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 .
Claims 29, 32, 34, 37-42, and 44-58 are pending. Claims 44-50 are withdrawn from consideration as being drawn to a nonelected invention.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06 March 2026 has been entered.
Status of the Application
Applicant’s response and amendment filed 17 February 2026 are acknowledged and entered.
Applicant has amended Claims 29, 32, 34, 53, and 57-58. Applicant has cancelled Claims 30-31 and 35-36.
Response to Amendment
Applicant has amended the claims to overcome Objections; the previous objections are withdrawn.
Applicant has amended the claims to overcome the 112(a) rejection; the 112(a) rejection is maintained.
The 102 rejection over Claim 29 is withdrawn but is applied to Claim 57.
Applicant has amended the claims to overcome the 103 rejection; the 103 rejection is updated in response to the claim amendments.
The NSDP rejections over US 5276141, US 8058049, US 8415133, and US 8415134 are withdrawn. The other NSDP rejections are maintained.
Claims 29, 32, 34, 37-42, and 51-58 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Drawings
The drawings are objected to because of the following informalities:
Fig. 6—some text is cut off from the x-axis label on the right.
Fig. 11—the y-axis label should read secretion.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The Spec. indicates (p. 5 L10) that native means wild-type.
The term “oncolytic virus” is interpreted as a virus that has the capacity to selectively replicate in dividing cells. That interpretation is based on the instant Spec. defining (p. 20-21 L 34-10) “oncolytic” to mean a capacity to selectively replicate in dividing cells. The definition reads:
the term "oncolytic" refers to the capacity of a poxvirus of selectively replicating in dividing cells (e.g. a proliferative cell such as a cancer cell) with the aim of slowing the growth and/or lysing said dividing cell, either in vitro or in vivo, while showing no or minimal replication in non-dividing (e.g. normal or healthy) cells. "Replication" (or any form of replication such as "replicate" and "replicating", etc.,) means duplication of a virus that can occur at the level of nucleic acid or, preferably, at the level of infectious viral particle.
The portion of that definition that reads with the aim of slowing the growth and/or lysing said dividing cell, either in vitro or in vivo is not considered relevant because a virus does not have any capacity for an “aim” (which indicates intention).
Claims 29 and 57 recite an engineered poxvirus that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus. The Spec. discloses (p. 17 L10-20) those poxviruses do not have an M2L in their native form:
In the context of the invention, the term "poxvirus" does not include poxviruses which in the native context have genomic deletion(s) or mutation(s) encompassing M2L locus (or equivalent) which thus, lack a m2 polypeptide or encode a non-functional m2 protein such as Pseudocowpox virus (PCPV), MVA and NYVAC virus.
Claims 34 and 53 recite an m2 coding sequence. That is interpreted as referring to an M2L locus encoding a functional m2 poxviral protein.
Claim 55 recites at least one ligand. The Spec. does not provide any special definition for a ligand so it’s interpreted as anything that forms a complex with a biomolecule. Therefore cytokines and chemokines are kinds of ligands.
Claims 57-58 recite that the engineered poxvirus lyses dividing cells. An oncolytic virus is understood to lyse cells because such lytic activity is in the name oncolytic.
Claim Objections
Claims 29, 42, 52, 57-58 are objected to because of the following informalities:
Claim 29 should be amended as follows:
Italicize Orthopoxvirus.
To specify exactly how many modifications are required, the claim should recite:
…wherein the engineered poxvirus is further engineered in:
(i) the J2R locus and
(ii) the I4L locus and/or in the F4L locus,
resulting in an engineered poxvirus defective for m2, tk, and rr activities.
Claims 42 and 52: to be less redundant, the claims should remove is a poxvirus defective for m2, tk, and rr activities (which is already recited in Claim 29): The engineered poxvirus of Claim 41, wherein the engineered poxvirus encodes an anti PD-L1 antibody (Claim 42) or The engineered poxvirus of Claim 51, wherein the engineered poxvirus encodes an anti-CTLA-4 antibody (Claim 52).
Claim 53: the claim should use consistent language for “m2-coding”. Claims 29 and 34 use hyphens so Claim 53 should, too. Also, the claim should recite: The engineered poxvirus of Claim 29, wherein the genetic lesion is a partial deletion within the M2L locus selected from the group consisting of:
a partial deletion extending from upstream of the m2-coding sequence to at least the first 100 codons of the m2-coding sequence, and
a partial deletion extending from 64 nucleotides upstream of the m2-coding sequence to the 169 first codons of the m2-coding sequence.
Claim 57 should be amended to put wherein the inability to bind… the M2L locus at the same indent level as wherein the engineered poxvirus is not… (like what’s in Claim 29).
Claim 58 should delete even and should recite …mammalian cells in the absence of cytokines.
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.
Claims 32 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. These rejections are new in response to claim amendments.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 32 depends from Claim 31. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. There is no Claim 31 so the dependency of Claim 32 is unclear.
In the interest of compact prosecution Claim 32 is interpreted to depend from Claim 29.
Claim 58 recites: The engineered poxvirus of Claim 29, wherein the engineered poxvirus selectively replicates in human and mammalian dividing cells and lyses said dividing human and mammalian cells in vitro in non-dividing human and mammalian cells, even in the absence of cytokines. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because the bolded/underlined part of the claim isn’t clear.
In the interest of compact prosecution the claim will be interpreted as if it recites: The engineered poxvirus of Claim 29, wherein the engineered poxvirus selectively replicates in human and mammalian dividing cells and lyses said dividing human and mammalian cells in the absence of cytokines.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 29, 32, 34, 37-42, and 51-58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection. These rejections are maintained and updated in response to claim amendments.
Claims 29, 32, 34, 37-42, and 51-58 recite the following genera:
Claims 29, 42, 52, and 57: an engineered poxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus. Claims 29, 42, and 52 further recite wherein the genetic lesion comprises a partial deletion within the M2L locus wherein the partial deletion is within the m2-coding sequence and/or in an m2 promoter, or a total deletion of the m2-coding sequence or m2 promoter or a total deletion of the M2L locus, wherein the engineered poxvirus is obtained by engineering a poxvirus of the Orthopoxvirus genus, wherein the engineered poxvirus is oncolytic, and wherein the engineered poxvirus is further engineered in (a) the J2R locus and (b) the I4L locus and/or F4L locus, which results in a virus defective for m2, tk, and rr activities.
The Spec. does not demonstrate possession of engineered poxviruses generated or obtained from a representative number of Orthopoxviruses. The Spec. does not adequately describe what nts make the recited loci “defective”.
Claim 34: the genetic lesion is a partial deletion within the m2 coding sequence and/or in a m2 promoter, or is a total deletion of the m2 coding sequence or m2 promoter.
Claims 37-39, : wherein the engineered poxvirus is recombinant (Claim 37) and
(Claim 38) is engineered to express at least one cytokine and (Claim 39) wherein the cytokine is IL-12;
(Claim 54) wherein the engineered poxvirus is engineered to express at least one chemokine;
(Claim 55) wherein the engineered poxvirus is engineered to express at least one ligand;
(Claim 56) wherein the engineered poxvirus is engineered to express at least one antibody (Ab),
(Claim 40) wherein the Ab specifically binds an immune checkpoint protein,
(Claim 41) wherein engineered poxvirus expresses an antagonist Ab that specifically binds to PD-L1, (Claim 42) wherein the engineered poxvirus is defective for m2, tk, and rr activities and encodes an anti-PD-L1 Ab;
(Claim 51) wherein the wherein engineered poxvirus expresses an antagonist Ab that specifically binds to CTLA-4, (Claim 52) wherein the engineered poxvirus is defective for m2, tk, and rr activities and encodes an anti-CTLA-4 Ab.
Regarding Claims 37-42, 51-52, and 54-56, the Spec. does not demonstrate possession of engineered viruses engineered to express a representative number of the recited species.
Claims 57-58: wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro, including in the absence of cytokines. The Spec. does not adequately describe the structure responsible for the claimed functions, or (Claim 58) the structures that operate differently in the presence vs. the absence of cytokines.
These broad claims encompass numerous large genera and subgenera of defects, viruses, mutations, or molecules. The claims encompass agents identified solely by their functions.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
Claims 29 and 57 recite any modified poxvirus wherein the m2 poxvirus protein has been modified so that it’s unable to bind CD80/CD86 which encompasses any modified poxvirus wherein the m2 poxvirus protein has been modified so that it’s unable to bind CD80/CD86 costimulatory ligands. Additionally, Claims 29 and 57 recite that the inability to bind CD80/CD86 originates from a total or partial genetic lesion in the M2L locus. Claims 29 and 57 require the poxvirus to be oncolytic and they exclude the specific poxviruses MVA, PCPV, and NYVAC. Claim 29 recites that the virus can be engineered from any member of the genera Orthopoxvirus. Claim 58 recites that the engineered poxvirus selectively replicates in human and mammalian dividing cells and does so in the absence of cytokines.
Any member of the Orthopoxvirus genus comprising a “defective” m2 poxvirus protein would be encompassed by the claims as instantly presented. Those claims encompass a but the Spec. does not divulge any requisite structure that will render the protein defective and unable to bind CD80/86 costimulatory ligands. The claims require the virus selectively replicates in human and mammalian dividing cells but shows no or minimal replication in nondividing human and mammalian cells but do not recite any structure responsible for that function and the Spec. does not disclose any structure responsible for the function.
