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. Claims 1-3, 9, 11, 54, 64, 67, 78-80, 88, 94, 102, 105, 106, 112, 115, and 117 are pending and being examined.
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.
2. Claims 1-3, 9, 11, 54, 64, 67, 78-80, 88, 94, 102, 105, 106, 112, 115, and 117 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 1 recites “A fusion protein comprising an interleukin-2 (IL-2) domain, a
programmed cell death-1 (PD-1) binding domain, and a half-life-extension domain; wherein the IL-2 domain comprises: (i) a replacement of the amino acid residues from positions N29 to A50 with an IL-15 hinge fragment-containing peptide; (ii) an amino acid substitution at position E15, H16, D20, K32, K76, S87, N88, or I92; (iii) an amino acid substitution at a position from R38 to Y45; and/or (iv) a disulfide bond formed between two amino acid residues from positions N30 to L80.
Claim 1 is unclear with regard to which amino acid residues of “IL-2 domain” are from N29 to A50, E15, H16, D20, K32, K76, S87, N88, I92, R38 to Y45, and N30 to L80 because there is no reference amino acid sequence recited for the IL-2 domain in order for one to determine which amino acids are at the positions claimed.
Further, the phrase “an amino acid substitution at a position from R38 to Y45” is unclear with regard to whether the claim recites all of the amino acid residues from R38 through Y45 are substituted, or if there is a substitution at one residue selected from R38 and Y45. Clarification is required.
Further, the phrase “a disulfide bond formed between two amino acid residues from positions N30 to L80” is unclear with regard to whether the claim recites a disulfide bond is formed between two amino acid residues found anywhere in amino acids N30 through L80, a disulfide bond is formed between two amino acid residues at every position from N30 to L80, or if a disulfide bond is formed between the two amino acid residues N30 and L80. Clarification is required.
Claim 2 recites: “wherein the IL-2 domain comprises a replacement of the amino acid residues from positions N29 to A50 with an IL-15 hinge fragment-containing peptide, and optionally an amino acid substitution at position E15, H16, D20, S87, N88, or I92.” Claim 2 is unclear with regard to which amino acid residues of “IL-2 domain” are N29 to A50, E15, H16, D20, S87, N88, and I92 because there is no reference sequence to identify the residues.
Claim 3 recites the IL-2 domain optionally comprises “a replacement of the amino acid residues from positions N29 to L40 having an amino acid sequence of SEQ ID NO:39: and “an amino acid substitution of E15K, H16E, H16I, H16V, D20A, D20E, D20K, D20T, S87D, N88A, I92A, 192D, I92E, or I92G”. Claim 3 is unclear with regard to which amino acid residues of “IL-2 domain” are N29 to L40, E15K, H16E, H16I, H16V, D20A, D20E, D20K, D20T, S87D, N88A, I92A, 192D, I92E, or I92G because there is no reference sequence to identify the residues.
Claim 9 recites: “and optionally an amino acid substitution of I92A, I92D, I92E, or I92G.” Claim 9 is unclear with regard to which amino acid residues of “IL-2 domain” are I92A, I92D, I92E, or I92G because there is no reference sequence to identify the residues.
Claim 11 recites: “the IL-2 domain comprises an amino acid substitution at position E15, H16, D20, K32, K76, S87, N88, or I92.” Claim 11 is unclear with regard to which amino acid residues of “IL-2 domain” are E15, H16, D20, K32, K76, S87, N88, or I92 because there is no reference sequence to identify the residues.
Claim 54 recites: “the interleukin-2 domain comprises a disulfide bond formed between two different amino acid residues from positions N30 to L80.” Claim 54 is unclear with regard to which amino acid residues of “IL-2 domain” are positions N30 to L80 because there is no reference sequence to identify the residues. Further, the claim is unclear with regard to whether the claim recites a disulfide bond is formed between two amino acid residues found anywhere in amino acids N30 through L80, a disulfide bond is formed between two amino acid residues at every position from N30 to L80, or if a disulfide bond is formed between the two amino acid residues N30 and L80. Clarification is required.
Dependent claims are rejected for encompassing the rejected limitations of claim 1.
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)(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.
3. Claim interpretation: Claim 64 recites that the IL-2 domain comprises an amino acid sequence of any one of SEQ ID NOs:6 to 37, 42 to 81, 255, and 256. The claim is reasonably interpreted to broadly encompass any (an) amino acid sequence found in (of) SEQ ID NO:6 or the other listed SEQ ID NOs. wherein the sequence is as small as two consecutive amino acids long.
