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 .
Claim Status
Claims 1, 16-17, 26, 29-30, 44, 46, 48, 58-59, and 62 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 9-10, 13, 16-17, 23, 26, 29-30, 42-44, 46, 48, and 56-58, in the reply filed on April 9, 2024 is acknowledged. Claims 59 and 62 have been withdrawn for being drawn to non-elected subject matter, and claims 1, 16-17, 26, 29-30, 44, 46, 48, and 58 have been considered on the merits.
Previous Rejections
Status of the rejections: the previous rejections pursuant to section 112(a) are withdrawn in view of the claim amendments.
Claim Interpretation
In the claims, the term “full length” with regard to an antibody is interpreted to require the antibody comprises at least two heavy chains and two light chains, wherein the heavy chains each comprise both a Fab portion and an Fc portion.
In claim 1, the term “monoclonal” is interpreted as not limiting in anyway because a polynucleotide encoding a monoclonal antibody has no additional feature, either explicitly or implicitly, and the claim is not interpreted as a product-by-process with regard to the polynucleotide being produced by the creation of a monoclonal antibody.
In claim 1, the limitations to the following elements in frame in an orientation from 5' to 3' of (1) “a polynucleotide encoding the light chain of an antibody binding to CD137” – (2) “a first early and late promoter pSE/L” – (3) “a second early and late promoter pSE/L” – (4) “a polynucleotide encoding the heavy chain of an antibody binding to CD137” – (5) “a polynucleotide encoding the heavy chain of an antibody binding to PD-1” – (6) “a first late promoter pSL” – (7) “a second late promoter pSL” – and (8) “a polynucleotide encoding the light chain of an antibody binding to PD-1” are interpreted to require: 2) the first early and late promoter being operably linked to (1) the polynucleotide encoding the light chain of an antibody binding to CD137; (3) the second early and late promoter being operably linked to (4) the polynucleotide encoding the heavy chain of an antibody binding to CD137; (6) the first late promoter being operably linked to the polynucleotide encoding the heavy chain of an antibody binding to PD-1; and (7) the second late promoter being operably linked to (8) the polynucleotide encoding the light chain of an antibody binding to PD-1. Each of the four encoding elements (1, 4, 5, and 8) are implied to be operably linked to a promoter from among the four required promoter elements (2, 3, 6, and 7) with the most adjacent promoter being the most parsimonious interpretation but other interpretations are encompassed by the claim. For example, wherein the promoter elements (2 and 3) and/or (4 and 5) are optionally in a “head-to-head orientation” as explained in the instant specification at [0172]-[0173]. Furthermore in this configuration, not only are the PD-1 inhibitor from the first heterologous polynucleotide and the CD37 activator expressed from the second heterologous expressed as separate proteins but each of their respective heavy and light chains are expressed as separate polypeptides of said respective proteins.
Claim Rejections - 35 USC § 112(b) (new)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 16-17, 26, 29-30, 44, 46, 48, and 58 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.
In claim 1, the virus genome “comprises at least one deletion” “in an Open Reading Frame (ORF) encoding at least part of thymidine kinase” and the first and second heterologous polynucleotides are inserted “in place of” that deletion, which is incoherent, ambiguous and unclear. One of ordinary skill in the art would not be appraised of the metes and bounds of this limitation when a deletion can be a single nucleotide or more than one thousand nucleotides as compared to an unrecited vaccinia reference genome and that is “replaced” by a two heterologous polynucleotides insertion. Neither the claim nor the instant specification provides how to identify or ascertain any such deletion replacing insertions given a modified vaccinia genome to analyze. Also, how a single deletion is “replaced” with two different polynucleotides is unclear. Are the two polynucleotides fused together to form a single combination polynucleotide? Further, a claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). Here, the determination of the scope of “insertion” “in place of” a “deletion” in a vaccinia viral genome is an indefinite variable. Claims 16-17, 26, 29-30, 44, 46, 48, and 58 are included in this rejection for being dependent on indefinite claim 1.