Claim 34 recites that the inability to bind CD80/CD86 costimulatory ligands originates from any partial or total genetic lesion within the M2L locus or within the m2 promoter (Claim 34).
Any genetic lesion within the M2L locus (including any partial or total deletion of the M2L locus) or within the m2 promoter would be encompassed by the claims as instantly presented. Those modifications encompass a huge set of potential modifications and encompass even a single deletion within the m2 promoter or M2L locus. The Spec. does not disclose the specific portions of the m2 promoter or M2L locus that must be deleted to prevent CD80/CD86 binding. Therefore an artisan would not know what structures are required and excluded by the claims.
The Spec. describes (p. 13; p. 18) two poxvirus M2L genes as SEQ ID NOs 1 and 2. The Spec. teaches (p. 18 L9-15) those two sequences have only 50% sequence identity. The Spec. teaches about (pp. 18-19 L15-11) defective m2 poxvirus protein function. However, nowhere in those teachings is any description of the specific regions or sites that must be modified to affect m2 poxvirus protein function or to make m2 poxvirus protein have a defective function including such that it cannot bind CD80/CD86.
Furthermore, an extent of protein defect to produce a protein with function deficient in CD80/CD86 costimulatory ligand binding is not discussed, except for one species (discussed below). Although the Spec. (cited §) teaches applying point and other mutations, it does not address whether an m2 poxvirus protein that is partially active or which has reduced CD80/86 costimulatory ligand binding is “defective” enough to meet the claim requirements. The claim requires that the defective m2 poxvirus protein is unable to bind CD80 and CD86 costimulatory ligands, but does not teach what parts of m2 are responsible for the CD80/CD86 binding and what parts should be altered to prevent its binding. What if the M2L locus is modified in such a way that the resulting protein binds one of those but not the other? Although the Spec. says (p. 5 L20-30) the entire locus may be deleted, the claims allow for partial deletion—and the claim recites any genetic lesion—and the Spec. does not divulge what specific nucleotides should or should not be modified to produce a sufficiently defective m2 poxvirus protein function such that the m2 protein does not bind CD80/CD86. Note that a “partial deletion” encompasses deleting a single nt. The Spec. hasn’t disclosed what individual nt(s) should be deleted to render the defective m2 protein unable to bind CD80/CD86.
Although Claims 29, 32, 34, 37-42, and 51-58 claim a functional characteristic (i.e., wherein the defective m2 poxvirus protein is unable to bind CD80/CD86 costimulatory ligands), the functional characteristic is not coupled with a known structure. Will any genetic modification of the recited loci be sufficient to produce defective protein function? Even though the claims recite genetic lesions, various genetic lesions can be more or less detrimental depending on where they occur, or whether the genetic lesions results in an amino acid that is similar enough to the amino acid of the non-lesioned form such that the mutated protein can retain partial function. However, depending on perspective, such partial function could be considered to control M2L expression.
Further regarding the structure/function relationship of a genetic lesion that comprises a partial deletion, the art of Hinthong (et al. 2008. Characterization of wild-type and mutant vaccinia virus M2L proteins’ abilities to localize to the endoplasmic reticulum and to inhibit NF-κB activation during infection. Virology 373(2):248–262; “Hinthong”, of record on IDS filed 14 February 2022) teaches (§The M2L protein sequence possesses motifs associated with ER localization and retention ¶2) that vaccinia M2L comprises two ER retention signal motifs and that (§Discussion ¶4-5) although loss of those signals was predicted to result in an m2 protein that did not localize to the ER, only some of the mutant M2L proteins lost their ER association phenotype and it is unknown why some of the mutant M2L proteins still remain in the ER. Those teachings discuss mutations that could be considered a genetic lesion and which impair some m2 poxvirus protein function and protein expression but, contrary to expectations, the mutations did not completely diminish ER retention. That is all to say that the relationship between what part of the M2L locus is mutated or undergoes genetic lesion does not have a predictable effect on CD80/CD86 costimulatory ligand binding (location of m2 protein will affect whether it can or cannot bind CD80/86). And the Spec. has not described what part of the M2L locus must be mutated or lesioned for the function of interfering with CD80/CD86 costimulatory ligand binding to occur.
Example 2 teaches (p. 54 L11-20) a segment that was deleted to suppress m2 poxvirus protein expression: The M2L partial deletion which extends from 64 nucleotides upstream the m2 ORF to the 169 first codons resulted in a suppressed expression of m2 protein (m2-) and did not have any significant impact on the virus replication on CEF compared to the parental one (data not shown). However, that teaches about one single genetic lesion in one single virus species, the vaccinia virus, whereas what is claimed is any Orthopoxvirus and any genetic lesion.
To that point and regarding the vast genus of a modified poxvirus that is claimed, the art of Brennan (et al. 2023. Molecular Mechanisms of Poxvirus Evolution. mBio 14[1]: e01526-22; “Brennan”, of record) teaches that (§Abstract):
poxviruses have highly adaptable genomes and can undergo relatively rapid genotypic and phenotypic change, as illustrated by the recent increase in human-to-human transmission of monkeypox virus. Advances in deep sequencing technologies have demonstrated standing nucleotide variation in poxvirus populations, which has been underappreciated.
For that reason an artisan would not expect that a mutation in certain sites in the M2L locus of vaccinia virus and which results in an m2 poxvirus protein with defective CD80/CD86 costimulatory ligand binding would be applicable to any other poxvirus m2 protein.
Similarly, Claims 29, 42, and 52 recite that the modified poxvirus wherein the engineered poxvirus is further engineered [a] in the J2R locus and [b] in the I4L and/or F4L locus/loci, resulting in an engineered poxvirus defective for m2, tk and rr activities. That recitation encompasses any further modification in any of those recited loci. However, the functional characteristic of producing any defective locus/defective tk function/activity or a defective I4L or F4L locus/defective rr function/activity is not coupled with a known structure that must be modified for each respective locus/protein, particularly in the context of the claims. Will any genetic modification of the recited loci be sufficient to produce defective protein function?
The Spec.’s Examples 2 and 3 discuss modifying the m2, tk, and rr proteins in particular ways, but does not discuss structures that should be modified to result in the claimed outcome of producing defective m2, tk, and rr activities. Notably, Examples 2 and 3 do not discuss any particular nucleotides that must be modified to produce defective m2, tk, or rr proteins. Will modifying any nucleotides of the respective loci result in defective m2, tk, or rr proteins? Since the claim recites modifying certain loci resulting in defective protein function, an artisan seeking to carry out the claims would need to know what nucleotides must be modified to produce the defective proteins.
Altogether, the Specification does not provide sufficient evidence that Applicants were in full possession of what is encompassed by Claims 29, 32, 34, 42, and 57-58, namely any modified poxvirus comprising an M2L locus that encodes a defective m2 poxvirus protein that is unable to bind CD80/CD86 costimulatory ligands; wherein the modified poxvirus is generated or engineered from the Orthopoxvirus genus; or wherein the inability to bind CD80/CD86 originates from a genetic lesion within the M2L locus and can comprise a partial deletion, wherein the genetic lesion includes partial or total deletion of the M2L locus and/or one or more partial or total deletions within the m2 coding sequence and/or in an m2 promoter; or wherein the modified poxvirus comprises a further modification in any region other than the M2L locus or any of the loci recited in Claims 29 and 42. The Spec. does not describe the specific core structures (i.e., in terms of nucleotide bases or amino acid residues) that are necessary for or responsible for making the proteins have defective functions. No core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the defective m2 poxvirus protein or other defective protein, or for the defective M2L locus expression is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. The broad genus of Orthopoxviruses, their defective m2 poxvirus proteins, mutations, etc. do not share a core structure. A protein domain responsible for m2 poxvirus protein binding to CD80/CD86 and which must be mutated and which is common to the various m2 poxvirus proteins across poxvirus species is not identified. There are many places to inflict a genetic lesion or mutation, and the Specification does not teach any defining characteristics of such lesions or mutations that impair m2 protein function (or rr or tk protein functions). Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus of modified Orthopoxviruses and genetic lesions and defective proteins claimed.
Regarding Claims 38-42 and 51-56, the Spec. has not provided examples showing possession of modified poxviruses engineered to express any cytokine (Claim 38), wherein the cytokine is IL-12 (Claim 39); or is engineered to express any chemokine (Claim 54), any ligand (Claim 55), or any antibody (Claim 56); wherein the antibody specifically binds any immune checkpoint protein (Claim 40); or wherein the modified poxvirus expresses any antagonist antibody that specifically binds PD-L1 or any antibody that binds CTLA4, or the modified Orthopoxvirus that has defective m2, tk, rr and also encodes any anti-CTLA4 or any anti-PD-L1 antibody (Claims 41-42 and 51-52).