4. Claim(s) 1, 11, 64, 78, 79, 106, 112, 115, and 117 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/184964, Codarri Deak et al.
With regards to claims 1, 11, 78 and 79, Codarri Deak teaches a fusion protein “PDl-IL2v” comprising:
(i) an intact anti-PD-1 antibody comprising two heavy and two light chains;
(ii) Fc half-life extension domain; and
(iii) a mutant IL-2 domain that comprises amino acid substitutions of D20T, F42, Y45, and/or R38 of human IL-2 SEQ ID NO:19; wherein the N-terminus of the IL-2 is connected to the C-terminus of the heavy chain directly or by peptide linker (Figure 1; p. 5-8, 25-27, 30, 32, 34, 35, 48-50; claims 1-23),
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470
610
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With regards to claim 64, IL-2 domain SEQ ID NO:19 is 97.5% identical to instant IL-2 domain SEQ ID NO:6, therefore the IL-2 domain of Codarri Deak comprises an amino acid sequence of instant SEQ ID NO:6 (see sequence alignment below).
With regards to claim 106, Codarri Deak teaches the fusion protein is comprised in a pharmaceutical composition comprising a pharmaceutically acceptable excipient (p. 59-65).
With regards to claims 112, 115, and 117, Codarri Deak further teaches the fusion protein is an immunotherapeutic. Codarri Deak teaches administering the fusion protein to a subject to treat and inhibit the proliferative disease of cancer, and to activate and induce proliferation of effector cells, like NK and T cells (p. 26, 29, 63-69; Examples 3-6; claims 35-37).
IL-2 domain instant SEQ ID NO:6 aligned with Codarri Deak SEQ ID NO:19
Qy= instant SEQ ID NO:6
Db = SEQ ID NO:19
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396
792
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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.
5. Claim(s) 1, 78, 79, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/184964, Codarri Deak et al; in view of US Patent Application Publication 2022/0048966, Lowe, claiming priority to September 2018.
Codarri Deak teaches a fusion protein “PDl-IL2v” comprising:
(i) an intact anti-PD-1 antibody comprising two heavy and two light chains;
(ii) Fc half-life extension domain; and
(iii) a mutant IL-2 domain that comprises amino acid substitutions of D20T, F42, Y45, and/or R38 of human IL-2 SEQ ID NO:19; wherein the N-terminus of the IL-2 is connected to the C-terminus of the heavy chain directly or by peptide linker, as set forth above.
Codarri Deak teaches their cytokine-antibody conjugate functions to reduce cytotoxicity of the cytokine, enhance efficacy of IL-2 therapy by directly targeting IL-2 into a tumor microenvironment, enhance circulating half-life of IL-2, treat cancer, and activate and induce proliferation of effector cells such as NK and T cells (p. 29-31, 63-69; Examples 3-6; claims 35-37).
Codarri Deak does not teach attaching an IL-2 to each of the C-terminus of the heavy chains so there are two IL-2 domains.
Lowe teaches different antibody fusion formats for fusing cytokines to antibodies through a linker to produce “immunocytokines”, wherein the N-terminus of a first cytokine is fused to the C-terminus of one antibody heavy chain, and the N-terminus of a second cytokine is fused to the C-terminus of the other antibody heavy chain (Figure 1):
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398
284
media_image3.png
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Lowe teaches the antibody is an anti-PD-1 antibody ([77]), and the cytokine is IL-2 ([4]; [89]).
Lowe teaches immunocytokines allow for tumor-targeted delivery of cytokines, extend the half-life of cytokines, activate effector cells including NK and T cells, reduce the side effects of cytokines, and treat cancer ([3]; [36-39]; [92]; [148-151]).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to attach the IL-2 to each heavy chain of the antibody of Codarri Deak. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Lowe teaches various configurations for attaching cytokines to antibodies, including attaching a cytokine to each antibody heavy chain; and (2) Lowe suggests the immunocytokine comprises anti-PD-1 antibody and IL-2 cytokine; and (3) Lowe teaches the immunocytokine serves the same function as the fusion protein taught by Codarri Deak, that is, to achieve targeted delivery of the cytokine to the tumor, extend the half-life of cytokines, activate effector cells including NK and T cells, reduce the side effects of cytokines, and treat cancer.