In claim 1, the “Open Reading Frame (ORF) encoding at least part of thymidine kinase” is incoherent, ambiguous and unclear. The naturally occurring vaccina virus thymidine kinase gene (J2R) comprises an ORF encoding the entire thymidine kinase (VVTK). Thus, the claim is an ambiguous as to whether the genome of the modified virus claimed has a synthetic thymidine ORF(s) encoding only a part of a thymidine kinase, such as a heteromeric thymidine kinase, and further ambiguous to the precise location of the deletion in the genome to provide notice on how to identify such. Claims 16-17, 26, 29-30, 44, 46, 48, and 58 are included in this rejection for being dependent on indefinite claim 1.
Claim Rejections - 35 USC § 103 (modified)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 16, 26, 29, 44, 46, 48, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Song (WO2018049261A1) in view of Maecker (US Patent 9,724,413 B2), Jure-Kunkel (US Patent 7,288,638 B2), Amendola (Amendola et al., Nat Biotechnol 23: 108-16 (2005)), Chakrabarti (Chakrabarti et al., Biotechniques 23: 1094-7 (1997)), and Schaefer (Schaefer et al., PNAS U.S.A. 108: 11187-92. (2011)).
The claims are interpreted as explained in a previous section.
Regarding claim 1, Song teaches oncolytic vaccinia viruses ([0008]-[0009]; [0169]) having a modified genome comprising a deleted thymidine kinase (TK) gene that increases selective replication in tumor cells ([0173], [0009]) by a targeted insertion ([0436]; [0564]) of heterologous polynucleotides ([0191]) encoding an immune checkpoint inhibitor full-length antibody ([0324]; [0192]) capable of specifically binding to PD-1 wherein expression is controlled by a pSL late promoter(s) ([0063]; [0071]; [0357]; [0192]; [0176]; [0228]; [0008]; [0459]; [0468]; [0511]; [0063], [0067]; [0069]; [0088]; [0092]; [0072]). Song further teaches wherein the virus comprises only two heterologous polynucleotides: (1) a first heterologous polynucleotide encoding a full-length PD-1 inhibitor antibody operably linked to a pSL late promoter(s) and (2) a second heterologous polynucleotide operably linked to a pSE/L promoter(s) ([0024]) and encoding a protein comprising an antigen binding domain recognizing a cell surface CD137 ([0260]; [0019]; [0105]) on an immune effector cell to provide activation ([0013]; [0016]; [0086]; [0093]; [0502]; [0261]) (engager or bispecific molecule), such as an antibody binding two different epitopes on a single CD137 molecule ([0047]-[0049]). In addition, Song teaches synthetic early/late and late promoters are relatively strong promoters for use in transgene expression ([0227]).
Although Song teaches coexpressing a vaccinia virus-delivered PD-1 inhibitor antibody and a CD137 agonist antibody constructs driven by different promoters PSL and PSEL ([0008]; [0064]; [0467]-[0468]; [0502], [0511]), Song does not teach wherein (I) the two heterologous polynucleotide are configured such that they are expressed in different stages of the replicative cycle of the modified oncolytic virus and wherein the modified oncolytic virus genome comprises (II) the following elements in-frame in an orientation from 5' to 3' of the sense strand of a polynucleotide: (1) a polynucleotide encoding the light chain of an antibody binding to CD137 – (2) a first early and late promoter pSE/L – (3) a second early and late promoter pSE/L – (4) a polynucleotide encoding the heavy chain of an antibody binding to CD137 – (5) a polynucleotide encoding the heavy chain of an antibody binding to PD-1 – (6) a first late promoter pSL – (7) a second late promoter pSL – and (8) a polynucleotide encoding the light chain of an antibody binding to PD-1.
However Chakrabarti teaches compact synthetic viral promoters like the pSE/L and pSL late promoter provide robust expression of transgenes in host cells after viral delivery, with the late promoter PSL (vMJ441) and the early/late promoter PSEL (vSC56) exhibiting the strongest expression out of 10 poxvirus promoters tested for transgene expression (Table 1; pg. 1096, middle col.). Chakrabarti teaches specifically using a “back-to back” arrangement of synthetic early later promoters (e.g., PSEL) for expressing two different polypeptides simultaneously from a genetically modified oncolytic poxvirus (pg. 1097, last para.).