The Spec. describes (pp. 27-29) tumor-associated antigens, cytokines, chemokines, ligands, and antibodies. Those categories are very large and have diverse structures. The examples in the Spec. do not discuss any Orthopoxvirus modified to express a representative number of species from all those encompassed by the claims. In fact, no examples demonstrating possession of any Orthopoxvirus modified to express any of the recited kinds of polypeptide is provided in the Spec. The Spec. discusses Examples 2 and 3 in which a vaccinia virus is modified for tk, rr, and an m2 poxvirus protein, but none of those examples discusses that the modified virus also expresses an anti-CTLA4 or anti-PD-L1 antibody. The structure of such antibodies is not provided. The Spec. does not provide details of any structure common to the recited species that is responsible for the virus being engineered to express any tumor-associated antigen, any cytokine or chemokine, any ligand, or any antibody; for the cytokine IL-12 recited in Claim 39, or for the antibody specifically binding any immune checkpoint protein, or for the modified poxvirus being able to express any antagonist antibody that specifically binds to PD-L1 or CTLA4. Specifically regarding PD-L1 or CTLA4, those two proteins have different structures so an antibody that binds each protein would need to be specific to the structure, and the Spec. does not describe the structure of the antibody that would bind either PD-L1 or CTLA4.
Although Claims 38-42 and 51-56 claim functional characteristics (i.e., any cytokine or chemokine, any ligand, or any antibody; the IL-12 cytokine recited in Claim 39, any antibody that specifically binds an immune checkpoint protein, and any antibody that binds PD-L1 or CTLA4, etc.), no functional characteristic is coupled with a known structure. The Specification does not identify any core structure requisite to cytokines, cytokine that is IL-12, chemokines, ligands, and antibodies, antibody that binds PD-L1 or CTLA4, etc. No core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for recited polypeptides is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. The Spec. does not disclose any examples of viruses that are engineered to express the specific cytokine IL-12. It is simply not plausible that, at time of filing, Applicants had possession of recombinant viruses capable of expressing all the species recited in the claims—or viruses capable of expressing a representative number of them.
Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus of modified poxviruses engineered to express at least one polypeptide of the various sorts claimed.
While none of these elements is specifically required to demonstrate possession, in combination their lack means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of an invention any modified poxvirus comprising/encoding a defective m2 protein that is modified to be unable to bind CD80/CD86; any such modified poxvirus engineered from a member of the Orthopoxvirus genus; wherein the inability to bind CD80/CD86 originates from a genetic lesion within the M2L locus and can comprise a partial or total deletion; wherein the genetic lesion includes partial or total deletion of the M2L locus and/or the m2 promoter; wherein the modified poxvirus is further modified in the J2R locus and I4L or F4L loci; wherein the modified poxvirus is recombinant and is engineered to express any at least one polypeptide selected from the group consisting of any cytokines, the specific cytokine IL-12, or any chemokines, ligands, and antibodies; wherein the antibody specifically binds any immune checkpoint protein; or wherein the antibody binds PD-L1 or CTLA4. Claims 29, 34, 38-42, and 51-58 are rejected for failing to demonstrate possession of the claimed invention. Claims 32, 34, 37-42, 51-56, and 58 are rejected because they depend from Claims 29, 34, 38-42, and 51-58 and do not remedy the issues.
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.
Claim(s) 57 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hinthong (et al. 2008. Characterization of wild-type and mutant vaccinia virus M2L proteins’ abilities to localize to the endoplasmic reticulum and to inhibit NF-κB activation during infection. Virology 373(2):248–262; “Hinthong”, of record on IDS filed 14 February 2022) as evidenced by Kleinpeter (et al. 2019. By binding CD80 and CD86, the vaccinia virus M2 protein blocks their interactions with both CD28 and CTLA4 and potentiates CD80 binding to PD-L1. J. Virol. 93:e00207-19; “Kleinpeter”, of record on IDS filed 14 February 2022) and Guo (et al. 2005. The Enhanced Tumor Selectivity of an Oncolytic Vaccinia Lacking the Host Range and Antiapoptosis Genes SPI-1 and SPI-2. Cancer Res. 65[21]:9991-9998, “Guo”, of record). This rejection is new.
Hinthong teaches (§Abstract) the M2L protein is unique to poxviruses and quells inflammatory response, that M2L protein is expressed during early infection and inhibits NF-kB, and that eliminating the M2L protein compromises WR’s ability to inhibit virus-induced NF-kB activation. That is, usually a virus triggers host NF-kB activation but some poxviruses, including vaccinia strain WR, have evolved the m2 protein which inhibits host NF-kB activation. But Hinthong’s mutated WR virus wherein M2L protein is deficient (called ΔM2L) has lost the ability to inhibit host NF-kB activation. Note that Hinthong’s M2L protein is the same as what is instantly claimed as m2 protein.
Hinthong teaches (§Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1) WR (i.e. vaccinia virus strain Western Reserve) contains M2L protein that was recognized by anti-M2L antibodies (Ab) but no M2L protein was detected in cells infected with a mutant WR virus lacking the M2L ORF (called ΔM2L).
That indicates that Hinthong discloses an engineered poxvirus (i.e., ΔM2L) that is different from a nonengineered poxvirus in its native form (i.e. WR strain) wherein the nonengineered poxvirus genome comprises an M2L locus encoding a functional m2 poxviral protein wherein the engineered poxvirus is modified in the M2L locus, leading to the lack of m2 protein synthesis, wherein the engineered poxvirus is not a PCPV, an MVA virus, or a NYVAC virus.
Lacking m2 protein, ΔM2L would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Kleinpeter, drawn to the finding that the vaccinia virus m2 protein binds to CD80 and CD86, provides evidences for that. Kleinpeter teaches that binding of m2 to CD80/CD86 is the inherent function of the m2 protein (§Abstract):
the M2 protein encoded by the vaccinia virus is secreted as a homo-oligomer by infected cells and binds two central costimulation molecules, CD80 (B7-1) and CD86 (B7-2). These interactions block the ligation of the two B7 proteins to both soluble CD28 and soluble cytotoxic T-lymphocyte associated protein 4 (CTLA4).
Kleinpeter teaches (same §) they generated a version of the Copenhagen VV with the M2L locus deleted and that mutated virus was not able to interfere with the B7-CD28/CTLA4 interaction: A Copenhagen vaccinia virus with a deletion of the nonessential M2L locus was generated and compared with its parental virus. This M2L-deleted vaccinia virus, unlike the parental virus, does not generate interference with the B7-CD28/CTLA4/PD-L1 interactions. Kleinpeter further teaches that (§Importance) the binding of m2 poxvirus protein to CD80/CD86 is inherent to m2:
We report here several new putative immunosuppressive activities of M2 protein. M2 protein is secreted and binds cornerstone costimulatory molecules (CD80/CD86). M2 binding to CD80/CD86 blocks their interaction with soluble CD28/CTLA4 but also favors the soluble PD-L1-CD80 association.
Since m2 inherently binds to CD80/CD86, removing it (as was done in Hinthong) produces a modified poxvirus wherein the m2 poxvirus protein is defective and is unable to bind CD80/CD86. Hinthong produced a modified vaccinia virus strain WR by removing the M2L coding sequence. Since Hinthong’s virus lacked m2 protein, the component that binds CD80 and CD86, it inherently possesses the instantly claimed feature of wherein said defective m2 function is unable to bind said CD80 and CD86 co-stimulatory ligands.
Hinthong teaches (§Materials and methods-Cells and viruses ¶6) the WR construct deleted for the M2L ORF was produced using homologous recombination wherein the ORF was removed. That indicates that the lack of m2 protein originated from a genetic lesion within the M2L locus wherein the genetic lesion comprises a partial or total deletion of the M2L locus.
Guo provides evidence that the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells: Guo teaches (§Introduction ¶1-2) a resulting trend in vector development for cancer therapy has been to explore replicating oncolytic viruses, such as adenovirus, herpes simplex virus, and vaccinia virus… and our laboratory has explored the application of tumor-selective replicating vaccinia virus (WR strain) for cancer therapy... That indicates that the WR strain of vaccinia virus is oncolytic and selectively replicates in tumor cells. A person of ordinary skill understands that tumor cells are dividing cells. Therefore Hinthong as evidenced by Kleinpeter and Guo anticipates Claim 57.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 29, 32, 34, 53, and 57-58 and are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (et al. 2008. Characterization of wild-type and mutant vaccinia virus M2L proteins’ abilities to localize to the endoplasmic reticulum and to inhibit NF-κB activation during infection. Virology 373(2):248–262; “Hinthong”, of record on IDS filed 14 February 2022) as evidenced by Kleinpeter (et al. 2019. By binding CD80 and CD86, the vaccinia virus M2 protein blocks their interactions with both CD28 and CTLA4 and potentiates CD80 binding to PD-L1. J. Virol. 93:e00207-19; “Kleinpeter”, of record on IDS filed 14 February 2022) and Guo (et al. 2005. The Enhanced Tumor Selectivity of an Oncolytic Vaccinia Lacking the Host Range and Antiapoptosis Genes SPI-1 and SPI-2. Cancer Res. 65[21]:9991-9998, “Guo”, of record) as applied to Claim 57 in the 102 rejection above, and further in view of Guo (of record) and Li (et al. 2017. STAT3 and NF-κB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer. Sci. Rep. 7:45395, “Li”, of record), Potts (et al. 2017. Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models. EMBO Molec. Med. 9:638-654, “Potts”, of record), and evidence from Wikipedia (Vaccinia. Page archived on 12 October 2017. Available online at Wikipedia.org. Accessed on 04 April 2026, “Wikipedia”). This rejection is updated in response to the claim amendments.