6. Claim(s) 67 and 88 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/184964, Codarri Deak et al; and US Patent Application Publication 2022/0048966, Lowe, claiming priority to September 2018 as applied to claims 1, 78, 79, and 80 above, and further in view of WO 2016024231, Hamdy et al.
Codarri Deak and Lowe (the combined references) teach an immunocytokine fusion protein comprising an anti-PD-1 antibody with an Fc region fused to mutant IL-2 domain, as set forth above. Lowe further suggests the anti-PD-1 antibody can be nivolumab ([77]). Codarri Deak demonstrated nivolumab blocked PD-1/PD-L1 with the same tendency as the anti-PD-1 antibody used in their fusion protein (Figure 15A).
The combined references do not teach the sequence of the anti-PD-1 antibody in the fusion protein comprises instant VL and VH SEQ ID NOs 116 and 117 (comprising CDR SEQ ID NOs:111-115), that is nivolumab.
Hamdy teaches the known sequences of nivolumab. The VH of nivolumab is SEQ ID NO:3, which is 100% identical to instant SEQ ID NO:117, and the VL is SEQ ID NO:4, which is 100% identical to instant SEQ ID NO:116 and comprises instant CDR SEQ ID NOs:111-115 ([230-239]; Table 1) (see sequence alignments below). Hamdy teaches nivolumab is a known anti-PD-1 antibody used for the treatment of cancer (claims 1, 14, 25-28. 35; [791]; [796-797]).
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 sequences of nivolumab as the anti-PD-1 antibody in the fusion protein of the combined references. One would have been motivated to, and have a reasonable expectation of success to, because the combined references suggest utilizing nivolumab as the anti-PD-1 antibody fused to IL-2, all of the cited references teach nivolumab is a known anti-PD-1 antibody, the sequences of nivolumab are readily available according to Hamdy, and Codarri Deak demonstrated nivolumab was functionally equivalent to the anti-PD-1 antibody used in their fusion protein.
Nivolumab VL SEQ ID NO:116 aligned with Hamdy SEQ ID NO:4:
BCM19127
ID BCM19127 standard; protein; 107 AA.
XX
AC BCM19127;
XX
DT 21-APR-2016 (first entry)
XX
DE Anti-PD-1 antibody nivolumab VL protein, SEQ ID 4.
XX
KW 5C4; PD-1 protein; PDCD1 protein; Programmed cell death protein 1;
KW antibody therapy; cytostatic; hematological neoplasm; hematological-gen.;
KW light chain variable region; monoclonal antibody; neoplasm; nivolumab;
KW programmed death 1; solid tumor; therapeutic.
XX
OS Mus sp.
XX
CC PN WO2016024231-A1.
XX
CC PD 18-FEB-2016.
XX
CC PF 11-AUG-2015; 2015WO-IB056127.
XX
PR 11-AUG-2014; 2014US-0035812P.
PR 05-DEC-2014; 2014US-0088357P.
PR 12-FEB-2015; 2015US-0115489P.
PR 17-JUN-2015; 2015US-0181164P.
XX
CC PA (ACER-) ACERTA PHARMA BV.
XX
CC PI Hamdy A, Rothbaum W, Izumi R, Lannutti B, Covey T, Ulrich R;
CC PI Johnson D, Barf T, Kaptein A;
XX
DR WPI; 2016-11390K/23.
XX
CC PT Treating cancer e.g. gastric cancer, kidney cancer, and liver cancer, by
CC PT co-administering to mammal in need programmed death 1 (PD-1) inhibitor or
CC PT programmed death ligand 1 (PD-L1) inhibitor, and Bruton's tyrosine kinase
CC PT inhibitor.
XX
CC PS Disclosure; SEQ ID NO 4; 680pp; English.
XX
CC The present invention relates to a method for treating cancer in a
CC subject. The method involves co-administering a programmed death 1 (PD-1)
CC inhibitor or programmed death ligand 1 (PD-L1) inhibitor, or its antigen-
CC binding fragment, variant, conjugate, or its biosimilar, and a Bruton's
CC tyrosine kinase (BTK) inhibitor or its salt, solvate, hydrate, cocrystal,
CC or its prodrug. The method further involves administering an anti-cluster
CC of differentiation (CD)20 antibody chosen from rituximab, obinutuzumab,
CC ofatumumab, veltuzumab, tositumomab, ibritumomab, or their fragments. The
CC invention further relates to: (1) a method for treating a solid tumor
CC cancer in a human; (2) a method for treating a cancer in a human
CC sensitive to bleeding events including B cell hematological malignancy;
CC and (3) a composition and a kit comprising a therapeutically effective
CC amount of the PD-1 inhibitor, BTK inhibitor, janus kinase 2 (JAK-2)
CC inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor. The
CC present sequence represents an anti-PD-1 antibody nivolumab light chain
CC variable region (VL), which is useful for preparing the composition of
CC the invention involved in treating cancer in a subject.