Amendola teaches using a bidirectional promoter viral vector approach for expressing two transgenes from a single polynucleotide construct by joining flanking core promoters in opposing orientations (back-to-back arrangement) provides benefits of coordinate regulation and avoids mutual interference as well as avoids limitations observed for other approaches like using two vectors or bicistronic mRNA formats with an IRES or self-cleaving 2A peptide (pg. 108, left col., last para., to right col., 3rd para.; Abstract).
Maecker teaches a monoclonal anti-PD-1 antibody (nivolumab or MDX-1106) that binds a polypeptide comprising instant SEQ ID NO: 1 and comprising a heavy chain comprising instant SEQ ID NO: 6 and SEQ ID NOs: 2, 3, and 4 (SEQ ID NO: 22), as shown below, and a light chain comprising instant SEQ ID NO: 13 and SEQ ID NOs: 9, 10, and 11 (SEQ ID NO: 23; col. 29, lines 31-61), as shown below.
US-14-236-064-22
Sequence 22, US/14236064
Patent No. 9724413
GENERAL INFORMATION
APPLICANT: GENENTECH, INC.
APPLICANT: MAEACKER, Heather
TITLE OF INVENTION: METHODS OF TREATING CANCER USING PD-1 Axis
CURRENT APPLICATION NUMBER: US/14/236,064
CURRENT FILING DATE: 2014-01-29
PRIOR APPLICATION NUMBER: PCT/US2012/049233
PRIOR FILING DATE: 2012-08-01
PRIOR APPLICATION NUMBER: US 61/574,406
PRIOR FILING DATE: 2011-08-01
LENGTH: 440
TYPE: PRT
OTHER INFORMATION: Synthetic Construct
Query Match 100.0%; Score 2348; Length 440;
Best Local Similarity 100.0%;
Matches 440; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
Qy 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPS 120
Qy 121 VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 180
Qy 181 VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP 240
Qy 241 KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT 300
Qy 301 VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC 360
Qy 361 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV 420
Qy 421 MHEALHNHYTQKSLSLSLGK 440
||||||||||||||||||||
Db 421 MHEALHNHYTQKSLSLSLGK 440
US-14-236-064-22
Sequence 23, US/14236064
Patent No. 9724413
Query Match 100.0%; Score 1106; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Jure-Kunkel teaches an agonistic anti-CD137 (4-1BB) antibody (urelumab) comprising a heavy chain comprising instant SEQ ID NO: 21 and SEQ ID NOs: 17, 18, and 19 (SEQ ID NO: 3), as shown below, and a light chain comprising instant SEQ ID NO: 29 and SEQ ID NOs: 24, 25, and 26 (SEQ ID NO: 6; col. 7, lines 37-41; FIG. 3A-D), as shown below, as well as polynucleotides encoding the aforementioned (col. 8, lines 12-19). Jure-Kunkel teaches antibodies comprising these sequences (mab 20H4.9-IgG4 and mab 20H4.9-IgG1) resulted in increased immuno-activation in vitro and in vivo (e.g., enhanced cellular responses to antigens, increased IFN-γ secretion, and increased T cell survival) (Examples 2-3; FIG. 13-16).
