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. This is a Track I prioritized examination application. The Election filed June 24, 2026, in response to the Office Action of May 6, 2026, is acknowledged and has been entered. Applicants elected without traverse Group I and the species of:
IL-2 Polypeptide SEQ ID NO:754 that comprises a deletion of amino acids 74-83 within SEQ ID NO:701 and the insertion of peptide GDGSIN (SEQ ID NO:700) in their place;
IL-2 Polypeptide comprising the mutations: T3A, E15D, N88D, and C125;
First binding domain targeting PD-1 comprising:
VH CDR1: NYYMY (SEQ ID NO: 80)
VH CDR2: GINPSNGGTNFNEKFKN (SEQ ID NO: 81)
VH CDR3: RDYRFDMGFDY (SEQ ID NO: 82)
VL CDR1: RASKGVSTSGYSYLH (SEQ ID NO: 83)
VL CDR2: LASYLES (SEQ ID NO: 84)
VL CDR3: QHSRDLPLT (SEQ ID NO: 85);
VH domain of amino acids 1-120 of SEQ ID NO:46 from Table 1A, which is a sequence that shares at least 98.33% identity to instant SEQ ID NO:48 (claim 14);
VL domain comprising SEQ ID NO:49;
Second binding domain targeting VEGFA comprising: VHH SEQ ID NO:221;
First, Second, and Third Polypeptide Chains comprising the elected species above:
SEQ ID NO:47 -first polypeptide chain (comprising SEQ ID NO:49 PD-1 targeting domain);
SEQ ID NOs: 163, 164, 169, 171, and 172 - second polypeptide chain that each comprise the species of VEGF VHH SEQ ID NO:221; and
SEQ ID NOs:802, 806, and 809 – third polypeptide chain that each comprise the elected IL-2 species of SEQ ID NO:754, encompassing (claim 24):
SEQ ID NOs: 47, 163, and 802;
SEQ ID NOs: 47, 164, and 806;
SEQ ID NOs: 47, 169, and 802;
SEQ ID NOs: 47, 172, and 802;
SEQ ID NOs: 47, 163, and 806;
SEQ ID NOs: 47, 169, and 806; and
SEQ ID NOs: 47, 171, and 809.
The species mutation L19D from claim 6 is rejoined for examination.
Claims 1-30 are pending. Claims 28-30 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 11, 12, 16, 17, 25, 26, and 27 are withdrawn as being drawn to non-elected species. Claims 1-10, 13-15, 19-24 are currently under prosecution as drawn to the elected and rejoined species.
Claim Objections
2. Claim 3 is objected to because of the following informalities: Claim 3 contains a typo where the Q is missing in “SEQ ID NO: 700”. Appropriate correction is required.
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 2 and 5-9 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 2 is indefinite in the use of the expression in parenthesis “(SEQ ID NO:701)” in that it is not clear whether this recitation is intended to be part of the claim or not. It is unclear if SEQ ID NO:701 is an exemplary species of possible wild-type IL-2 sequences, or if it required to be the wild-type IL-2 sequence used for identity purposes.
Examiner Suggestion: Remove the parenthesis in claim 2.
Claims 5-9 each recite the IL-2 polypeptide comprises a substitution at a specifically numbered amino acid residue. The claims are unclear as to what amino acid residue is being referenced because there is no previously recited sequence or SEQ ID NO containing the claimed amino acid positions. There is insufficient antecedent basis for these limitations in the claims.
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.
4. Claim(s) 1, 2, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0275353, Sheng et al, published September 2017; in view of Prodi et al (OncoTargets and Therapy, 17:697-715; August 28, 2024); Holcomb et al (Journal of Clinical Investigation, 2022, 132(3):e156628); and WO 2022/140797, Wu et al, published June 2022.
Sheng teaches a multispecific antibody comprising:
a) a first binding domain targeting PD-1; and
b) a second binding domain targeting VEGF (abstract; [6-22]; [91-121]; [128-135]; Examples; Figures 7-11).
Figure 10 demonstrates one exemplary bispecific antibody with anti-PD-1 scFv fused to the C-terminus of the heavy chain of the VEGF IgG antibody, or vice versa; wherein the antibody comprises a first polypeptide chain comprising the VL of anti-PD-1 antibody, a second polypeptide chain comprising the VH of the anti-PD-1 antibody, and a third polypeptide chain comprising a third binding moiety; wherein the second polypeptide chain comprises in N-terminal to C-terminal direction, the VH of the Fab, an antibody constant region, and a second binding domain that is an scFv (Figure 10):
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Sheng teaches multispecific antibody functions to target and treat cancer, block PD-1/PD-L1 interaction, restore anti-cancer T cell function, block VEGF/VEGFR2 interaction, and inhibit angiogenesis ([183-197]; Examples 2, 6, 9). The multispecific antibody simultaneously reduces angiogenesis in tumor tissue and enhances antitumor immunity ([6]).
