific antibody comprising:
(a) a first antibody moiety that binds to human CD40; and
(b) a second antibody moiety that binds to PD-1 and comprises the heavy and light chain sequences of Ly516 comprising VH SEQ ID NO:231 that comprises 100% of instant SEQ ID NO:3, and VL SEQ ID NO:228 that comprises 100% of instant SEQ ID NO:4 (see sequence alignments below).
Wu and Wang do not teach or suggest that the bispecific antibody binds to human CD137 and do not disclose anti-CD137 antibody Ly1630 comprising instant VH and VL SEQ ID NOs:1 and 2, therefore do not teach or suggest the instant invention.
Instant anti-PD-1 Ly516 antibody VH SEQ ID NO:3 aligned with Wu and Wang SEQ ID NO:231:
RESULT 8
BJG36914
ID BJG36914 standard; protein; 450 AA.
XX
AC BJG36914;
XX
DT 10-JUN-2021 (first entry)
XX
DE Anti-PD-1 antibody (Ly516) heavy chain with IgG1 mutant Fc, SEQ 231.
XX
KW CD279; PD-1 protein; antibody; antibody production; antibody therapy;
KW autoimmune disease; cancer; cytostatic; diagnostic test; heavy chain;
KW immune disorder; immune modulation; immuno-diagnosis;
KW immunoglobulin gamma 1; immunomodulator; mutein;
KW programmed cell death protein 1; prophylactic to disease; therapeutic.
XX
OS Mus sp.
OS Synthetic.
XX
CC PN WO2021081303-A1.
XX
CC PD 29-APR-2021.
XX
CC PF 23-OCT-2020; 2020WO-US057019.
XX
PR 23-OCT-2019; 2019WO-CN112809.
XX
CC PA (LYVG-) LYVGEN BIOPHARMA SUZHOU CO LTD.
CC PA (LYVG-) LYVGEN BIOPHARMA CO LTD.
CC PA (WANG/) WANG J.
XX
CC PI Wang J, Wu Y;
XX
DR WPI; 2021-425202/040.
XX
CC PT Humanized antibody specific to human CD40 comprises a heavy chain
CC PT variable region (VH) and a light chain variable region (VL), where the VH
CC PT comprises a framework and heavy chain complementary determining regions.
XX
CC PS Example 8; SEQ ID NO 231; 306pp; English.
XX
CC The present invention relates to a humanized antibody, which is useful
CC for treating cancer or an immune disorder such as autoimmune diseases.
CC The antibody specifically binds to a human CD40 and comprises a heavy
CC chain variable region (VH) of SEQ ID NO: 10-14 (see BJG36693-BJG36697),
CC light chain variable region (VL) of SEQ ID NO: 15 (see BJG36698),
CC framework region (FR), heavy and light chain constant regions and
CC complementarity determining region (CDR) of SEQ ID NO: 1-9 and 16-21 (see
CC BJG36684-BJG36692 and BJG36699-BJG36704). The invention further claims:
CC (1) an isolated anti-PD-L1 antibody; (2) an isolated anti-B7H3 antibody
CC and anti-B7H4 antibody; (3) a bispecific antibody; (4) a nucleic acid or
CC a nucleic acid set encoding the antibody; (5) a host cell comprising the
CC nucleic acid; (6) a method for producing the antibody; (7) a
CC pharmaceutical composition comprising the antibody and a pharmaceutically
CC acceptable carrier; and (8) a method for modulating an immune response,
CC which involves administering to the subject an effective amount of the
CC antibody. The antibody of the invention is useful for diagnosing,
CC treating and preventing cancer and autoimmune disorder.
XX
SQ Sequence 450 AA;
Query Match 100.0%; Score 654; Length 450;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGTCVSWIRQPPGKALEWLATICWEDSKG 60 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGTCVSWIRQPPGKALEWLATICWEDSKG 60
Qy 61 YNPSLKSRLTISKDTSKNQAVLTMTNMDPVDTATYYCARREDSGYFWFPYWGQGTLVTVS120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YNPSLKSRLTISKDTSKNQAVLTMTNMDPVDTATYYCARREDSGYFWFPYWGQGTLVTVS120
Qy 121 S 121
|
Db 121 S 121
Instant anti-PD-1 Ly516 antibody VL SEQ ID NO:4 aligned with Wu and Wang SEQ ID NO:228:
RESULT 2
BJG36911
ID BJG36911 standard; protein; 213 AA.