XX
SQ Sequence 107 AA;
Query Match 100.0%; Score 553; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 107
Nivolumab VH SEQ ID NO:117 aligned with Hamdy SEQ ID NO:3:
BCM19126
ID BCM19126 standard; protein; 113 AA.
XX
AC BCM19126;
XX
DT 21-APR-2016 (first entry)
XX
DE Anti-PD-1 antibody nivolumab VH protein, SEQ ID 3.
XX
KW 5C4; PD-1 protein; PDCD1 protein; Programmed cell death protein 1;
KW antibody therapy; cytostatic; heavy chain variable region;
KW hematological neoplasm; hematological-gen.; monoclonal antibody;
KW neoplasm; nivolumab; programmed death 1; solid tumor; therapeutic.
XX
OS Mus sp.
XX
CC PN WO2016024231-A1.
XX
CC PD 18-FEB-2016.
XX
CC PF 11-AUG-2015; 2015WO-IB056127.
XX
PR 11-AUG-2014; 2014US-0035812P.
PR 05-DEC-2014; 2014US-0088357P.
PR 12-FEB-2015; 2015US-0115489P.
PR 17-JUN-2015; 2015US-0181164P.
XX
CC PA (ACER-) ACERTA PHARMA BV.
XX
CC PI Hamdy A, Rothbaum W, Izumi R, Lannutti B, Covey T, Ulrich R;
CC PI Johnson D, Barf T, Kaptein A;
XX
DR WPI; 2016-11390K/23.
XX
CC PT Treating cancer e.g. gastric cancer, kidney cancer, and liver cancer, by
CC PT co-administering to mammal in need programmed death 1 (PD-1) inhibitor or
CC PT programmed death ligand 1 (PD-L1) inhibitor, and Bruton's tyrosine kinase
CC PT inhibitor.
XX
CC PS Disclosure; SEQ ID NO 3; 680pp; English.
XX
CC The present invention relates to a method for treating cancer in a
CC subject. The method involves co-administering a programmed death 1 (PD-1)
CC inhibitor or programmed death ligand 1 (PD-L1) inhibitor, or its antigen-
CC binding fragment, variant, conjugate, or its biosimilar, and a Bruton's
CC tyrosine kinase (BTK) inhibitor or its salt, solvate, hydrate, cocrystal,
CC or its prodrug. The method further involves administering an anti-cluster
CC of differentiation (CD)20 antibody chosen from rituximab, obinutuzumab,
CC ofatumumab, veltuzumab, tositumomab, ibritumomab, or their fragments. The
CC invention further relates to: (1) a method for treating a solid tumor
CC cancer in a human; (2) a method for treating a cancer in a human
CC sensitive to bleeding events including B cell hematological malignancy;
CC and (3) a composition and a kit comprising a therapeutically effective
CC amount of the PD-1 inhibitor, BTK inhibitor, janus kinase 2 (JAK-2)
CC inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor. The
CC present sequence represents an anti-PD-1 antibody nivolumab heavy chain
CC variable region (VH), which is useful for preparing the composition of
CC the invention involved in treating cancer in a subject.
XX
SQ Sequence 113 AA;
ALIGNMENT:
Query Match 100.0%; Score 602; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
Qy 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS 113
7. Claim(s) 1, 94, 102, and 105 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/184964, Codarri Deak et al; in view of WO 2019/236567, Vincent et al; and WO 2019/246004, Zhong et al; Coppieters et al (Arthritis & Rheumatism, 2006, 54:1856-1866); and US Patent Application Publication 2023/0340157, Liang, claiming priority to 2019.
Codarri Deak teaches a fusion protein “PDl-IL2v” comprising:
(i) an anti-PD-1 antibody;
(ii) Fc half-life extension domain; and
(iii) a mutant IL-2 domain that comprises amino acid substitutions of D20T, F42, Y45, and/or R38 of human IL-2 SEQ ID NO:19; wherein the N-terminus of the IL-2 is connected to the C-terminus of the Fc directly or by peptide linker, as set forth above.