The teachings of Hinthong as evidenced by Kleinpeter and Guo as applicable to Claim(s) 57 have been described in the 102 rejection above.
Hinthong teaches an engineered vaccinia virus strain WR that has a genetic lesion that removes its M2L locus. Kleinpeter provides evidence that m2 protein is what binds CD80 and CD86 and Guo provides evidence that vaccinia virus strain WR is an oncolytic virus that selectively replicates in tumor cells which are dividing cells.
Hinthong teaches that (§Abstract) proinflammatory factors like NF-kB attract immune cells to areas of infection and that vaccinia viruses that comprise a functional M2L ORF are able to inhibit NF-kB. Hinthong teaches (§Discussion ¶1) deletion of M2L/m2 protein removes an ability to downregulate NF-kB activation.
Regarding the limitation of Claim 29 that the engineered poxvirus be of the Orthopoxvirus genus, Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus. Therefore Hinthong’s modified WR virus, ΔM2L, is an engineered poxvirus obtained by engineering a poxvirus of the Orthopoxvirus genus. Therefore Hinthong inherently teaches that limitation of Claim 29.
Regarding limitations of Claim 53, Hinthong teaches (§Materials and methods-Cells and viruses ¶6) a 4.2 kb DNA segment containing the M2L ORF and flanking sequences was PCR amplified… [emphasis added.] That indicates that they amplified not only the M2L ORF but its flanking sequences which includes upstream sequences. Hinthong teaches (same §) using [their] process, most of the M2L ORF was removed from pNEB193, and replaced with the neo-gus cassette. However, enough viral DNA flanking the M2L ORF was retained in the plasmid to allow for successful homologous recombination. Hinthong teaches (same §) The absence of the M2L ORF in the recombinant WR-based viruses was verified by PCR analysis of the genomes of plaque-purified viruses, and by immunoblotting lysates from ΔM2L-infected cells. Hinthong teaches (§The M2L product is N-linked glycosylated, Figs. 2 and 3) exposure to drugs that inhibit glycosylation had no effect on the lack of M2L protein (i.e., “m2 protein”) in the ΔM2L WR virus: exposure to either tunicamycin or monensin did not affect the lack of M2L protein expression by the MVA or ΔM2L virus, nor did it affect the expression of cellular genes, since actin levels were similar in untreated versus treated cells. Fig. 2 shows that the glycosylation sites are at AA residues 49, 79, 118, and154. That indicates that the ΔM2L virus had at least the first 100 codons deleted. That indicates that the genetic lesion of Hinthong is a partial deletion wherein the partial deletion extends from upstream of the m2 coding sequence to at least 100 codons of the m2 coding sequence. Therefore Hinthong teaches some limitations of Claim 53.
Hinthong as evidenced by Kleinpeter and Guo does not teach that the engineered poxvirus is further modified in a region other than the M2L locus to remove specifically the J2R locus (which encodes the tk protein) and also lacks the F4L locus (which encodes the rr protein (Claim 29).
However, as discussed in the 102 rejection, Guo teaches vaccinia viruses including the WR strain are oncolytic: (§Introduction ¶1-2) a resulting trend in vector development for cancer therapy has been to explore replicating oncolytic viruses, such as adenovirus, herpes simplex virus, and vaccinia virus… and our laboratory has explored the application of tumor-selective replicating vaccinia virus (WR strain) for cancer therapy.... Guo teaches (same §) the TK deletion leads to preferential viral replication in dividing cells and in tumor models in mice, the TK/VGF double-deletion mutant displayed higher tumor-targeting capacity and potent tumoricidal activity with reduced viral pathogenicity. That indicates that oncolytic vaccinia viruses whose tk protein is deleted replicate more in dividing mammalian cells than in nondividing mammalian cells and such viruses can be used to fight cancer.
Li teaches (§Abstract) tumor-induced dendritic cell (DC) dysfunction plays an important role in cancer immune escape and that cancer sera represses the NF-kB signaling pathway, indicating that attenuated NF-kB signaling underlies DC dysfunction in cancer. Li indicates that deactivated NF-kB signaling is undesirable in cancer treatment.
As discussed above, Hinthong teaches deletion of M2L/m2 protein removes an ability to deter NF-kB activation.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify Hinthong’s engineered vaccinia virus wherein the M2L locus is lesioned (or deleted) with Guo’s teachings regarding TK deletion leading to preferential viral replication in dividing cells and potent tumoricidal activity in mice and Li’s teachings that attenuated NF-kB signaling causes DC dysfunction in cancer. One would have modified Hinthong’s engineered virus by also deleting the tk protein. They would have done so for the benefit of using a modified version of Hinthong’s virus, wherein TK is deleted, as an oncolytic virus to treat cancer. One would have been motivated to do so with a reasonable expectation of success because Hinthong teaches the M2L/m2 protein inhibits NF-kB and thereby downregulates immune responses, and because Guo teaches vaccinia strain WR is an oncolytic virus used to treat cancer and that using TK-deleted vaccinia virus leads to preferential viral replication in dividing cells and potent tumoricidal activity in mice.
One would have wanted to use an m2-deficient oncolytic virus when treating cancer because Li teaches that deactivated NF-kB signaling has a negative effect in cancer (i.e., NF-kB deactivation causes DC dysfunction). Hinthong teaches that m2 protein inhibits NF-kB and related immune protein expression. To avoid inducing DC dysfunction (which would occur if m2 protein were expressed, as disclosed by Hinthong), an artisan would have wanted to use an oncolytic virus that would not deactivate NF-kB, so they would have used a WR strain deficient in m2 protein. As discussed, they also would have wanted to use a virus that exhibits preferential replication in viral cells and potent tumoricidal activity. That would have led them to modify Hinthong’s m2-deficient virus by further deleting the J2R locus, thereby producing a virus deficient in both m2 and tk. Modifying the engineered virus wherein the M2L locus is lesioned of Hinthong with the teachings of Guo and Li would have produced an engineered poxvirus, specifically vaccinia virus strain WR, wherein the virus is defective for both m2 and tk because both loci (i.e., M2L which encodes m2 protein and J2R which encodes tk protein) are lesioned.
Hinthong, Guo, and Li (as evidenced by Kleinpeter, Guo, and Wikipedia) do not teach an oncolytic virus that also lacks the rr protein because the F4L locus is deleted.
However, Potts, drawn to deleting the F4L locus to delete ribonuclease reductase in vaccinia virus to produce a selective oncolytic virus with anti-tumor immunity and superior safety, teaches (§Abstract) F4L encodes the rr protein. Potts teaches (same §) F4L‐deleted vaccinia viruses (VACVs) are highly attenuated in normal tissues and have tumor‐selective replication and cell killing. Potts teaches (same §) their F4L‐deleted VACVs replicated selectively in rat and human bladder cancer models and caused significant tumor regression or complete ablation with no toxicity. Potts teaches (same §) that rats cured with their treatment developed anti‐tumor immunity and their results were replicated in primary human bladder cancer explants. Potts teaches (same §) their findings demonstrate the enhanced safety and selectivity of F4L‐deleted VACVs, with application as a promising therapy for patients with BCG‐refractory cancers and immune dysregulation.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the engineered, oncolytic poxvirus that lacks m2 and tk proteins of Hinthong, Guo, and Li with the teachings about deleting the F4L locus of Potts for the benefit of producing an oncolytic virus that is highly attenuated in non-cancerous cells and can be used to treat cancer. One would have been motivated to do so with a reasonable expectation of success because Potts teaches that (§Abstract, §The paper explained) their virus wherein F4L locus is deleted is both safe and effective for treating cancer. Producing an engineered, oncolytic poxvirus that lacks m2, tk, and rr proteins, which would have been obvious based on the teachings of Hinthong, Guo, Li, and Potts, would have produced all the limitations of Claims 29, 32, 34, 53, and 57.
Guo teaches that (§Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) vaccinia virus replication can be modulated by host cytokines, wherein the host cytokines can inhibit viral cell growth. That indicates that viral replication occurs in the absence of cytokines. Therefore the limitations of Claim 58 would have been obvious in view of Hinthong, Guo, Li, and Potts.
Claim(s) 29, 32, 34, 37-39, 53, 55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, and Potts as applied to claims 29, 32, 34, 53, and 57-58 above, and further in view of McCart (et al. 2001. Systemic Cancer Therapy with a Tumor-selective Vaccinia Virus Mutant Lacking Thymidine Kinase and Vaccinia Growth Factor Genes. Canc. Res. 61:8751-8757; “McCart”). This rejection is new.
The teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, and Potts as applicable to Claim(s) 29, 32, 34, 53, and 57-58 have been described above.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, and Potts teach an engineered, oncolytic poxvirus that lacks m2, tk, and rr proteins that replicates in rapidly dividing cells more than in healthy cells. Since Guo’s virus is oncolytic, it by definition lyses dividing tumor cells (and Guo teaches that).