Sheng teaches the targeting domains of the multispecific antibody can be in the form of single domain antibody (sdAb, VHH), or Fab fragment ([8]; [92]; claim 1-2).
Sheng suggests their multispecific antibody can be formatted as a non-IgG fusion protein, such as an immunocytokine ([76]).
Sheng does not teach:
the multispecific antibody is covalently linked to an IL-2 cytokine (claim 1),
the IL-2 comprises an amino acid sequence at least 80 – 100% identical to wildtype IL-2 instant SEQ ID NO:701 (claim 2);
the VEGF binding domain, specifically, is a single domain antibody or VHH (claim 22);
the arrangement of three polypeptide chains as recited in instant claims 21-23.
Prodi teaches motivation to attach IL-2 to antibodies (immunocytokines), especially anti-PD-1 antibodies. Prodi teaches IL-2 enhances immune surveillance and boosts anti-tumor responses by stimulating T cells and natural killer (NK) cells. IL-2 marks a significant chapter in the history of cancer immunotherapy. It promotes the proliferation and activation of T cells and NK cells (p. 697). Prodi teaches an FDA-approved recombinant IL-2 therapy (PROLEUKIN®) for treating cancer can provide durable and long-lasting antitumor responses in high-dose therapy, however, it can result in severe side effects or systemic toxicity, such as vascular leak syndrome and cytokine release syndrome (p. 698). Immunocytokines solve this problem by fusing the IL-2 to an antibody that targets IL-2 delivery to the tumor microenvironment. For proof-of-concept, a tumor-homing antibody-IL12 fusion was found to be substantially more active compared to its non-targeted IL-12 counterpart, achieving anti-cancer activity with a more than 20-fold dose reduction (p. 699, Figure 1). Prodi teaches cis-acting immunocytokines achieve therapeutic modulation by targeting the cytokine payload to the same immune cell which is recognized by the antibody it is attached to. While the cytokine payload may also affect neighboring cells “in trans”, the cis-acting immunocytokine will activate the cell targeted cells by the antibody component (Figure 2; p. 702-703). The cis-acting immunocytokine binds specific receptors on the T cell, boosts activity of tumor-reactive T cells, and directly engages T cells at the tumor site (Figure 2). An example of cis-acting immunocytokine is anti-PD-1 antibody fused to an IL2 variant “PD1-IL2v”. This immunocytokine facilitates simultaneous binding to PD-1 and the IL-2 receptor βγ chains on the same T cell. This dual engagement selectively bolsters the activity of tumor-reactive T cells expressing PD-1 while avoiding undesired stimulation of regulatory T cells (Tregs). Studies demonstrate that PD1-IL2v activated PD-1+ T cells and initiated robust tumor regression in a mouse tumor model. PD1-IL2v is being evaluated clinically to treat patients with advanced and/or metastatic solid tumors. Studies suggest the engagement of IL-2 receptor (IL-2Rα) is indispensable for optimizing the synergistic impact of combined PD-1 and IL-2v therapy (p. 703).
Prodi states again: Immunocytokines harness the targeting capabilities of antibodies to deliver cytokines directly to tumor sites, enhancing therapeutic efficacy while minimizing systemic toxicity (p. 703, last section).
Prodi reviews common antibody formats for producing immunocytokines including IgG and scFv-Fc (Figure 3). Antibody fragments can be genetically fused to various cytokines without compromising the payload’s bioactivity of the fragment’s targeting ability, allowing for a wide range of therapeutic applications and customization (p. 704). An advantage of the full-length IgG format containing an Fc region is the extended half-life of the IgG antibody in serum, prolonging circulatory half-life, extending their window of activity, and enhancing their therapeutic efficacy (p. 703, last section). Prodi teaches (p. 708):
The integration of immunocytokines with ICIs [immune checkpoint inhibitors], such as anti-PD1, can enhance immune activation by simultaneously stimulating effector T cells and relieving inhibitory checkpoints. This synergy can result in a more robust and sustained immune attack of tumor cells. Preclinical and clinical studies have shown that immunocytokines, by enhancing T cell infiltration and activation within the tumor microenvironment, can potentiate the efficacy of ICIs, leading to improved outcome.
Holcomb teaches an immunocytokine comprising PD-1 antibody covalently associated with, or fused to, IL-2 (Figure 1). Holcomb teaches PD-1 antibody covalently joined with IL-2 successfully enhanced anti-tumor T cell responses and without systemic toxicity. Fusion of IL-2 to antigen-specific antibodies allows for targeted delivery of IL-2 to cancer cells or effector T cells within the tumor (p. 2, col. 1). PD-1 is highly expressed on tumor-infiltrating CD8+ T cells that become functionally exhausted, and the immunocytokine targets the intratumoral CD8+ T cells, reducing systemic toxicity, reactivating the T cells, enhancing antitumor activity, and enhancing control of tumors (p. 2, col. 2-3).