Codarri Deak teaches their cytokine-antibody conjugate functions to reduce cytotoxicity of the cytokine, enhance efficacy of IL-2 therapy by directly targeting IL-2 into a tumor microenvironment, enhance circulating/serum half-life of IL-2, treat cancer, and activate and induce proliferation of effector cells such as NK and T cells (p. 29-31, 63-69; Examples 3-6; claims 35-37). Codarri Deak teaches the Fc domain, despite extending half-life, may have an undesirable side effect:
The Fc domain confers to the immunoconjugate favorable pharmacokinetic properties, including a long serum half-life which contributes to good accumulation in the target tissue and a favorable tissue-blood distribution ratio. At the same time it may, however, lead to undesirable targeting of the immunoconjugate to cells expressing Fc receptors rather than to the preferred antigen- bearing cells. Moreover, the co-activation of Fc receptor signaling pathways may lead to cytokine release which, in combination with the IL-2 polypeptide and the long half-life of the immunoconjugate, results in excessive activation of cytokine receptors and severe side effects upon systemic administration. In line with this, conventional IgG-IL-2 immunoconjugates have been described to be associated with infusion reactions (see e.g. King et al, J Clin Oncol 22, 4463-4473 (2004)).
Codarri Deak does not teach substituting the Fc half-life extending domain with an anti-serum albumin binding domain that is a single domain antibody (sdAb, or VHH) and comprises SEQ ID NO:90 or 97.
Vincent teaches anti PD-1 antibody-cytokine fusion proteins for targeted delivery of a drug moiety including cytokines, such as IL-2 (p. 34, 37, 50, 110-112, 126, 149, 153) and suggests extending the circulating half-life of the fusion protein by including a “half-life extending moiety” in the fusion protein, wherein the half-life extending moiety can be an Fc region or an albumin binding moiety (p. 20-21, 126-128, 144-145). Vincent suggests the albumin binding moiety can be an albumin binding domain antibody including known single domain antibodies in the art (p. 145, lines 29-30). Vincent teaches administering the fusion protein to enhance T cell function, induce the production of proinflammatory cytokines, and treat cancer (p. 38-41, 79, 156-167).
Zhong teaches tumor antigen-binding antibody-cytokine fusion proteins for the treatment of cancer, and teaches extending the serum half-life of the proteins by including an Fc domain or an albumin binding moiety in the protein, such as a sdAb (VHH) that binds to albumin (i.e., anti-HSA) ([269-273]; [398-436]; Example 1). Zhong teaches the albumin binding sdAb comprises SEQ ID NO:168 that is 100% identical to instant SEQ ID NO:90 ([261-268]) (see alignment below), or comprises SEQ ID NO:169 that is 100% identical to instant SEQ ID NO:97 ([261-268]) (see alignment below). Zhong demonstrates successfully constructing a cytokine fusion protein containing a half-life extending domain that is an anti-HSA VHH, and successfully treating cancer with the fusion protein in combination with an anti-PD-1 antibody, where combination treatment reduced tumor growth better than single agents (Examples 8, 34, 35, Figures 26 and 27).
Coppieters teaches it is known that noncovalent association with albumin extends the half-life of short-lived proteins (p. 1857, col. 1). Coppieters demonstrates successfully producing an anti-tumor antibody (TR2)-anti-HSA VHH (AR1) fusion protein that substantially extended serum half-life of the antibody (p. 1860, col. 2 to p. 1861, col. 1).
Liang demonstrates successfully producing fusion proteins comprising an anti-PD-L1 antibody – anti-HSA VHH – additional functional protein ([146-148]; Figures 13, 16, 17). Liang teaches the HSA-binding domain confers extended half-life in the body while the other domains provide a therapeutic effect ([8]; [128]). Liang teaches that fusion to an anti-albumin sdAb (single domain antibody) has been used to increase the half-life of an antitumor single chain antibody from 1-2 hr to approximate 10 days ([44]). Liang teaches administering the fusion protein to target and treat cancer ([155-156]).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the Fc domain for an anti-HSA VHH domain as the half-life extending domain in the fusion protein of Codarri Deak. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Codarri Deak teaches the function of the Fc is to extend half-life, however, Codarri Deak recognizes there can be undesirable side effects from the Fc domain; (2) Vincent suggests the half-life extending domain of an antibody-cytokine fusion protein can be either an Fc domain or an albumin-binding domain, indicating functional equivalence, and suggests utilizing known anti-HSA VHH in the art; (3) Zhong also teaches antibody-cytokine fusion proteins and suggests the half-life extending domain of an antibody-cytokine fusion protein can be either an Fc domain or an albumin-binding domain, indicating functional equivalence, and suggests the albumin-binding domain is a sdAb (VHH) that binds to albumin; (4) Zhong teaches known anti-HSA VHH SEQ ID NOs:168 and 169 (identical to instant SEQ ID NOs:90 and 97) to use as the albumin-binding domain in the fusion protein; and (5) Coppieters and Liang teach or demonstrate that the addition of an anti-HSA VHH domain in a fusion protein significantly increases the protein’s half-life and therapeutic efficacy.