XX
AC BJG36911;
XX
DT 10-JUN-2021 (first entry)
XX
DE Anti-PD-1 antibody (Ly516) light chain, SEQ 228.
XX
KW CD279; PD-1 protein; antibody; antibody production; antibody therapy;
KW autoimmune disease; cancer; cytostatic; diagnostic test; immune disorder;
KW immune modulation; immuno-diagnosis; immunomodulator; light chain;
KW programmed cell death protein 1; prophylactic to disease; therapeutic.
XX
OS Mus sp.
XX
CC PN WO2021081303-A1.
XX
CC PD 29-APR-2021.
XX
CC PF 23-OCT-2020; 2020WO-US057019.
XX
PR 23-OCT-2019; 2019WO-CN112809.
XX
CC PA (LYVG-) LYVGEN BIOPHARMA SUZHOU CO LTD.
CC PA (LYVG-) LYVGEN BIOPHARMA CO LTD.
CC PA (WANG/) WANG J.
XX
CC PI Wang J, Wu Y;
XX
DR WPI; 2021-425202/040.
XX
CC PT Humanized antibody specific to human CD40 comprises a heavy chain
CC PT variable region (VH) and a light chain variable region (VL), where the VH
CC PT comprises a framework and heavy chain complementary determining regions.
XX
CC PS Example 8; SEQ ID NO 228; 306pp; English.
XX
CC The present invention relates to a humanized antibody, which is useful
CC for treating cancer or an immune disorder such as autoimmune diseases.
CC The antibody specifically binds to a human CD40 and comprises a heavy
CC chain variable region (VH) of SEQ ID NO: 10-14 (see BJG36693-BJG36697),
CC light chain variable region (VL) of SEQ ID NO: 15 (see BJG36698),
CC framework region (FR), heavy and light chain constant regions and
CC complementarity determining region (CDR) of SEQ ID NO: 1-9 and 16-21 (see
CC BJG36684-BJG36692 and BJG36699-BJG36704). The invention further claims:
CC (1) an isolated anti-PD-L1 antibody; (2) an isolated anti-B7H3 antibody
CC and anti-B7H4 antibody; (3) a bispecific antibody; (4) a nucleic acid or
CC a nucleic acid set encoding the antibody; (5) a host cell comprising the
CC nucleic acid; (6) a method for producing the antibody; (7) a
CC pharmaceutical composition comprising the antibody and a pharmaceutically
CC acceptable carrier; and (8) a method for modulating an immune response,
CC which involves administering to the subject an effective amount of the
CC antibody. The antibody of the invention is useful for diagnosing,
CC treating and preventing cancer and autoimmune disorder.
XX
SQ Sequence 213 AA;
Query Match 100.0%; Score 561; Length 213;
Best Local Similarity 100.0%;
Matches 106; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 NIQMTQSPSSLSASVGDRVTITCKAGQNVNNYLAWYQQKPGKAPKVLIFNANSLQTGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 NIQMTQSPSSLSASVGDRVTITCKAGQNVNNYLAWYQQKPGKAPKVLIFNANSLQTGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSWPTFGGGTKVEIK 106
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSWPTFGGGTKVEIK 106
Additional prior art made of record but not relied upon is WO 2017/087599. WO 2017/087599 discloses anti-PD-1 antibody comprising a VH SEQ ID NO:9 that is 100% identical to instant SEQ ID NO:3 of Ly516, and VL SEQ ID NO:7 that is 98.6% identical to instant SEQ ID NO:4 of Ly516. However, WO 2017/087599 does not disclose bispecific antibodies binding to CD137 and PD-1.