Wu also teaches and exemplifies making immunocytokines including anti-PD-1 -IL2 variant fusion protein, wherein the IL-2 variant comprises mutations R38D/K43E/E61R compared to wild-type IL-2, and the IL-2 is positioned in the hinge region of the PD-1 antibody (Example 3; Figures 2-4). Wu suggests antibodies used in immunocytokine construction include multispecific or bispecific antibodies having more than one binding target ([64]; [92]; [120-125]; [128]; [265]), wherein the antibodies bind targets on the surface of tumor cells and/or immune cells including PD-1 ([266]; [270]; [280]; [281]; [398]). Wu teaches the IL-2 comprises mutations, compared to wild-type IL-2, that increase the cytokine’s activation of immune effector cells (e.g., CD8+ T cells for treating cancer) ([192-194]). Wu teaches it is known IL-2 is FDA approved to treat cancer ([198]). Wu teaches the known wild type sequence of IL-2 as SEQ ID NO:1 ([199]). The IL-2 variant can comprise one or more mutations selected from the group consisting of F24A, R38D, K43E, E61R, and P65L relative to a wildtype IL-2 comprising the sequence of SEQ ID NO: 1 that functions expand cytotoxic T cells, but with minimal expansion of Tregs compared to wild-type IL-2. The P65L mutation reduces systemic toxicity and has greater antitumor efficacy compared to wild-type IL-2 ([202]). IL-2 SEQ ID NO:1 is 100% identical to instant SEQ ID NO:701, therefore the IL-2 taught by Wu comprises an amino acid sequence having at least 80-100% sequence identity to instant SEQ ID NO:701 (see sequence alignment below).
Wu teaches the binding domains of the immunocytokine can comprise VHH and/or Fab ([47]; [51-53]; [67]; [70-73]; [119-122]; [234-236]; [249]; [252-255]; [263]; [265]).
With regards to claims 21 and 23, Wu teaches the immunocytokine comprises a Fab first binding domain and: a first polypeptide chain comprising the VL of a first binding domain, a second polypeptide chain comprising the VH of the first binding domain, and a third polypeptide chain comprising the IL-2 cytokine (Figures 1B, 2A, 2B, 2C, 3A, 3B, 3C; [119-122]; [128]; [234-236]; [249]; [252-255]; [265]; [307]);
wherein the third polypeptide chain comprises in N-terminal to C-terminal order, the IL-2 polypeptide and an antibody constant region (Figures 1B, 2A, 2B, 2C, 3A, 3B, 3C; [119-122]; [128]; [234-236]; [249]; [252-255]; [265]; [307]):
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Wu teaches that placing the cytokine in the hinge region of the antibody promoted antigen-antibody binding first, then cytokine-cytokine receptor binding second for effective targeting of cytokine (Example 3).
Wu teaches the immunocytokine functions to treat cancer ([399-400]). Immunocytokines function to target delivery of cytokines to tumor sites through the tumor-targeting antibody, which overcomes the side effects of cytokine therapy such as vascular leak syndrome, cytokine toxicity, and activation of Tregs ([4-5]). Placing the cytokine at the hinge region of the antibody enhances the safety profile and reduces side effects ([49-50]).