US-10-961-567A-3
Patent No. 7288638
GENERAL INFORMATION
APPLICANT: Jure-Kunkel, Maria
TITLE OF INVENTION: FULLY HUMAN ANTIBODIES AGAINST HUMAN 4-1BB
CURRENT APPLICATION NUMBER: US/10/961,567A
CURRENT FILING DATE: 2004-10-08
PRIOR APPLICATION NUMBER: US 60/510193
PRIOR FILING DATE: 2003-10-10
SEQ ID NO 3
LENGTH: 467
TYPE: PRT
ORGANISM: Artificial
Query Match 100.0%; Score 2406; Length 467;
Best Local Similarity 100.0%;
Matches 448; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 20 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYN 79
Qy 61 PSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 80 PSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVS 139
Qy 121 SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 140 SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 199
Qy 181 SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 200 SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS 259
Qy 241 VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 260 VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST 319
Qy 301 YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 320 YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT 379
Qy 361 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 380 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE 439
Qy 421 GNVFSCSVMHEALHNHYTQKSLSLSLGK 448
||||||||||||||||||||||||||||
Db 440 GNVFSCSVMHEALHNHYTQKSLSLSLGK 467
US-10-961-567A-6
Sequence 6, US/10961567A
Patent No. 7288638
Query Match 100.0%; Score 1118; Length 236;
Best Local Similarity 100.0%;
Matches 216; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 80
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIKRTVAAPSVFIF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIKRTVAAPSVFIF 140
Qy 121 PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 200
Qy 181 LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 216
||||||||||||||||||||||||||||||||||||
Db 201 LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 236
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select for use in the virus taught by Song two transgenes, one encoding a PD-1 antibody and the other encoding a CD137 antibody. One of ordinary skill in the art would be motivated to make as strong as anticancer virus as possible by combining multiple anticancer features into a single virus (oncolytic activity, PD-1 axis inhibition, immune stimulation) as taught by Song generally ([0294, [0302], [0366]-[0367]), as regarding CD137 specifically as Jure-Kunkel teaches CD137 antibodies for use as enhancers of cancer therapies (col. 7, lines 3-14Examples 2-3; FIG. 13-16) and regarding PD-1 specifically as taught by Song ([0184]) and Maecker that PD-1 axis inhibition by antibodies enhances ither anti-cancer treatments (col. 2, lines 29-34). Further, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the checkpoint inhibitor anti-PD-1 monoclonal antibody comprising instant SEQ ID NOs: 2, 3, and 4 (e.g., 100% sequence identity to SEQ ID NO: 6) paired with SEQ ID NOs: 9, 10, and 11 (e.g., 100% sequence identity SEQ ID NO: 13) as taught by Maecker and the anti-CD137 full-length antibody taught by Jure-Kunkel. One of ordinary skill in the art would be motivated to because Maecker teaches this particular PD-1 antibody is an antagonist to PD-1 immune checkpoint signaling resulting in PD-1 axis blockade and enhanced immune responses (col. 2, lines 21-52; col. 7, lines 8-15), and Jure-Kunkel validated this CD137 antigen binding antibody as an effective agonist to CD137 resulting in immune activation in vivo for administering the modified virus to a subject to enhance immune effector cell activation.
Further, one of ordinary skill in the art is aware of an antibody chain mismatch association problem in view of Schaefer (pg. 11187, right col., 2nd para.; Fig. 1A) when coexpressing two different full-length antibodies in a cell at the same time whereby light chains and heavy chains heterodimerize, potentially forming a high percentage of nonfunctional antibodies and a minor amount of bispecific antibodies able to bind both targets. Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to construct the modified virus of Song wherein the first and second heterologous polynucleotides are in-frame in an orientation from 5' to 3' of the sense strand: (1) a polynucleotide encoding the light chain of a agonistic full-length antibody binding to CD137 – (2) the first early and late promoter pSE/L – (3) the second early and late promoter pSE/L – (4) a polynucleotide encoding the heavy chain of the CD137 antibody - (5) a polynucleotide encoding the heavy chain of an inhibitory antibody binding to PD-1 – (6) a first late promoter pSL – (7) a second late promoter pSL – and (8) a polynucleotide encoding the light chain of the PD-1 antibody. One of ordinary skill in the art would be motivated to select the strongest pSE/L and pSL promoters taught by Chakrabarti and wherein the promoters are in a bidirectional head-to-head orientation to better provide coordinated expression of the respective pairs of light and heavy antibody chains and avoid the limitations of alternative approaches as taught by Amendola. Regarding the choice of the pSE/L promoter for one antibody and the pSL promoter for the other antibody, the skilled artisan aware of problematic antibody chain mismatch association as taught by Schaefer would be motivated to use different promoters with asynchronous expression (e.g., early or late) so that the two antibodies could be produced at different times whereby the two strongest synthetic promoters pSE/L and pSL taught by Chakrabarti provide for this in the form of early expression by pSE/L and exclusively late expression by pSL.