Anti-serum albumin sdAb SEQ ID NO:90 aligned with Zhong SEQ ID NO:168:
RESULT 1
BHB69288
(NOTE: this sequence has 11 duplicates in the database searched.
See complete list at the end of this report)
ID BHB69288 standard; protein; 116 AA.
XX
AC BHB69288;
XX
DT 06-FEB-2020 (first entry)
XX
DE Anti-HSA antibody VL domain, SEQ ID 168.
XX
KW antibody; antiinflammatory; cancer; cytostatic;
KW heavy chain variable region; inflammatory disease; protein therapy;
KW recombinant protein; serum albumin.
XX
OS Unidentified.
XX
CC PN WO2019246004-A1.
XX
CC PD 26-DEC-2019.
XX
CC PF 17-JUN-2019; 2019WO-US037558.
XX
PR 18-JUN-2018; 2018US-0686481P.
PR 22-FEB-2019; 2019US-0809496P.
XX
CC PA (ANWI-) ANWITA BIOSCIENCES INC.
XX
CC PI Zhong Z, Ye F, Siegel M, Huang J, Liao E, Li E;
XX
DR WPI; 2019-A85129/004.
XX
CC PT New fusion protein comprises cytokine (e.g. interleukin (IL)-21, IL-7, IL
CC PT -15, IL-15 bound to IL-15R-alpha or fragment, IL-33, and IL-22), and
CC PT albumin binding moiety, for treating cancer or inflammatory disease in
CC PT individual.
XX
CC PS Disclosure; SEQ ID NO 168; 208pp; English.
XX
CC The present invention relates to a novel fusion protein comprising a
CC cytokine, and an albumin binding moiety useful for treating cancer or
CC inflammatory disease in individual. The invention also provides: a
CC pharmaceutical composition comprising the fusion protein; and a method
CC for treating a disease or condition in an individual.
XX
SQ Sequence 116 AA;
Query Match 100.0%; Score 610; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGSTWSINTLAWYRQAPGKQRDLVARISSGGSTYYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGSTWSINTLAWYRQAPGKQRDLVARISSGGSTYYA 60
Qy 61 DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYAQSTWYPPSWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYAQSTWYPPSWGQGTLVTVSS 116
Anti-serum albumin sdAb SEQ ID NO:97 aligned with Zhong SEQ ID NO:169:
RESULT 1
BHB69289
(NOTE: this sequence has 11 duplicates in the database searched.
See complete list at the end of this report)
ID BHB69289 standard; protein; 116 AA.
XX
AC BHB69289;
XX
DT 06-FEB-2020 (first entry)
XX
DE Anti-HSA antibody VL domain, SEQ ID 169.
XX
KW antibody; antiinflammatory; cancer; cytostatic;
KW heavy chain variable region; inflammatory disease; protein therapy;
KW recombinant protein; serum albumin.
XX
OS Unidentified.
XX
CC PN WO2019246004-A1.
XX
CC PD 26-DEC-2019.
XX
CC PF 17-JUN-2019; 2019WO-US037558.
XX
PR 18-JUN-2018; 2018US-0686481P.
PR 22-FEB-2019; 2019US-0809496P.
XX
CC PA (ANWI-) ANWITA BIOSCIENCES INC.
XX
CC PI Zhong Z, Ye F, Siegel M, Huang J, Liao E, Li E;
XX
DR WPI; 2019-A85129/004.
XX
CC PT New fusion protein comprises cytokine (e.g. interleukin (IL)-21, IL-7, IL
CC PT -15, IL-15 bound to IL-15R-alpha or fragment, IL-33, and IL-22), and
CC PT albumin binding moiety, for treating cancer or inflammatory disease in
CC PT individual.
XX
CC PS Disclosure; SEQ ID NO 169; 208pp; English.