Instant SEQ ID NO:701 wild-type IL-2 aligned with Wu SEQ ID NO:1:
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce an immunocytokine from the multipecific antibody of Sheng and with IL-2 cytokine based on instant wild type IL-2 SEQ ID NO:701. One would have been motivated to, and have a reasonable expectation of success to because: (1) Shen suggests formatting their PD-1 x VEGF antibody as an immunocytokine IgG fusion protein and teaches administering their PD-1 x VEGF antibody to treat cancer by simultaneously targeting tumor-expressed VEGF and PD-1 expressed on tumor infiltrating immune cells to enhance anti-tumor immunity and treatment; (2) Prodi, Holcomb, and Wu teach and demonstrate therapeutic advantages for treating cancer by fusing IL-2 to tumor-targeting or immune cell-targeting antibodies, particularly anti-PD-1 antibodies; wherein the antibodies serve to target IL-2 delivery to the tumor microenvironment and immune cells, stimulate CD8+ T cells, enhance anti-tumor immune response, minimize Treg cell activation, and minimize toxicity associated with IL-2 therapy; (3) Prodi teaches the synergistic impact of combined PD-1 and IL-2 cancer therapy; and (4) Prodi and Wu teach and demonstrate the known and routine construction of immunocytokines, including multispecific immunocytokines, wherein Wu teaches the sequence of wild-type IL-2 for immunocytokine construction is known.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce three polypeptide chains as recited in instant claims 21-23, with the VHH second binding domain, to construct the multispecific immunocytokine of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sheng suggests known antibody fragments can be used for the different antigen binding domains in their multispecific antibody, including Fab and single domain antibodies(VHH), and exemplifies covalently attaching a second binding domain to the heavy chain (containing VH and antibody constant regions) of the first binding domain; (2) Prodi teaches antibody fragments can be genetically fused to various cytokines without compromising the payload’s bioactivity of the fragment’s targeting ability, allowing for a wide range of therapeutic applications and customization; (3) Shen and Wu teach the antigen binding domains of the multispecific antibody or immunocytokine can be Fab and/or VHH; (4) Wu teaches and suggests numerous combinations of three polypeptide chains to construct immunocytokines that include: i) a first polypeptide chain comprising a Fab VL; ii) a second polypeptide chain comprising from N- to C-terminal direction a Fab VH and constant region, and iii) a third polypeptide comprising from N- to C-terminal direction IL-2 fused to an antibody constant region; and (5) Shen demonstrates successfully constructing multispecific antibodies with the second antigen binding domain fused to the C-terminus of the heavy chain of the first binding domain comprising the VH and antibody constant region.
Given: (1) the cited prior art teaches known methods for constructing multispecific antibodies with Fab binding domains and VHH binding domains, wherein second binding domains are fused to the C-terminus of the heavy chain of the first binding domain comprising a Fab VH domain and constant domain, (2) the known methods for producing the three polypeptide chains to incorporate IL-2 cytokine into an antibody to produce an immunocytokine, (3) the advantages taught by Wu to attach the IL-2 to the hinge/constant region of the antibody, and the advantages taught by Prodi, Holcomb, and Wu to fuse IL-2 cytokine to anti-PD-1 antibodies for cancer therapy, it is well within the level of the ordinary skilled artisan to fuse IL-2 to the PD-1 x VEGF antibody of Sheng, and to arrive at the three polypeptide chains instantly claimed utilizing the known anti-PD-1 antibody, anti-VEGF antibody, and IL-2 sequences and methods of construction taught by the prior art.
5. Claim(s) 3-6, 8, 9 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0275353, Sheng et al, published September 2017; Prodi et al (OncoTargets and Therapy, 17:697-715; August 28, 2024); Holcomb et al (Journal of Clinical Investigation, 2022, 132(3):e156628); and WO 2022/140797, Wu et al, published June 2022 as applied to claims 1, 2, 21-23 above, and further in view of US Patent Application Publication 2022/0170028, Li et al, published June 2022; and WO 2023/045977, He et al, published March 30, 2023 (English Translation of specification provided).
Sheng, Prodi, Holcomb, and Wu (the combined references) teach a multifunctional immunocytokine comprising:
a) a first binding domain targeting PD-1;
b) a second binding domain targeting VEGF; and
c) an IL-2 polypeptide, that are in covalent association, wherein the multifunctional immunocytokine serves to stimulate cytotoxic T effector and NK cells, minimizing stimulation of Tregs, as set forth above.
The combined references do not teach the IL-2 comprises mutations:
N88D (claim 5);
L19D (claim 6);
T3A (claim 7); and
C125S (claim 9), relative to wild-type IL-2 SEQ ID NO:701.
Li teaches an IL-2 mutein comprising mutations relative to wild type IL-2, wherein the IL-2 mutein functions to stimulate CD8+ cytotoxic T effector and NK cells, minimizing stimulation of Tregs. Li teaches this IL-2 mutein comprises the mutation N88D ([247]; Example 8), where N88 is a known energetic hot spot for the IL-2/IL-2Rβ interaction, engaging in critical hydrogen bonds with the receptor chain ([211]). Li further teaches IL-2 mutations for preferentially activating CD8+ T cells over Treg cells include L19D (claim 46; Tables 4A and 4H; [234]; [238]). Li teaches exemplifies producing immunocytokines with an IL-2 mutein fused to a targeting antibody, and suggests fusing the IL-2 mutein to an anti-PD-1 antibody (claims 44-50; Example 15). Li teaches administering the IL-2 mutein having reduced ability to stimulate Treg cells to treat cancer, and suggests administering fusion proteins of the IL-2 mutein to an anti-PD-1 antibody ([82]; [192]; claims 50, 52-53).