Regarding the limitation to the 5' to 3' on the sense strand of the viral genome, the skilled worker would only have a limited number of options to choose from and the instant application provides no evidence the other options are not equivalent in function. Thus, the particularly recited structural option is equally obvious as the other options, e.g., 3’ to 5’ on the sense strand or 5’ to 3’ on an antisense strand. See MPEP 2144.08.ii.a.4. Similarly, regarding the order of each antibody’s heavy and light chains with respect to their head-to-head reporters, the skilled worker would only have a limited number of two options to choose from and the instant application provides no evidence the other option is not equivalent in function for each antibody. Therefore, the recited format is functionally equivalent to and equally obvious as any other the limited possible orientations. See MPEP 2144.08.ii.a.4.
Regarding the order of the two antibody encoding constructs (CD137 then PD-1 5’ to 3’), the skilled worker would only have a limited number of two options to choose from. Therefore, the format recited in the claims is obvious as a limited possible orientations. See MPEP 2144.08.ii.a.4.
Regarding the specific use of the pSE/L promoter for the CD137 antibody and the pSL promoter for the PD-1 antibody, the instant application provides no evidence this selection has any functional consequence as to antibody expression, and thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to choose from any suitable and equivalent promoter, e.g., from the top expressing promoters taught in Chakrabarti (Table 1). Furthermore regarding the claim language “such that they are expressed in different stages of replicative cycle of the modified oncolytic virus” is considered both an intended use and an inherent feature of the promoter arrangement of the pSL and pSE/L promoters operably linked to the respective antibody chains. Any intended use of the claimed product to express a PD-1 antibody and CD137 antibody “in different stages of a replicative cycle of the modified oncolytic virus” is not given patentable weight when it does not imply anything more to the virus as positively recited in claim 1 and would be an inherent capability of the arrangement taught by the prior art when selecting from the top two best expressing promoters taught by Chakrabarti (Table 1).
Regarding claim 16, Maecker teaches the anti-PD-1 antibody (nivolumab) comprises a heavy chain comprising instant SEQ ID NO: 6 (SEQ ID NO: 22) and a light chain comprising instant SEQ ID NO: 13 (SEQ ID NO: 23; col. 29, lines 31-61).
Regarding claims 29, Jure-Kunkel teaches the agonistic anti-CD137 (4-1BB) antibody (urelumab) comprises a heavy chain comprising instant SEQ ID NO: 21 (SEQ ID NO: 3) and a light chain comprising instant SEQ ID NO: 29 (SEQ ID NO: 6; col. 7, lines 37-41; FIG. 3A-D).
Regarding claim 44, as laid out above regarding claim 1, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing in view of the combination of Song, Amendola, Chakrabarti, and Schaefer to design a modified oncolytic virus comprising an engineered genome comprising the following elements in-frame in an orientation from 5' to 3' of a sense strand: (1) a polynucleotide encoding the light chain of the antibody binding to CD137 – (2) a first early and late promoter pSE/L – (3) a second early and late promoter pSE/L – (4) a polynucleotide encoding the heavy chain of the antibody binding to CD137 – (5) a polynucleotide encoding the heavy chain of the antibody binding to PD-1 – (6) a first late promoter pSL – (7) a second late promoter pSL – and (8) a polynucleotide encoding the light chain of the antibody binding to PD-1 wherein the elements (4) and (5) are adjacent to each other as the most parsimonious design. Because no element is implied or required to be between elements (1)-(4) and (5)-(8), it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the modified oncolytic wherein the first (5)-(8) and second (1)-(4) heterologous polynucleotides are immediately upstream or downstream of each other because the skilled artisan only has a limited number of options to choose from and would be motivated by the limited packaging size of engineering oncolytic virus genomes to minimize spacing between the heterologous polynucleotides.
Regarding claim 46, as set forth above for claim 1, the combination of Song, Amendola, Chakrabarti, and Schaefer teaches a PD-1 antibody viral transgene arrangement comprising: two pSL promoters taught by Song and Chakrabarti driving expression of (5) the polynucleotide encoding the heavy chain of the PD-1 antibody and (8) the polynucleotide encoding the light chain of PD-1 antibody wherein the two promoters (6) and (7) are arranged head-to-head and the antibody chains are arranged in back-to-back fashion as taught by Amendola to provide more equivalent and coordinated expression of the assembling subcomponents of the PD-1 inhibitor antibody.