XX
CC The present invention relates to a novel fusion protein comprising a
CC cytokine, and an albumin binding moiety useful for treating cancer or
CC inflammatory disease in individual. The invention also provides: a
CC pharmaceutical composition comprising the fusion protein; and a method
CC for treating a disease or condition in an individual.
XX
SQ Sequence 116 AA;
Query Match 100.0%; Score 604; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGGSLRLSCAASGFAFRGFGMSWVRQAPGKGLEWVSSINNGGSDTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGGSLRLSCAASGFAFRGFGMSWVRQAPGKGLEWVSSINNGGSDTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIGGPGASPSGQGTQVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIGGPGASPSGQGTQVTVSS 116
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 1-3, 9, 11, 54, 64, 67, 78-80, 88, 94, 102, 105, 106, 112, 115, and 117 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 9, 13, 16, 46-49, 69, 80, 81, 83, 86, 90, 92, 101-107, 115, 116, 122, and 125 of copending Application No. 18/291,286 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application is claiming an anti-PD1 antibody-IL-2 mutein fusion protein comprising the same components, mutations, and sequences instantly claimed, as well as methods of administering the fusion protein to treat the same conditions instantly claimed, thereby rendering obvious the instant fusion protein and methods. The copending application claims:
Claim 1. A fusion protein comprising an interleukin-2 (IL-2) domain and an
anti-PD-1 antibody; wherein the IL-2 domain comprises: (i) an amino acid substitution at position L18, Q126, or S130; and (ii) a replacement of the amino acid residues from positions N29 to L40 with an IL-15 hinge fragment-containing peptide; a disulfide bond formed between two amino acid residues from positions N30 to L80; or an amino acid substitution at position E15, H16, D20, K32, R38, M39, L40, T41, F42, K43, F44, Y45, K76, S87, N88, or I92.
Claim 16. The fusion protein of claim 1, wherein the IL-2 domain comprises a replacement of the amino acid residues from positions N29 to L40 having an amino acid sequence of SEQ ID NO: 217 with an IL-15 hinge fragment-containing peptide having an amino acid sequence of SEQ ID NO:218 or 219.
Claim 47. The fusion protein of claim 1, wherein the IL-2 domain comprises an amino acid substitution of 192A, I92D, 192E, or I92G.
Claim 69. The fusion protein of claim 1, wherein the IL-2 domain comprises a disulfide bond formed between two different amino acid residues from positions N30 to L80.
Claim 81. A fusion protein comprising an IL-2 domain and a half-life-extension domain, wherein the IL-2 domain comprises the amino acid sequence of the IL-2 mutein of claim 2.
Claim 83. The fusion protein of claim 81, wherein the half-life-extension domain is an albumin binding domain.
Claim 86. The fusion protein of claim 83, wherein the albumin binding domain is an anti-HSA VHH single domain antibody.
Claim 90. The fusion protein of claim 81 or 82, wherein the half-life-extension domain is a Fc domain.
Claim 92. The fusion protein of claim 81, further comprising a programmed cell death-1 (PD-1) binding domain.
Claim 101. The fusion protein of claim 1, comprising an IL-2 domain, and an intact anti-PD-1 antibody comprising two light chains and two heavy chains.
Claim 102. The fusion protein of claim 1, comprising an IL-2 domain, an intact anti-PD-1 antibody comprising first and second light chains and first and second heavy chains, and optionally a peptide linker; wherein the C-terminus of the first heavy chain of the intact anti-PD-1 antibody is connected to the N-terminus of the IL-2 domain directly or via the peptide linker.
Claim 103. The fusion protein of claim 1, comprising two IL-2 domains, and an intact anti-PD-1 antibody comprising two light chains and two heavy chains.
Claim 104. The fusion protein of claim 1, comprising first and second IL-2 domains, an intact anti-PD-1 antibody comprising first and second light chains and first and second heavy chains, and optionally first and second peptide linkers; wherein the C-terminus of the first heavy chain of the intact anti-PD-1 antibody is connected to the N-terminus of the first IL-2 domain directly or via the first peptide linker, and the C-terminus of the second heavy chain of the intact anti-PD-1 antibody is connected to the N-terminus of the second IL-2 domain directly or via the second peptide linker.