He teaches an immunocytokine comprising IL-2 mutein used for the treatment of cancer, wherein the IL-2 comprises mutations in the IL-2Rβγ binding interface, including N88D mutation (English translation p. 17-18), further wherein mutein comprises a N88D substitution and the B'C' loop sequence AGDASIH, and T3A mutation (p. 18-19, 23). He teaches conjugating the IL-2 mutein to an anti-PD-1 antibody or fragment thereof, including Fab, scFv, or VHH (p. 24-25). He teaches exemplary IL-2 mutein SEQ ID NO:4 that is 97.7% identical to instant SEQ ID NO:754, and comprises mutations T3A + N88D + C125S (see sequence alignments below). He teaches the IL-2 mutein-anti-PD-1 antibody conjugate has the advantages of selectively activating CD8+ T cells expressing PD-1, having stronger antitumor effects, lower toxicity (p. 29).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to include the mutations N88D, L19D, T3A, and C125S in the IL-2 mutein of the immunocytokine of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) all of the cited references teach administering IL-2 to serve the same function of treating cancer by activating PD-1 + CD8+ T cells, reducing Treg stimulation, enhancing antitumor immune response, and reducing toxicity; and (2) Li and He teach and demonstrate known IL-2 mutations T3A + L19A + N88D + C125S all serve the same purpose to enhance activation of cytotoxic CD8+ T cells and reducing stimulation of Treg cells to enhance anti-tumor immune responses for cancer treatment.
Instant IL-2 mutein SEQ ID NO:754 (Qy) aligned with He SEQ ID NO:4 (Db):
BMQ73466
ID BMQ73466 standard; protein; 129 AA.
XX
AC BMQ73466;
XX
DT 04-MAY-2023 (first entry)
XX
DE Human mature IL-2 protein T3A/N88D mutant, SEQ ID 4.
XX
KW IL-2 protein; Interleukin 2; Interleukin-2 ligand; T cell growth factor;
KW TCGF protein; cancer; colon tumor; colorectal tumor; cytostatic;
KW dermatological; gastrointestinal tumor; gastrointestinal-gen.;
KW hematological neoplasm; hematological-gen.; immunoconjugate;
KW immunotherapy; melanoma; mutein; prophylactic to disease; solid tumor;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2023045977-A1.
XX
CC PD 30-MAR-2023.
XX
CC PF 21-SEP-2022; 2022WO-CN120265.
XX
PR 22-SEP-2021; 2021CN-11110032.
XX
CC PA (INNO-) INNOVENT BIOLOGICS SUZHOU CO LTD.
XX
CC PI He K, Fu F, Wu W, Zhou S, Guan J;
XX
DR WPI; 2023-323445/032.
XX
CC PT New immunoconjugate comprising antibody binding to programmed cell death
CC PT protein 1 and interleukin-2 mutein, useful in preparing medicine for
CC PT preventing and/or treating cancer, e.g. gastrointestinal tumor or
CC PT melanoma.
XX
CC PS Claim 3; SEQ ID NO 4; 101pp; Chinese.
XX
CC The present invention relates to an immunoconjugate, useful in preparing
CC a medicine for preventing and/or treating cancer. The immunoconjugate
CC comprises an antibody binding to programmed cell death protein 1 (PD-1,
CC CD279) and interleukin-2 (IL-2, T cell growth factor, TCGF) mutein. The
CC invention also includes: (1) an isolated polynucleotide, encoding more
CC than one chains in the immune conjugate or first monomer and/or a second
CC monomer; (2) an expression vector, comprising the polynucleotide; (3) a
CC host cell, comprising the polynucleotide or vector, preferably host cell
CC is a yeast cell or a mammalian cell, preferably human embryonic kidney
CC 293 cell or a Chinese hamster ovary cell; (4) a method for producing the
CC immunoconjugate; (5) a medicine composition, comprising the
CC immunoconjugate, and medicinally acceptable auxiliary material; and (6) a
CC method for preventing and/or treating cancer in a subject. The
CC immunoconjugate or medicine composition of the invention is useful in
CC preparing a medicine for preventing and/or treating cancer is a PD-1
CC antibody for treating resistant cancer, preferably cancer is a solid
CC tumor or blood tumor, gastrointestinal tumor or melanoma, colorectal
CC cancer or colon cancer.
XX
SQ Sequence 129 AA;
ALIGNMENT:
Query Match 97.7%; Score 637; Length 129;
Best Local Similarity 97.7%;
Matches 126; Conservative 2; Mismatches 1; Indels 0; Gaps 0;
Qy 1 APASSSTKKTQLQLDHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLE 60
||||||||||||||:|||||||||||||||||||||||||||||||||||||||||||||
Db 1 APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLE 60
Qy 61 EELKPLEEVLNLAGDGSINDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITF 120
||||||||||||||| ||:|||||||||||||||||||||||||||||||||||||||||
Db 61 EELKPLEEVLNLAGDASIHDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITF 120
Qy 121 SQSIISTLT 129
|||||||||
Db 121 SQSIISTLT 129
6. Claim(s) 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0275353, Sheng et al, published September 2017; Prodi et al (OncoTargets and Therapy, 17:697-715; August 28, 2024); Holcomb et al (Journal of Clinical Investigation, 2022, 132(3):e156628); and WO 2022/140797, Wu et al, published June 2022 as applied to claims 1, 2, 21-23 above, and further in view of WO 2021007428, Bedi et al.