Regarding claim 48, as set forth above for claim 1, the combination of Song, Amendola, Chakrabarti, and Schaefer teaches a transgene arrangement comprising: two pSE/L promoters taught by Song and Chakrabarti driving expression of (1) the polynucleotide encoding the light chain of the CD137 antibody and (4) the polynucleotide encoding the heavy chain of the CD137 antibody wherein the two promoters (2) and (3) are arranged head-to-head and the antibody chains are arranged in back-to-back fashion as taught by Amendola to provide more equivalent and coordinated expression of the assembling subcomponents of the CD137 activating antibody.
Regarding claim 58, Song teaches wherein the modified oncolytic virus is a component of a pharmaceutical composition also comprising a pharmaceutically acceptable carrier ([0516]; [0026]; [0293]).
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Dec. 22, 2025 (at pg. 8-16) have been fully considered but not found persuasive.
Applicant traverses the previous rejection in part by arguing, although Song teaches generally using both immune checkpoint inhibitors and activators of immune stimulation, that Song does not teach, suggest, or motivate the combination of both in a single modified oncolytic virus nor specifically selecting CD137/4-lBB as the preferred target of a stimulatory antibody amongst numerous disclosed options nor more specifically coexpressing a full-length anti-PD-1 antibody and a full-length anti-CD137 antibody.
Song teaches using engineered oncolytic viruses as cancer therapeutics via expression of various immune checkpoint modulators, including PD-1 inhibitory antibodies and stimulatory activators, such as anti-4-1BB antibodies ([0003], [0005]; [0011]; [0182]; [0039]; [0050]-[0051]; [0292]-[0293]).
Although Song may not expressly state to combine the PD-1 antibody with the anti-4-1BB antibody in a single modified vaccinia virus, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
A person of ordinary skill in the art before the earliest effective filing date would be well aware and motivated by the potential benefits of combining multiple anti-cancer therapeutics into a single therapy (see Song at [0294, [0302], [0366]-[0367]), such as providing two different antibodies simultaneously or combining an antibody gene therapy with an oncolytic viral therapy. Song at least establishes the prior art combination of an oncolytic vaccinia virus expressing a stimulatory anti-4-1BB antibody and another oncolytic vaccinia virus expressing an inhibitory anti-PD-1 antibody. This is sufficient motivation to combine these into a single virus based on logic and knowledge generally available at the time. Furthermore, there is a reasonable expectation of successfully producing such a virus encoding two antibodies as this within the routine skills of one of ordinary skill at the time. Song teaches specific examples doing so not encompassed by the instant claims wherein the virus expresses a PD-1 antibody transgene and a bispecific antibody simultaneously (FIG. 1), as well as virus expressing a plurality of different transgenes ([0025]).
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
Applicant argues that Song’s discussion of preferred embodiments and focus on other embodiments constitutes a “lack of motivation” to arrive the precise combination rendered obvious by the prior art collectively. However the motivations in the prior art can exist despite the art being focused on other technical solutions. Combining species listed in a single references is obvious if there is a supporting rationale to do so, such as combining two known anti-cancer therapeutics into a single therapy. The fact that the disclosure in Song may be broad and non-selective and/or focused on different embodiments is irrelevant here.
Applicant discussion of FIG. 1 in Song is irrelevant as this figure is of an “exemplary” embodiment and non-limiting as noted by Song ([0029]; [0564]; [0561]). It is irrelevant if Song’s preferred embodiments rely on different targets (e.g., CD3) or scFv formats. The skilled artisan is not limited by the preferences or goals expressed in Song so long as Song does not teach away from the combination of claimed features rendered obvious. Song clearly teaches full length monoclonal antibodies to PD-1 and CD137 ([0182]), teachings which the skilled artisan can use to formulate as a combination of prior art elements. Song need not provide any “priority” to this combination amongst all the other teachings contained within Song for the ordinary person of skill in the art to come to such a conclusion. There is no requirement that prior art must show actual implementation of a combination taught as the teachings alone (in the absence of working embodiments or empirical evidence) can provide constructive reduction to practice.