Additional prior art made of record but not relied upon is WO 2020231809, Wang & Wu, claiming priority to May 2019, and having a different Applicant than the instant application. WO 2020231809 teaches anti-CD137 antibody comprising VH SEQ ID NO:3 and VL SEQ ID NO:5 that comprise 100% of instant Ly1630 SEQ ID NOs:1 and 2, respectively. WO 2020231809 does not teach or suggest a bispecific antibody binding to CD137 and PD-1.
Instant anti-CD137 Ly1630 VH SEQ ID NO:1 aligned with WO 2020231809 SEQ ID NO:3:
RESULT 1
BIQ48281
ID BIQ48281 standard; protein; 116 AA.
XX
AC BIQ48281;
XX
DT 07-JAN-2021 (first entry)
XX
DE Anti-CD137 humanized antibody VH region (LYV371_VH-1), SEQ ID 3.
XX
KW 4-1BB; CD137; CDw137; TNFRSF9; antibody production; antibody therapy;
KW autoimmune disease; cancer; celiac disease; colon tumor; cytostatic;
KW graft versus host disease; heavy chain variable region;
KW humanized antibody; immune disorder; immune stimulation; immunomodulator;
KW immunosuppressive; infectious disease; insulin dependent diabetes;
KW melanoma; multiple sclerosis; prognosis; prophylactic to disease;
KW prostate tumor; rheumatoid arthritis; systemic lupus erythematosus;
KW therapeutic; tumor necrosis factor receptor subfamily 9.
XX
OS Mus sp.
OS Homo sapiens.
OS Chimeric.
XX
FH Key Location/Qualifiers
FT Region 26..35
FT /label= CDR1
FT Region 50..66
FT /label= CDR2
FT Region 99..105
FT /label= CDR3
XX
CC PN WO2020231809-A1.
XX
CC PD 19-NOV-2020.
XX
CC PF 08-MAY-2020; 2020WO-US032095.
XX
PR 10-MAY-2019; 2019WO-CN086364.
XX
CC PA (LYVG-) LYVGEN BIOPHARMA CO LTD.
CC PA (LYVG-) LYVGEN BIOPHARMA SUZHOU.
CC PA (WANG/) WANG J.
XX
CC PI Wang J, Wu Y;
XX
DR WPI; 2020-B4921E/099.
XX
CC PT Humanized antibody used in pharmaceutical composition for modulating
CC PT immune responses in a subject suspected of having, or at risk for cancer,
CC PT immune disorder and/or infection, is one that binds to cluster of
CC PT differentiation-137.
XX
CC PS Claim 8; SEQ ID NO 3; 104pp; English.
XX
CC The present invention relates to a novel humanized antibody used in a
CC pharmaceutical composition for modulating immune responses in a subject.
CC The humanized antibody specifically binds to CD137 (4-1BB, tumor necrosis
CC factor receptor subfamily 9 or TNFRSF9) and the subject is suspected of
CC having or at risk for cancer, immune disorder and/or infection. The
CC invention further provides: an isolated nucleic acid encoding the
CC humanized anti-CD137 antibody; a host cell comprising the isolated
CC nucleic acid; the pharmaceutical composition comprising the humanized
CC anti-CD 137 antibody and a pharmaceutically acceptable carrier; a method
CC for modulating the immune responses in the subject by administering an
CC effective amount of the pharmaceutical composition; a method for
CC producing the humanized anti-CD137 antibody; and a method for treating
CC cancer (prostate cancer, colon cancer and melanoma) and immune disorders
CC (i.e., autoimmune disease such as rheumatoid arthritis (RA), systemic
CC lupus erythematosus (SLE), Type I diabetes, multiple sclerosis, celiac
CC disease and graft-versus- host (GVH) disease). Note: This sequence is a
CC parent of the mutant sequences shown as SEQ ID NO: 8-9 (see BIQ48286-
CC BIQ48287).