Sheng, Prodi, Holcomb, and Wu (the combined references) teach a multifunctional immunocytokine comprising:
a) a first binding domain targeting PD-1;
b) a second binding domain targeting VEGF; and
c) an IL-2 polypeptide, that are in covalent association, wherein the binding domain can be an scFv or Fab, as set forth above.
Sheng further suggests the domain targeting PD-1 is derived from pembrolizumab (MK-3475, lambrolizumab, KEYTRUDA™) (Merck) ([116]).
The combined references do not teach the PD-1 binding domain of the multifunctional immunocytokine comprises instant VH and VL SEQ ID NOs:46 and 49, respectively, which comprise the CDRs recited in instant claim 13.
Bedi teaches making a multifunctional fusion protein for the treatment of cancer that comprises a first binding domain to PD-1 and a second binding domain to inhibit VEGF/VEGFR2 interaction ([15-17]), wherein the binding domain to PD-1 comprises pembrolizumab light chain domain SEQ ID NO:455 that comprises 100% identity to instant SEQ ID NO:46, and comprises pembrolizumab light chain SEQ ID NO:101 that comprises 100% identity to instant SEQ ID NO:49 ([219-220]; [236]; [594]) (see sequence alignments below). Bedi exemplifies producing a multifunctional fusion protein with pembrolizumab sequences that functioned to treat cancer ([630]; [667]).
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 known pembrolizumab VH and VL sequences in the multifunctional immunocytokine of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) Shen suggests utilizing pembrolizumab as the anti-PD-1 antibody in the multifunctional PD-1 x VEGF protein for the treatment of cancer, (2) Bedi teaches the sequence of pembrolizumab are known and readily available for successful construction of multifunctional fusion proteins, and (3) Bedi also suggests utilizing pembrolizumab to construct a multifunctional protein with a binding domain that blocks VEGF/VEGFR for the treatment of cancer.
Instant anti-PD-1 heavy chain SEQ ID NO:46 aligned with Bedi SEQ ID NO:455:
RESULT 19
BIW36154
ID BIW36154 standard; protein; 581 AA.
XX
AC BIW36154;
XX
DT 04-MAR-2021 (first entry)
XX
DE Anti-PD1 antibody heavy chain-SIRPa ECD fusion protein, SEQ:455.
XX
KW PD1 protein; SIRPA protein; Tyrosine phosphatase substrate 1; antibody;
KW cancer; cytostatic; fusion protein; heavy chain; immune stimulation;
KW immunoconjugate; neoplasm; programmed death-1; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Chimeric.
OS Synthetic.
OS Unidentified.
XX
CC PN WO2021007428-A2.
XX
CC PD 14-JAN-2021.
XX
CC PF 09-JUL-2020; 2020WO-US041403.
XX
PR 09-JUL-2019; 2019US-0872194P.
XX
CC PA (UYJO ) UNIV JOHNS HOPKINS.
CC PA (YTRA-) Y-TRAP INC.
XX
CC PI Bedi A, Bedi R;
XX
DR WPI; 2021-06463X/010.
XX
CC PT New fusion protein, comprising antibody and ligand traps, used to treat
CC PT neoplastic disease or cancer and to promote immune response.
XX
CC PS Disclosure; SEQ ID NO 455; 387pp; English.
XX
CC The present invention relates to a novel fusion protein to counteract
CC immune dysfunction in tumor microenvironment. The fusion protein
CC comprises an antibody and one or more ligand antibody-ligand trap (ALT),
CC or the fusion protein comprises two or more ligand traps (LT-LT), where a
CC ligand trap is a ligand-binding sequence of a receptor extracellular
CC domain (ECD) or its fragment selected from the group consisting of: (a)
CC tumor growth factor beta receptor (TGFbR) ecd, programmed death-1 (PD-1)
CC ECD, Vascular endothelial growth factor receptor (VEGFR) ecd, TIM3 ecd, B
CC - and T-lymphocyte attenuator (BTLA) ecd, SIRPa-ecd, or Sialic Acid
CC Binding Ig Like Lectin 10 (SIGLEC10) ecd. The invention further
CC discloses: (1) a method for conjugating a cytotoxic agent to the fusion
CC protein in a site-specific manner; (2) a method for treating a subject
CC having neoplastic disease or cancer, which involves administering the
CC ALT, LT-LT, or ALT-DC in combination with another agent; (3) a
CC composition comprising the molecule and a pharmaceutically acceptable
CC carrier; and (4) a method for treating a subject to promote immune
CC response, which involves administering the molecule. The novel fusion
CC protein of the invention is useful for treating cancer. The present
CC sequence represents an anti-PD1 antibodyheavy chain-SIRPa ECD fusion
CC protein, which is useful for treating cancer.