Hinthong (as evidenced by Kleinpeter, Guo. and Wikipedia), Guo, Li, and Potts do not explicitly teach that the modified poxvirus selectively replicates in dividing cells in vitro in the absence of cytokines (Claim 58), that the engineered virus is recombinant (i.e., Claim 37) and expresses an antigen (i.e., the ligand of Claim 55) or cytokine (i.e., Claim 38), wherein the cytokine can be IL-12 (i.e., Claim 39).
However, McCart, the paper from which Guo’s teachings about increased replication by a vaccinia virus lacking tk protein are drawn, teaches limitations that the other references don’t teach.
Regarding Claim 58, McCart teaches that (§Abstract, §Discussion ¶1) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro compared with nondividing cells. McCart teaches their tk-modified virus kills cancer cells: (§Discussion ¶4) in addition to the high levels of gene expression resulting from the tumor-specific replication, we have shown that vaccinia alone, in the absence of a therapeutic gene, is capable of causing an antitumor effect from viral replication and subsequent cell death. McCart teaches (§Discussion, final ¶) their vaccinia virus (the same one as Guo) has broad potential utility in that it may be used as an antitumor agent on its own or by expressing suicide or cytokine genes [emphasis added].
McCart’s teachings indicate that that an engineered, oncolytic poxvirus of Hinthong, Guo, Li, and Potts that lacks m2, tk, and rr proteins and which replicates in rapidly dividing cells more than in healthy cells (and which would have been obvious in view of the cited prior art) would have possessed the properties of (1) lysing dividing tumor cells (because it’s a demonstrated oncolytic virus) and (2) selectively replicating in dividing cells in vitro, even in the absence of cytokines (because McCart teaches it selectively replicates in dividing cells in vitro, because Guo teaches it has preferential replication in dividing cells, and because Guo teaches cytokines can have an inhibitory effect on viral replication, which indicates the absence of cytokines would only be beneficial for virus replication). Furthermore, McCart teaches that their virus has broad utility and can be used as an antitumor agent on its own, even when it doesn’t express cytokine genes.
Regarding Claims 37-39 and 55, McCart teaches (§Introduction ¶3) vaccinia viruses have been modified to carry various antigens, cytokines, and immunostimulatory molecules including carcinoembryonic antigen… and IL-12. A person of ordinary skill would immediately recognize that an antigen is a kind of ligand (i.e., Claim 55). That passage also teaches producing a recombinant vaccinia virus that expresses the cytokine IL-12 was routine and conventional.
McCart teaches (§Discussion, final ¶) their vaccinia virus has broad potential utility in that it may be used as an antitumor agent on its own or by expressing suicide or cytokine genes [emphasis added]. McCart teaches (same § and ¶) their vector can be used in immunotherapy trials expressing tumor-associated antigens and costimulatory molecules… Its efficiency and selectivity compares favorably with other replicating viral vectors currently in clinical trials… [and is] worthy of consideration as a systemic vector in human cancer trials. McCart teaches (§Discussion ¶3) the most important feature of this virus, however, is the ability to selectively replicate and express genes in tumor tissues compared with normal tissues.
Therefore it would have been obvious to a person of ordinary skill in the art before the filing date of the claimed invention to modify the engineered poxvirus of Hinthong, Guo, Li, Potts with McCart’s teachings about their tk-deficient oncolytic virus, including its ability to function alone (i.e., without cytokines) and using the virus to express an antigen or cytokine to treat cancer. One would have been motivated to do so with a reasonable expectation of success because McCart teaches that vaccinia viruses have already been used to express antigens (i.e., in the language of Claim 55, a “ligand”), the cytokine IL-12, and/or other immunostimulatory molecules, and because McCart suggests using their tk-deficient virus to express other molecules and using it to treat cancer. McCart teaches (§Discussion, final ¶) their virus exhibits tumor-selective replication and is less pathogenic to nontumor cells than other forms of the virus.
Therefore the limitations of Claims 37-39, 55, and 58 would have been obvious in view of Hinthong, Guo, Li, Potts, and McCart.
Claim(s) 29, 32, 34, 37-39, 53-55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart, as applied to claims 29, 32, 34, 37-39, 53, 55, and 57-58 above, and further in view of Li (et al. 2011. Chemokine Expression From Oncolytic Vaccinia Virus Enhances Vaccine Therapies of Cancer. Molec. Ther. 19[4]:650-657; “Li 2011”). This rejection is new in response to claim amendments.
The teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart as applicable to Claim(s) 29, 32, 34, 37-38, 53, 55, and 57-58 have been described above.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart teach an engineered, oncolytic poxvirus that is a vaccinia virus and lacks m2, tk, and rr proteins that replicates in rapidly dividing tumor cells more than in nondividing cells, wherein the engineered poxvirus that is a vaccinia virus is recombinant and engineered to express at least one cytokine that can be IL-12, or an antigen.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart do not teach that the modified poxvirus is further engineered to express a chemokine.
However, Li 2011, drawn to the same modified, tk-deficient vaccinia virus as Guo and McCart, teaches (§Abstract) using the virus to express a chemokine enhances vaccine therapies of cancer. Li teaches (same § and §Introduction, final ¶) they used the same vaccinia virus to express the chemokine CCL5 and found that it enhanced therapeutic in vivo which also correlated with increased persistence of the viral agent exclusively within the tumor.
Li 2011 teaches (§Introduction, final ¶) their chemokine-expressing virus represents a novel means to both enhance oncolytic viral therapy and to attract therapeutic immune cells into the tumor.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the modified vaccinia virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart with the chemokine expression of Li 2011 for the benefit of enhancing oncolytic viral therapy and attracting therapeutic immune cells into the tumor. One would have been motivated to do so with a reasonable expectation of success because Li 2011 teaches their chemokine-expressing virus enhances oncolytic viral therapy and attracts therapeutic immune cells into the tumor. One would have been motivated to do so with a reasonable expectation of success because McCart teaches (§Introduction ¶3) vaccinia virus has been modified to carry various antigens, cytokines, and immunostimulatory molecules, and (§Discussion) that their tk-deficient virus replicates selectively in tumor tissues, causes tumor cell death, and has broad utility in cancer therapy as an antitumor agent that also expresses tumor-associated antigens and costimulatory molecules. That indicates it was routine and conventional to modify a modified vaccinia virus to express other molecules and use the oncolytic virus to treat cancer. It would have been a simple matter to encode the chemokine of Li 2011 on the modified vaccinia virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart.
Therefore the limitations of Claim 54 would have been obvious in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Li 2011.
Claim(s) 29, 32, 34, 37-40, 53, and 55-58 are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart as applied to claims 29, 32, 34, 37-39, 53, 55, and 57-58 above, and further in view of Twumasi-Boateng (et al. 2018. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat. Rev. Canc. 18:419-432; “Twumasi”, of record). This rejection is updated in response to claim amendments.
The teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart as applicable to Claim(s) 29, 32, 34, 37-38, 53, 55, and 57-58 have been described above.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart teach an engineered, oncolytic poxvirus that is a vaccinia virus and lacks m2, tk, and rr proteins that replicates in rapidly dividing tumor cells more than in nondividing cells, wherein the engineered poxvirus that is a vaccinia virus is recombinant and engineered to express at least one cytokine that can be IL-12, or an antigen.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart do not teach that the modified poxvirus is further engineered to express an antibody that specifically binds to an immune checkpoint protein.
Regarding Claims 40 and 56: However, Twumasi, drawn to a discussion of oncolytic viruses as engineering platforms for combination immunotherapy, teaches that (§Using OVs to deliver immune checkpoint Inhibitors) oncolytic viruses (OV) can be used to deliver immune checkpoint inhibitors (ICI) and that OVs can be engineered to encode ICI. Twumasi teaches that strategy (same §) could provide a superior safety profile to systemic administration. Twumasi teaches the strategy has been employed and is effective:
(same §) Using an oncolytic vaccinia virus backbone, Kleinpeter and colleagues117 demonstrated that OV-encoded PD1 antibodies (including whole antibodies, antigen-binding fragment (Fab) domains or single-chain variable fragments (scFvs)) were produced by tumour cells and other components of the TME after OV infection, resulting in markedly better therapeutic efficacy than either OV or anti-PD1 therapy alone.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the modified virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart with the teachings about making the virus express an anti-PD1 antibody of Twumasi for the benefit of producing an oncolytic virus that results in markedly better therapeutic efficacy than either OV or anti-PD1 therapy alone. One would have been motivated to do so with a reasonable expectation of success because Twumasi teaches that when Kleinpeter applied that strategy, it result[ed] in markedly better therapeutic efficacy than either OV or anti-PD1 therapy alone and because it would have been a simple matter to include an anti-PD1 antibody in the oncolytic virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart.
One would have been motivated to do so with a reasonable expectation of success because McCart teaches (§Introduction ¶3) vaccinia virus has been modified to carry various antigens, cytokines, and immunostimulatory molecules, and (§Discussion) that their tk-deficient virus replicates selectively in tumor tissues, causes tumor cell death, and has broad utility in cancer therapy as an antitumor agent that also expresses tumor-associated antigens and costimulatory molecules. That indicates it was routine and conventional to modify a modified vaccinia virus to express other molecules and use the oncolytic virus to treat cancer. It would have been a simple matter to encode the anti-PD1 antibody on the modified vaccinia virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart.