Claim 105. The fusion protein of claim 1 wherein the PD-1 antibody comprises:
(i) a CDRL1 of SEQ ID NO: 29, a CDRL2 of DAS, a CDRL3 of SEQ ID NO: 30, a CDRH1 of SEQ ID NO: 31, a CDRH2 of SEQ ID NO: 32, and a CDRH3 of SEQ ID NO: 33;
(ii) a CDRL1 of SEQ ID NO: 38, a CDRL2 of LAS, a CDRL3 of SEQ ID NO: 39, a CDRH1 of SEQ ID NO: 40, a CDRH2 of SEQ ID NO: 41, and a CDRH3 of SEQ ID NO: 42;
(iii) a CDRL1 of SEQ ID NO: 47, a CDRL2 of KVS, a CDRL3 of SEQ ID NO: 48, a CDRH1 of SEQ ID NO: 49, a CDRH2 of SEQ ID NO: 50, and a CDRH3 of SEQ ID NO: 51;
(iv) a CDRL1 of SEQ ID NO: 56, a CDRL2 of TAT, a CDRL3 of SEQ ID NO: 57, a CDRH1 of SEQ ID NO: 58, a CDRH2 of SEQ ID NO: 59, and a CDRH3 of SEQ ID NO: 60;
(v) a CDRL1 of SEQ ID NO: 65, a CDRL2 of AAS, a CDRL3 of SEQ ID NO: 66, a CDRH1 of SEQ ID NO: 67, a CDRH2 of SEQ ID NO: 68, and a CDRH3 of SEQ ID NO: 69;
(vi) a CDRL1 of SEQ ID NO: 74, a CDRL2 of WAS, a CDRL3 of SEQ ID NO: 75, a CDRH1 of SEQ ID NO: 76, a CDRH2 of SEQ ID NO: 77, and a CDRH3 of SEQ ID NO:78;
(vii) a CDRL1 of SEQ ID NO: 83, a CDRL2 of YAF, a CDRL3 of SEQ ID NO: 84, a CDRH1 of SEQ ID NO: 85, a CDRH2 of SEQ ID NO: 86, and a CDRH3 of SEQ ID NO: 87;
(viii) a CDRL1 of SEQ ID NO: 92, a CDRL2 of AAS, a CDRL3 of SEQ ID NO: 93, a CDRH1 of SEQ ID NO: 94, a CDRH2 of SEQ ID NO: 95, and a CDRH3 of SEQ ID NO: 96;
(ix) a CDRL1 of SEQ ID NO: 101, a CDRL2 of WAS, a CDRL3 of SEQ ID NO: 102, a CDRH1 of SEQ ID NO: 103, a CDRH2 of SEQ ID NO: 104, and a CDRH3 of SEQ ID NO: 105; or
(x) a CDRL1 of SEQ ID NO: 110, a CDRL2 of AAS, a CDRL3 of SEQ ID NO: 111, a CDRH1 of SEQ ID NO: 112, a CDRH2 of SEQ ID NO: 113, and a CDRH3 of SEQ ID NO: 114.
Claim 106. The fusion protein of claim 1, wherein the PD-1 antibody comprises, comprising:
(i) a light chain variable region of SEQ ID NO: 34 and a heavy chain variable region of SEQ ID NO: 35;
(ii) a light chain variable region of SEQ ID NO: 43 and a heavy chain variable region of SEQ ID NO: 44;
(iii) a light chain variable region of SEQ ID NO: 52 and a heavy chain variable region of SEQ ID NO: 53;
(iv) a light chain variable region of SEQ ID NO: 61 and a heavy chain variable region of SEQ ID NO: 62;
(v) a light chain variable region of SEQ ID NO: 70 and a heavy chain variable region of SEQ ID NO: 71;
(vi) a light chain variable region of SEQ ID NO: 79 and a heavy chain variable region of SEQ ID NO: 80;
(vii) a light chain variable region of SEQ ID NO: 88 and a heavy chain variable region of SEQ ID NO: 89;
(viii) a light chain variable region of SEQ ID NO: 97 and a heavy chain variable region of SEQ ID NO: 98;
(ix) a light chain variable region of SEQ ID NO: 106 and a heavy chain variable region of SEQ ID NO: 107; or
(x) a light chain variable region of SEQ ID NO: 115 and a heavy chain variable region of SEQ ID NO: 116.
Claim 116. A pharmaceutical composition comprising the fusion protein of claim 1, and a pharmaceutically acceptable excipient.
Claim 122. A method of treating one or more symptoms of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the fusion protein of claim 1.
Claim 125. A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of the fusion protein of claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Conclusion: No claim is 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
Prosecution Insights