XX
SQ Sequence 581 AA;
Query Match 100.0%; Score 2393; Length 581;
Best Local Similarity 100.0%;
Matches 447; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF 60
Qy 61 NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS 120
Qy 121 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
Qy 181 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
Qy 241 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
Qy 301 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
Qy 361 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
Qy 421 NVFSCSVMHEALHNHYTQKSLSLSLGK 447
|||||||||||||||||||||||||||
Db 421 NVFSCSVMHEALHNHYTQKSLSLSLGK 447
Instant anti-PD-1 VL SEQ ID NO:49 aligned with Bedi pembrolizumab light chain SEQ ID NO:101
BIW35800
ID BIW35800 standard; protein; 218 AA.
XX
AC BIW35800;
XX
DT 04-MAR-2021 (first entry)
XX
DE Anti-PD1 monoclonal antibody (pembrolizumab) light chain, SEQ:101.
XX
KW PD1 protein; cancer; cytostatic; immune stimulation; immunoconjugate;
KW light chain; monoclonal antibody; neoplasm; pembrolizumab;
KW programmed death-1; protein therapy; recombinant protein; therapeutic.
XX
OS Unidentified.
XX
CC PN WO2021007428-A2.
XX
CC PD 14-JAN-2021.
XX
CC PF 09-JUL-2020; 2020WO-US041403.
XX
PR 09-JUL-2019; 2019US-0872194P.
XX
CC PA (UYJO ) UNIV JOHNS HOPKINS.
CC PA (YTRA-) Y-TRAP INC.
XX
CC PI Bedi A, Bedi R;
XX
DR WPI; 2021-06463X/010.
XX
CC PT New fusion protein, comprising antibody and ligand traps, used to treat
CC PT neoplastic disease or cancer and to promote immune response.
XX
CC PS Disclosure; SEQ ID NO 101; 387pp; English.
XX
CC The present invention relates to a novel fusion protein to counteract
CC immune dysfunction in tumor microenvironment. The fusion protein
CC comprises an antibody and one or more ligand antibody-ligand trap (ALT),
CC or the fusion protein comprises two or more ligand traps (LT-LT), where a
CC ligand trap is a ligand-binding sequence of a receptor extracellular
CC domain (ECD) or its fragment selected from the group consisting of: (a)
CC tumor growth factor beta receptor (TGFbR) ecd, programmed death-1 (PD-1)
CC ECD, Vascular endothelial growth factor receptor (VEGFR) ecd, TIM3 ecd, B
CC - and T-lymphocyte attenuator (BTLA) ecd, SIRPa-ecd, or Sialic Acid
CC Binding Ig Like Lectin 10 (SIGLEC10) ecd. The invention further
CC discloses: (1) a method for conjugating a cytotoxic agent to the fusion
CC protein in a site-specific manner; (2) a method for treating a subject
CC having neoplastic disease or cancer, which involves administering the
CC ALT, LT-LT, or ALT-DC in combination with another agent; (3) a
CC composition comprising the molecule and a pharmaceutically acceptable
CC carrier; and (4) a method for treating a subject to promote immune
CC response, which involves administering the molecule. The novel fusion
CC protein of the invention is useful for treating cancer. The present
CC sequence represents an anti-PD1 monoclonal antibody (pembrolizumab) light
CC chain, which is used in the fusion protein for treating cancer.
ALIGNMENT:
Query Match 100.0%; Score 576; Length 216;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES 60
Qy 61 GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 111
7. Claim(s) 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2017/0275353, Sheng et al, published September 2017; Prodi et al (OncoTargets and Therapy, 17:697-715; August 28, 2024); Holcomb et al (Journal of Clinical Investigation, 2022, 132(3):e156628); and WO 2022/140797, Wu et al, published June 2022 as applied to claims 1, 2, 21-23 above, and further in view of US Patent Application Publication 2018/0346559, Hilberg et al.
Sheng, Prodi, Holcomb, and Wu (the combined references) teach a multifunctional immunocytokine comprising:
a) a first binding domain targeting PD-1;
b) a second binding domain targeting VEGF; and
c) an IL-2 polypeptide, that are in covalent association, wherein the binding domain can be a VHH, as set forth above.