XX
SQ Sequence 116 AA;
Query Match 100.0%; Score 614; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFAGFEMHWVRQAPGQGLEWMGAIDPKTGGTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFAGFEMHWVRQAPGQGLEWMGAIDPKTGGTDY 60
Qy 61 NQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDLGYFDVWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDLGYFDVWGQGTLVTVSS 116
Instant anti-CD137 Ly1630 VL SEQ ID NO:2 aligned with WO 2020231809 SEQ ID NO:5:
RESULT 2
BIQ48283
ID BIQ48283 standard; protein; 108 AA.
XX
AC BIQ48283;
XX
DT 07-JAN-2021 (first entry)
XX
DE Anti-CD137 humanized antibody VL region (LYV371_VL-2), SEQ ID 5.
XX
KW 4-1BB; CD137; CDw137; TNFRSF9; antibody production; antibody therapy;
KW autoimmune disease; cancer; celiac disease; colon tumor; cytostatic;
KW graft versus host disease; humanized antibody; immune disorder;
KW immune stimulation; immunomodulator; immunosuppressive;
KW infectious disease; insulin dependent diabetes;
KW light chain variable region; melanoma; multiple sclerosis; mutein;
KW prognosis; prophylactic to disease; prostate tumor; rheumatoid arthritis;
KW systemic lupus erythematosus; therapeutic;
KW tumor necrosis factor receptor subfamily 9.
XX
OS Mus sp.
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 24..34
FT /label= CDR1
FT Region 50..56
FT /label= CDR2
FT Region 89..97
FT /label= CDR3
XX
CC PN WO2020231809-A1.
XX
CC PD 19-NOV-2020.
XX
CC PF 08-MAY-2020; 2020WO-US032095.
XX
PR 10-MAY-2019; 2019WO-CN086364.
XX
CC PA (LYVG-) LYVGEN BIOPHARMA CO LTD.
CC PA (LYVG-) LYVGEN BIOPHARMA SUZHOU.
CC PA (WANG/) WANG J.
XX
CC PI Wang J, Wu Y;
XX
DR WPI; 2020-B4921E/099.
XX
CC PT Humanized antibody used in pharmaceutical composition for modulating
CC PT immune responses in a subject suspected of having, or at risk for cancer,
CC PT immune disorder and/or infection, is one that binds to cluster of
CC PT differentiation-137.
XX
CC PS Claim 8; SEQ ID NO 5; 104pp; English.
XX
CC The present invention relates to a novel humanized antibody used in a
CC pharmaceutical composition for modulating immune responses in a subject.
CC The humanized antibody specifically binds to CD137 (4-1BB, tumor necrosis
CC factor receptor subfamily 9 or TNFRSF9) and the subject is suspected of
CC having or at risk for cancer, immune disorder and/or infection. The
CC invention further provides: an isolated nucleic acid encoding the
CC humanized anti-CD137 antibody; a host cell comprising the isolated
CC nucleic acid; the pharmaceutical composition comprising the humanized
CC anti-CD 137 antibody and a pharmaceutically acceptable carrier; a method
CC for modulating the immune responses in the subject by administering an
CC effective amount of the pharmaceutical composition; a method for
CC producing the humanized anti-CD137 antibody; and a method for treating
CC cancer (prostate cancer, colon cancer and melanoma) and immune disorders
CC (i.e., autoimmune disease such as rheumatoid arthritis (RA), systemic
CC lupus erythematosus (SLE), Type I diabetes, multiple sclerosis, celiac
CC disease and graft-versus- host (GVH) disease). The present seuqence
CC comprises (K42G/P44V/F71Y/Y87F) back mutations. Note: This sequence is a
CC mutant of the parent sequence shown in SEQ ID NO: 4 (see BIQ48282).
XX
SQ Sequence 108 AA;
Query Match 100.0%; Score 554; Length 108;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDIRSNLNWYQQKPGGAVKLLIYYTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDIRSNLNWYQQKPGGAVKLLIYYTSRLHSGVPS 60
Qy 61 RFSGSGSGTDYTLTISSLQPEDFATYFCQQSEKLPRTFGGGTKVEIR 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYTLTISSLQPEDFATYFCQQSEKLPRTFGGGTKVEIR 107
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Laura B Goddard/Primary Examiner, Art Unit 1642
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