Modifying the modified poxvirus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and McCart with the teachings about making the virus express an anti-PD1 antibody of Twumasi would have produced the limitations of Claims 40 and 56.
Claim(s) 29, 32, 34, 37-42, 53, and 55-58 are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi as applied to Claims 29, 32, 34, 37-40, 53, and 55-58 above, and further in view of Liu (et al. 2017. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat. Comm. 8:14754; “Liu”, of record), and Rabello Suarez (et al. 2016. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7[23]: 34341–34355; “Suarez”, of record). This rejection is updated in response to claim amendments.
The teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi as applicable to Claim(s) 29, 32, 34, 37-40, 53, and 55-58 have been described above.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi teach an engineered, oncolytic poxvirus that lacks m2, tk, and rr proteins that replicates in rapidly dividing cells more than in healthy cells, and that the engineered virus expresses an antibody that binds an immune checkpoint protein.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi do not teach that the oncolytic virus expresses an antibody that binds anti-PD-L1.
Regarding Claims 41-42: However, Liu, drawn to a combination of an oncolytic VV and PD-L1 blockade for synergistic enhancement of cancer therapeutic efficacy, teaches (§Abstract) a dual cancer therapy in which an oncolytic poxvirus and anti-PD-L1 antibodies are administered to cancer cells and which leads to reduced tumor burden and improved survival. Liu teaches (§Main text ¶2-3) cancer immunotherapy comprises strategies to modulate the immunosuppressive tumour microenvironment (TME) such as using antibodies that bind to and modulate the function of immune checkpoints (such as CTLA-4 and PD-1/PD-L1) and that tumour cells express PD-L1 on their surface… tumours with high levels of PD-L1 on their surface and a lymphocytic infiltrate have been shown to respond well to anti-PD-1/anti-PD-L1 therapy. Liu’s hypothesis is that (§Main text ¶4) an oncolytic vaccinia virus will cause tumors to upregulate PD-L1 expression on their surfaces and then treatment with anti-PD-L1 will lead to effective tumor clearance. Liu found (Fig. 4) that such strategy significantly increased mouse survival.
Suarez, drawn to chimeric antigen receptor T cells that secrete anti-PD-L1 antibodies, teaches engineered Tcells that secrete anti-PD-L1 antibodies. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) that those cells comprise coding sequences for the anti-PD-L1 antibodies.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the modified virus that expresses an anti-PD1 antibody of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi with the teachings about making the virus express an anti-PD-L1 antibody of Liu and the anti-PD-L1 coding sequence of Suarez for the benefit of producing a cancer treatment that can treat cancers that upregulate PD-L1 in response to the oncolytic virus. One would have been motivated to do so with a reasonable expectation of success because Liu teaches that the cancers in their study upregulated PD-L1 in response to the OV, and Suarez teaches that they produced Tcells encoding anti-PD-L1. One would have been motivated to do so because each cancer is different and the cancers of Liu upregulated PD-L1 on their surfaces. It would have been a simple matter for an artisan to swap the region coding an anti-PD1 antibody of Twumasi for a region coding an anti-PD-L1 antibody of Suarez. One would have been motivated to do so because Twumasi teaches when Kleinpeter applied a similar strategy, it result[ed] in markedly better therapeutic efficacy than either OV or anti-PD1 therapy alone and could result in a better safety profile.
One would have been motivated to do so with a reasonable expectation of success because McCart teaches (§Introduction ¶3) vaccinia virus has been modified to carry various antigens, cytokines, and immunostimulatory molecules, and (§Discussion) that their tk-deficient virus replicates selectively in tumor tissues, causes tumor cell death, and has broad utility in cancer therapy as an antitumor agent that also expresses tumor-associated antigens and costimulatory molecules. That indicates it was routine and conventional to modify a modified vaccinia virus to express other molecules and use the oncolytic virus to treat cancer. It would have been a simple matter to encode the anti-PD-L1 antibody on the modified vaccinia virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi.
Modifying the modified virus that expresses an anti-PD1 antibody of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi with the teachings about combining the OV with an anti-PD-L1 antibody of Liu and the anti-PD-L1 coding sequence of Suarez would have produced the limitations of Claims 41-42.
Claim(s) 29, 32, 34, 37-40, 51, 53, and 55-58 are rejected under 35 U.S.C. 103 as being unpatentable over Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, and Twumasi as applied to Claims 29, 32, 34, 37-40, 53, and 55-58, and further in view of Dias (et al. 2012. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4. Gene Therapy 19:988–998, “Dias”, of record). This rejection is updated in response to claim amendments.
The teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi as applicable to Claim(s) 29, 32, 34, 37-40, 53, and 55-58 have been described above.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi teach an engineered, oncolytic poxvirus that lacks m2, tk, and rr proteins that replicates in rapidly dividing cells more than in healthy cells, and that the engineered virus expresses an antibody that binds an immune checkpoint protein.
Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi do not teach that the oncolytic virus encodes an anti-CTLA-4 antibody.
Regarding Claims 51-52: However, Dias, drawn to targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4, teaches (§Abstract) they produced a targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing human mAb specific for CTLA-4 and tested it, including in peripheral blood mononuclear cells (PBMCs) of patients with advanced solid tumors. Dias teaches (§Abstract) their replication-competent Ad5/3-D24aCTLA4 resulted in much higher tumor mAb levels as compared with a replication-deficient control. Dias teaches (§Introduction ¶3) there are at least 5 different mechanisms that make anti-CTLA-4 an appealing and potent anti-tumor approach, including that CTLA-4-blocking antibodies (Abs) can interfere with immune-suppressive signaling and CTLA-4 is expressed on the surface of many tumor cells and anti-CTLA-4-blocking Abs can induce apoptosis in tumor cells. Dias teaches (Fig. 4) their replication-competent vector expressing an anti-CTLA-4 antibody significantly reduced tumor volume.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the modified poxvirus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi with the teachings about making an oncolytic virus express an anti-CTLA-4 antibody of Dias for the benefit of producing a cancer treatment that can treat cancers that upregulate CTLA-4. One would have been motivated to do so with a reasonable expectation of success because Dias teaches (§Discussion ¶6) their oncolytic virus combined oncolytic replication with anti-CTLA-4 Ab expression and retained the oncolytic potency of the virus. An artisan would have wanted to modify the oncolytic virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi for the benefit of determining whether another species of oncolytic virus (i.e., modified vaccinia virus) expressing anti-CTLA-4 Ab would improve upon the anticancer properties of the adenovirus-based oncolytic virus of Dias. It would have been a simple matter for an artisan to swap Dias’s region coding an anti-CTLA-4 Ab for the region coding an anti-PD1 antibody of Twumasi. One would have been motivated to do so because Dias teaches (§Introduction ¶3) there are many different mechanisms that make anti-CTLA-4 an appealing and potent anti-tumor approach.
One would have been motivated to do so with a reasonable expectation of success because McCart teaches (§Introduction ¶3) vaccinia virus has been modified to carry various antigens, cytokines, and immunostimulatory molecules, and (§Discussion) that their tk-deficient virus replicates selectively in tumor tissues, causes tumor cell death, and has broad utility in cancer therapy as an antitumor agent that also expresses tumor-associated antigens and costimulatory molecules. That indicates it was routine and conventional to modify a modified vaccinia virus to express other molecules and use the oncolytic virus to treat cancer. It would have been a simple matter to encode the anti-CTLA-4 antibody on the modified vaccinia virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi.
Modifying the modified poxvirus that expresses an anti-PD1 antibody of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi with the teachings about combining an oncolytic virus with an anti-CTLA-4 antibody of Dias would have produced the limitations of Claims 51-52.
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.
Claims 29, 32, 34, 37-42, and 51-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the patents listed below in view of Hinthong (et al. 2008. Characterization of wild-type and mutant vaccinia virus M2L proteins’ abilities to localize to the endoplasmic reticulum and to inhibit NF-κB activation during infection. Virology 373(2):248–262; “Hinthong”, of record on IDS filed 14 February 2022) as evidenced by Kleinpeter (et al. 2019. By binding CD80 and CD86, the vaccinia virus M2 protein blocks their interactions with both CD28 and CTLA4 and potentiates CD80 binding to PD-L1. J. Virol. 93:e00207-19; “Kleinpeter”, of record on IDS filed 14 February 2022), Guo (et al. 2005. The Enhanced Tumor Selectivity of an Oncolytic Vaccinia Lacking the Host Range and Antiapoptosis Genes SPI-1 and SPI-2. Cancer Res. 65[21]:9991-9998, “Guo”, of record) and Wikipedia (Vaccinia. Page archived on 12 October 2017. Available online at Wikipedia.org. Accessed on 04 April 2026, “Wikipedia”), and further in view of Guo (of record) and Li (et al. 2017. STAT3 and NF-κB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer. Sci. Rep. 7:45395, “Li”, of record), Potts (et al. 2017. Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models. EMBO Molec. Med. 9:638-654, “Potts”), McCart (et al. 2001. Systemic Cancer Therapy with a Tumor-selective Vaccinia Virus Mutant Lacking Thymidine Kinase and Vaccinia Growth Factor Genes. Canc. Res. 61:8751-8757; “McCart”), Li (et al. 2011. Chemokine Expression From Oncolytic Vaccinia Virus Enhances Vaccine Therapies of Cancer. Molec. Ther. 19[4]:650-657; “Li 2011”), Twumasi-Boateng (et al. 2018. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat. Rev. Canc. 18:419-432; “Twumasi”, of record), Liu (et al. 2017. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat. Comm. 8:14754; “Liu”, of record), and Rabello Suarez (et al. 2016. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7[23]: 34341–34355; “Suarez”, of record), and Dias (et al. 2012. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4. Gene Therapy 19:988–998, “Dias”, of record). This rejection is updated in response to claim amendments.