The combined references do not teach the VEGF binding domain is VHH SEQ ID NO:221 comprising the CDR sequences recited in instant claim 19.
Hilberg teaches producing a multifunctional fusion protein for the treatment of cancer comprising a VEGF VHH domain SEQ ID NO:11 that comprises 100% of instant SEQ ID NO:221 (see sequence alignment below). Hilberg further teaches administering anti-PD-1 antibody, such as pembrolizumab, in combination with the multifunctional fusion protein for the treatment of cancer ([116]; claims 1-7).
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 known VEGF VHH sequence in the multifunctional immunocytokine of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the cited combined references suggest utilizing VHH antibodies for the VEGF binding domain and for the purpose of targeting tumor cells to treat cancer, and (2) Hilberg teaches the known and readily available VEGF VHH SEQ ID NO:221 for construction of multifunctional fusion proteins for targeting tumor cells to treat cancer.
Instant VEGF VHH SEQ ID NO:221 aligned with Hilberg SEQ ID NO:11:
BFW06579
ID BFW06579 standard; protein; 387 AA.
XX
AC BFW06579;
XX
DT 10-JAN-2019 (first entry)
XX
DE Anti-VEGF-Ang2 bispecific single domain antibody, SEQ 11.
XX
KW Angiogenin-2; VEGF ligand; antibody therapy; bispecific antibody; cancer;
KW cytostatic; heavy chain variable region; non-small-cell lung cancer;
KW prophylactic to disease; respiratory-gen.; single domain antibody;
KW therapeutic.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN US2018346559-A1.
XX
CC PD 06-DEC-2018.
XX
CC PF 01-JUN-2018; 2018US-00995375.
XX
PR 02-JUN-2017; 2017EP-00174323.
PR 17-OCT-2017; 2017EP-00196949.
XX
CC PA (BOEH ) BOEHRINGER INGELHEIM INT GMBH.
XX
CC PI Hilberg F, Hofmann MH, Reschke M, Solca F;
XX
DR WPI; 2018-96864Q/83.
XX
CC PT Treating or preventing hyperproliferative disease comprises administering
CC PT bispecific binding molecule comprising e.g. vascular endothelial growth
CC PT factor-binding immunoglobulin single variable domain, and programmed cell
CC PT death-1 antagonist.
XX
CC PS Claim 5; SEQ ID NO 11; 37pp; English.
XX
CC The present invention relates to a method for treating or preventing an
CC oncological or hyperproliferative disease. The method involves
CC administering a therapeutically effective amount of a compound A and B to
CC a patient. The compound A comprising a VEGF-binding immunoglobulin single
CC variable domain, a serum albumin binding immunoglobulin single variable
CC domain and an Ang2- binding immunoglobulin single variable domain, where
CC the compound B is a PD-1 antagonist. The invention further discloses: (1)
CC a pharmaceutical composition comprising the compound A and the compound B
CC ; and (2) a kit comprising the compound A and the compound B. The method
CC of the invention is useful for treating or preventing an oncological or
CC hyperproliferative disease in a patient, where the oncological or
CC hyperproliferative disease is cancer or tumor disease, preferably non-
CC small cell lung cancer. The present sequence represents an anti-VEGF-Ang2
CC bispecific single domain antibody, which is useful for treating cancer.
XX
SQ Sequence 387 AA;
ALIGNMENT:
Query Match 100.0%; Score 645; Length 387;
Best Local Similarity 100.0%;
Matches 125; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DVQLVESGGGLVQPGGSLRLSCAASGRTFSSYSMGWFRQAPGKEREFVVAISKGGYKYDA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DVQLVESGGGLVQPGGSLRLSCAASGRTFSSYSMGWFRQAPGKEREFVVAISKGGYKYDA 60
Qy 61 VSLEGRFTISRDNAKNTVYLQINSLRPEDTAVYYCASSRAYGSSRLRLADTYEYWGQGTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VSLEGRFTISRDNAKNTVYLQINSLRPEDTAVYYCASSRAYGSSRLRLADTYEYWGQGTL 120
Qy 121 VTVSS 125
|||||
Db 121 VTVSS 125
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.
8. Claims 1-10, 13-15, and 19-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 13, 18, 21, 22-25, 35, 36, 44-46, 61-63, 67, 68, 105, 115, 131, 148, 149, 159, 169, 180, 181, and 187 of copending Application No. 19/359,286 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application is claiming a multifunctional immunocytokine composition comprising the same PD-1 binding domain, VEGF binding domain, and IL-2 polypeptide, IL-2 mutations and sequences, PD-1 binding domain and VEGF binding domain sequences, and first, second and third polypeptide chains instantly claimed, thereby rending the instantly claimed multifunctional immunocytokine composition obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Conclusion: No claims are allowed.
10. 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.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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