Applicant also traverses by arguing no reasonable expectation of success at arriving at the inventive solution (Response at pg. 13). However, the only success required once motivated is the genetic engineering of the vaccina genome as required by the claim limitations. All the structural features of the claimed virus can be made with success using routine methods known in the prior art as outlined in the modified rejection. Applicant is again reminded that the claims are directed to a product, not a process or intended use of said product.
Because the features combined from Song, Amendola, and Chakrabarti are all utilized for art-recognized oncolytic virus transgene expression vector construction purposes, one would arrive at the claimed invention with a reasonable expectation of success prior to the instant filing date.
Applicant further argues that prima facie obviousness is rebutted by evidence of unexpected superior technical effects of the claimed invention compared to the prior at (pg. 14-16). However this evidence is lacking when there is no comparative data or establishment of what is expected, e.g., comparing the claimed invention to viruses taught solely by Song. Furthermore, the intended use of expressing two different antibodies from a single viral vector is not considered for patentability over the prior art if the prior art suggests the claimed structural arrangement. The claims are directed to a product and not a method, such as of polynucleotide expression in a cell or administering a virus to a subject. Thus, so long as there is a rationale to produce a product with the claimed structural arrangement in the prior art, the product is obvious regardless of predictability of any result during an intended use.
Instead, such purported unexpected evidence is provided regarding the single embodiment named GS-600 or GS600 after administration to a mouse model of breast cancer (Response, pg. 15-16). FIG. 32 claims to show the biodistribution of GS600 in a recipient mouse administered the claimed virus via intratumoral injection (IT) results in relatively-specific tumor tissue-limited GS600 virus localization/distribution/targeting. However GS-610, which is not encompassed by the claims exhibits a similar distribution in vivo (FIG. 32; [00257]) and, thus, it is not clear what is being represented on the Y-axis (PFU/g) in FIG. 32. As it is, the unexpected effect appears unrelated to the claimed invention as demonstrated by GS-610. The other supporting figure discussed in the response has no comparison data.
Applicant argues that the data presented “proves” that GS-600 provides a technical advantage compared with the “prior art” by: (1) providing both high concentrations of the exogenous antibodies in the tumor tissue and (2) low-to-none in other tissues thereby reducing potential off-target side effects. However it is not clear what “prior art” this is being compared to, such as whether GS-610 and/or GS-620 is considered prior art.
As made of record, the prior art teaches engineering vaccinia viruses to express various transgenes, such as antibodies to PD-1 or CD137, and using various viral promoters, such as pSE/L and pSL. Thus, as an unexpected result over the prior art should be compared to the closest prior art, an appropriate comparison would be to viruses taught by Song, such as the result of administering two oncolytic vaccinia viruses, one expressing the prior art nivolmab antibody and the other expressing the prior art urelumab antibody, or even a similar singular virus combination expressing both as taught by Song but not using the promoter arrangements recited in the claims, i.e., structures other than (1) “a polynucleotide encoding the light chain of an antibody binding to CD137” – (2) “a first early and late promoter pSE/L” – (3) “a second early and late promoter pSE/L” – (4) “a polynucleotide encoding the heavy chain of an antibody binding to CD137” – (5) “a polynucleotide encoding the heavy chain of an antibody binding to PD-1” – (6) “a first late promoter pSL” – (7) “a second late promoter pSL” – and (8) “a polynucleotide encoding the light chain of an antibody binding to PD-1.”
A person of ordinary skill in the art would reasonably predict that both the anti-PD-1 and anti-4-1BB antibodies could be successfully expressed in tumor cells in mice upon administration of such a virus intratumorally via injection, and that this expression would be higher in tumor cells than other cells due to thymidine kinase deletion as taught by Song. Thus, the result is not unexpected and would be achieved with a reasonable expectation of success in view of the advanced transgene and viral vector knowledge known prior to the earliest effective filing date of Sept. 10, 2018.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638