This rejection applies to the following issued patents:
Patent No.
Abbreviation
Issue date
Claims #
US 8945581
US581
03 February 2015
1-7, 9
US 9295702
US702
29 March 2016
1-7, 9, 14
Although the claims at issue are not identical they are directed to overlapping subject matter because the US581/US702 claims are directed to a medicaments comprising a recombinant poxvirus that is an Orthopoxvirus or a vaccinia virus.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
Both/all claim sets are directed to recombinant poxviruses wherein the poxvirus can be an Orthopoxvirus or a vaccinia virus.
The patented US581/US702 claims don’t recite that the poxvirus is modified in the M2L, J2R, or I4L/4FL loci (and produces no or defective m2 protein and defective tk, and rr proteins). The patented claims don’t recite the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
Potts teaches (§Abstract) F4L‐deleted vaccinia viruses (VACVs) have tumor‐selective replication and cell killing, exhibit enhanced safety and selectivity, and are a promising therapy for patients with refractory cancers and immune dysregulation. McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the patented US581/US702 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The compositions of the US581/US702 claims plus the cited prior art broadly encompass the compositions of the instant claims. Therefore the instantly claimed compounds would have been obvious in view of the US581/US702 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
Claims 29, 32, 34, 37-42, and 51-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42-57, 54-61 of copending Application No. 18299858 (“App858”) in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias. This rejection is new.
Although the claims at issue are not identical they are directed to overlapping subject matter because the copending App858 claims are directed to a recombinant poxvirus that can be a vaccinia virus and which can be engineered to express therapeutic or immunostimulatory genes.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
Both sets are directed to recombinant poxviruses wherein the poxvirus can be a vaccinia virus and which can be engineered to express therapeutic or immunostimulatory genes.
The copending App858 claims don’t recite that the poxvirus is modified in the M2L, J2R, or I4L/4FL loci (and produces no or defective m2 protein and defective tk, and rr proteins). The copending claims don’t recite the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
Potts teaches (§Abstract) F4L‐deleted vaccinia viruses (VACVs) have tumor‐selective replication and cell killing, exhibit enhanced safety and selectivity, and are a promising therapy for patients with refractory cancers and immune dysregulation. McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the copending App858 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The instant claims would have been obvious in view of the compositions of the copending App858 claims plus the cited prior art. Therefore the instantly claimed compounds would have been obvious in view of the App858 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
This is a provisional NSDP rejection.
Claims 29, 32, 34, 37-42, and 51-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the patents listed below in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias. This rejection is new.
This rejection applies to the following issued patents:
Patent No.
Abbreviation
Issue date
Claims #
US 8778328
US328
15 July 2014
1-29
US 9687515
US515
27 June 2017
1-14
US 9884080
US080
06 February 2018
1-6
Although the claims at issue are not identical they are directed to overlapping subject matter because the patented US328/US515/US080 claims are directed to an oncolytic poxvirus comprising defective I4L/F4L and defective J2R genes, wherein the poxvirus further comprises a suicide gene, wherein the poxvirus cannot be NYAC but can be a vaccinia virus, and to methods for using the oncolytic poxvirus to treat tumors or cancer.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
Both/all claim sets are directed to oncolytic poxviruses wherein the poxvirus can be a vaccinia virus and can express heterologous proteins.
The patented US328/US515/US080 claims don’t recite that the poxvirus is modified in the M2L, (and produces no or defective m2 protein). The patented claims don’t recite the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the patented US328/US515/US080 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The instant claims and using them would have been obvious in view of the compositions of the US328/US515/US080 claims plus the cited prior art. Therefore the instantly claimed compounds would have been obvious in view of the US328/US515/US080 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
Claims 29, 32, 34, 37-42, and 51-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the patents or allowed applications listed below in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias. This rejections over US710 and All607 are new. The rejections over US981 and US619 are updated.
This rejection applies to the following issued patents or allowed applications:
Patent No.
Abbreviation
Issue date
Claims #
US 10555981
US981
11 February 2020
1-15
US 10765710
US710
08 September 2020
1-14
US 11779619
US619
10 October 2023
1-21
Allowed copending App. No. 16/985607
*Notice of Allowance has been mailed
All607
Mailed on:
26 January 2026
22, 25-29, 39, 42-44, 46-47
Although the claims at issue are not identical they are directed to overlapping subject matter because the patented US981/US710/US619 claims and allowed All607 claims are directed to an oncolytic poxvirus or specifically vaccinia virus comprising defective I4L/F4L and defective J2R genes, wherein the poxvirus further encodes an Ab that binds CTLA-4, PD-1, and/or PD-L1, and/or to methods of using the oncolytic poxvirus to treat cancer or a proliferative disorder.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
All claim sets are directed to oncolytic poxviruses wherein the poxvirus can be a vaccinia virus and can express heterologous proteins including Abs that bind CTLA-4, PD1, and/or PD-L1.
The patented US981/US710/US619 claims and allowed All607 claims don’t recite that the poxvirus is modified in the M2L, (and produces no or defective m2 protein). The patented claims don’t recite all the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the patented US981/US710/US619 claims and allowed All607 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The instant claims and using them would have been obvious in view of the compositions of the US981/US710/US619 claims or allowed All607 claims plus the cited prior art. Therefore the instantly claimed compounds would have been obvious in view of the US981/US710/US619 claims or allowed All607 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
Claims 29, 32, 34, 37-42, and 51-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the copending applications listed below in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias. This rejection is new.
This rejection applies to the following copending applications:
App. No.
Abbreviation
Claims #
18691186
App186
1, 5-6, 8-28, 30-32, 34
18873134
App134
1-78
19098185
App185
35-54
Although the claims at issue are not identical they are directed to overlapping subject matter because the copending App186/App134/App185 claims are directed to an oncolytic vaccinia virus comprising defective I4L/F4L and defective J2R genes or defective tk and rr activities, wherein the poxvirus further encodes an Ab wherein the Ab(s) can bind CTLA-4 and/or PD-L1, and/or to methods of using the oncolytic vaccinia virus to treat cancer or a proliferative disorder.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
All claim sets are directed to oncolytic vaccinia virus that can express heterologous proteins including Ab(s) that bind CTLA-4 and/or PD-L1.
The copending App186/App134/App185 claims don’t recite that the poxvirus is modified in the M2L, (and produces no or defective m2 protein). The copending claims don’t recite all the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the copending App186/App134/App185 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The instant claims and using them would have been obvious in view of the compositions of the copending App186/App134/App185 claims plus the cited prior art. Therefore the instantly claimed compounds would have been obvious in view of the copending App186/App134/App185 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
This is a provisional NSDP rejection.
Claims 29, 32, 34, 37-42, and 51-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the patents listed below in view of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias. This rejection is new.
This rejection applies to the following issued patents:
Patent No.
Abbreviation
Issue date
Claims #
US 7608267
US267
27 October 2009
1-25
US 12291569
US169
06 May 2025
1-8
Although the claims at issue are not identical they are directed to overlapping subject matter because the US267 claims are directed to a fusion protein comprising IL-12 and IL-18, and to poxvirus vectors for expressing it and the US169 claims are directed to an Ab molecule that specifically binds CTLA-4.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
The instant claims are directed to recombinant vaccinia viruses that express a cytokine that can be IL-12 or an Ab that binds CTLA-4 and the patented US267/US169 claims are directed to a vector for expressing IL-12 and to an Ab that binds CTLA-4. An artisan would have used what is available in the prior art to produce a vaccinia virus that expresses the product of the US267/US169 claims.
The patented US267/US169 claims don’t recite a poxvirus that is modified in the M2L, J2R, or I4L/4FL loci (and produces no or defective m2 protein and defective tk, and rr proteins). The patented claims don’t recite all the other limitations of the instant claims.
However, those limitations would have been obvious in view of the prior art:
Hinthong teaches (§Abstract, §Results-The M2L product is expressed early during vaccinia virus infection ¶2, Fig. 1, §Materials and methods-Cells and viruses ¶6, §Discussion ¶1, §The M2L product is N-linked glycosylated, Figs. 2 and 3) M2L protein inhibits NF-kB, and that eliminating the M2L protein in their modified vaccinia virus strain WR, called ΔM2L (which is not a PCPV, an MVA virus, or a NYVAC virus), compromises WR’s ability to inhibit virus-induced NF-kB activation.
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li teaches (§Abstract) attenuated NF-kB signaling underlies DC dysfunction in cancer and is undesirable in treating cancer.
Potts teaches (§Abstract) F4L‐deleted vaccinia viruses (VACVs) have tumor‐selective replication and cell killing, exhibit enhanced safety and selectivity, and are a promising therapy for patients with refractory cancers and immune dysregulation. McCart teaches that (§Abstract; §Discussion ¶1; §Discussion ¶3-4, final ¶) a virus lacking tk protein replicates preferentially in dividing mammalian cells in vitro and has broad potential utility for use as an antitumor agent on its own or by expressing suicide or cytokine genes.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the patented US267 claims with the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the CTLA-4–binding Ab of the patented US169 claims and encode it in the engineered vaccinia virus that would have been obvious in view of the teachings of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and/or Dias, for the benefits of producing an oncolytic virus that doesn’t downregulate NF-kB, that exhibits enhanced safety and selectivity, that has broad utility in treating cancer and can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4.
One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate modifying a vaccinia virus in that way or encoding an Ab in a vaccinia virus was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The compositions of the US267/US169 claims plus the cited prior art broadly encompass the compositions of the instant claims. Therefore the instantly claimed compounds would have been obvious in view of the US267/US169 claims, Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, Li 2011, Twumasi, Liu, Suarez, and Dias.
Claims 29-32, 34-42, and 51-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the copending applications listed below in view of Li 2011, Twumasi, Liu, Suarez, and Dias as evidenced by Kleinpeter and Wikipedia. The rejection over App073 is updated. The rejection over App438 is new.
This rejection applies to the following copending applications:
App. No.
Abbreviation
Claims #
18876073
App073
1-3, 5-15, 17, 19, 21-22, and 26
19102438
App438
56-83
Although the claims at issue are not identical they are directed to overlapping subject matter because the copending App073/App438 claims are directed to a chimeric poxvirus that is oncolytic and can be a vaccinia virus (including strain WR, App438 Claim 60), wherein the virus can have defects in the J2R, I4L/4FL, and M2L loci (i.e., App438 Claims 62, 69, 71 and App073 Claims 21-22), wherein the virus can express nucleic acids of interest, including a cytokine, ICI, or other agents, and to methods of using the virus to treat a proliferative disease.
The instant claims are directed to an engineered Orthopoxvirus (that is not PCPV, MVA, or NYVAC and wherein the nonengineered form of the virus comprises a functional M2L locus) comprising an M2L locus that is defective for m2 function and which is unable to bind CD80 and CD86 costimulatory ligands because either the m2 protein is defective or the virus does not synthesize m2 protein, wherein the inability to bind CD80 and/or CD86 is due to a partial genetic lesion within the M2L locus or a total deletion of the M2L locus, and wherein the engineered poxvirus is oncolytic and is defective for J2R and I4L/F4L loci which results in an engineered poxvirus defective for m2, tk and rr activities; wherein the engineered poxvirus is recombinant and engineered to express a cytokine (that can be IL-12), a chemokine, at least one ligand, at least one antibody (Ab) (wherein the Ab can specifically bind an immune checkpoint protein and the Ab can be an anti-PD-L1 Ab or an anti-CTLA-4 Ab); wherein the genetic lesion is a partial deletion that encompasses certain regions in the M2L locus or promoter; and wherein the engineered poxvirus selectively replicates in dividing human and mammalian cells and lyses them in vitro while showing no or minimal replication in non-dividing human and mammalian cells in vitro in the absence of cytokines.
All claim sets are directed to oncolytic vaccinia virus wherein the J2R, I4L/4FL, and M2L loci are defective and wherein the virus can be further modified to express a cytokine or ligand.
The copending App073/App438 claims do not recite that their modified poxvirus is unable to bind CD80/CD86 or all the other limitations of the instant claims.
However, those limitations are either inherent or would have been obvious in view of the prior art:
Kleinpeter provides evidence that binding of m2 to CD80/CD86 is the inherent function of the m2 protein: (§Abstract, §Importance); since ΔM2L is a modified vaccinia virus lacking m2 protein, it would inherently lack the ability to bind CD80 and/or CD86 costimulatory ligands. Guo provides evidence that (§Introduction ¶1-2, §Results-In vitro replication of vSP and vF13 viruses in normal and transformed cells ¶2) the vaccinia virus, including strain WR, is oncolytic and selectively replicates in tumor cells. Wikipedia provides evidence that the vaccinia virus is of the Orthopoxvirus genus.
Li 2011, teaches (§Abstract, §Introduction, final ¶) using the virus to express a chemokine enhances vaccine therapies of cancer.
Twumasi, teaches using (§Using OVs to deliver immune checkpoint Inhibitors) OV to deliver ICI and engineering OV to encode ICI, including an anti-PD1 antibody. Liu teaches (§Abstract, §Main text ¶2-3, §Main text ¶4, Fig. 4) administering anti-PD-L1 Ab to cancer cells to reduce tumor burden and improve patient survival. Suarez teaches (§Materials and Methods-Cloning of anti-PD-L1 scFv-Fc IgG1 and IgG4 into a bicistronic lentiviral vector encoding an anti-CAIX 2nd-generation CAR) coding sequences for anti-PD-L1 Ab. Dias teaches (§Abstract, §Introduction ¶3, Fig. 4, §Discussion ¶6) a virus that expresses CTLA-4–blocking Abs is good for treating tumors.
It would have been obvious to an artisan before the effective filing date of the claimed invention to modify the recombinant vaccinia virus of the copending App073/App438 claims with the teachings of Li 2011, Twumasi, Liu, Suarez, and/or Dias, as evidenced by Kleinpeter and Wikipedia for the benefits of producing an oncolytic virus that can be used to express immunostimulatory molecules, including molecules such as ligands (i.e., antigens), chemokines, cytokines or the cytokine IL-12, or antibodies, including Ab to PD-L1 and CTLA-4. One would have been motivated to do so with a reasonable expectation of success because the cited teachings indicate doing so was routine, conventional, and beneficial in the art of using oncolytic viruses to treat cancer.
The instant claims and using them would have been obvious in view of the compositions of the copending App073/App438 claims plus the cited prior art. Therefore the instantly claimed compounds would have been obvious in view of the copending App073/App438 claims and Li 2011, Twumasi, Liu, Suarez, and Dias as evidenced by Kleinpeter and Wikipedia.
This is a provisional NSDP rejection.
Response to Arguments
Applicant's arguments filed 17 February 2026 have been fully considered but they are not persuasive. Responses to arguments appear under each heading below. Arguments that are no longer relevant are not addressed.
Objections
There are minor informalities as explained.
112(b)
Claim 32 depends from a cancelled claim and Claim 58 has superfluous text that doesn’t make sense.
112(a) Written Description
The 112(a) rejection is maintained because the claims recite crucial functions caused by large genera of alterations (i.e., m2 that doesn’t bind CD80/CD86 and “partial deletions” that render m2 unable to bind CD80/CD86; wherein the poxvirus is engineered in the J2R locus and the I4L and/or F4L loci resulting in a poxvirus that is “defective” for m2, tk, and rr activities) but doesn’t disclose the structures responsible for those functions or defects. The Spec. does describe characteristics of defective m2 function (pp. 18-19) and (p. 54) one species of partial m2 deletion, but never discloses the amino acids or nucleotides that are responsible for the recited deficiency of an inability to bind CD80/CD86. Similarly, the Spec. discusses (pp. 19-21) characteristics of defective tk and rr activities, but never discloses the structures responsible for those functions or defects. The Spec. discusses (p. 25 L20-25) inactivating mutations of M2L, J2R, and I4L/F4L, but does not disclose any specifics of those inactivating mutations.
The Spec. never discloses the amino acids or nucleotides that are responsible for the deficiency. The claims recite partial deletions may be applied, but never discloses what constitutes a partial deletion. In its broadest sense a “partial deletion” encompasses a single base or a single codon. Yet Applicant has not disclosed which single base or codon may be deleted to render the m2 protein unable to bind CD80/CD86.
Applicant argues (pp. 23-24) that their Spec. does disclose how a person skilled in the art would test whether m2 is functionally inactivated for its ability to bind CD80/CD86. But that is not persuasive because what Applicant describes as detailed explanations on the procedure to be followed and techniques that can be used to verify the presence of an M2L locus and identify it, techniques that can verify m2 protein function, and methods of performing genetic lesions and modifying poxviruses are merely an invitation to experiment. Without crucial information about which nt or amino acids should be altered, a person of ordinary skill would have to run many experiments to make those determinations via trial and error. The Table 1 which Applicant references merely lists a slew of Genbank reference numbers and % protein identity to one variety of m2 protein. The sequences encoding a functional m2 protein don’t disclose what portions bind CD80/CD86. On p. 28 Applicant discusses that the claims now require the poxvirus is Orthopoxvirus and the species listed in the table share at least 72% protein identity. Applicant argues that a skilled person would consider a sequence identity of 72% of more sufficient to allow a person skilled in the art to identify modifications resulting in a deficiency for m2 function without undue burden. That is not persuasive because once, again, without disclosure of what nt or AA are responsible for CD80/CD86 binding (and whose alteration will result in a lack of CD80/CD86 binding), that is merely an invitation to experiment. Furthermore, Applicant hasn’t presented any evidence substantiating that allegation that an artisan would readily identify modifications resulting in a deficiency. A glance at the vaccinia virus genome (Cop. strain) indicates that it is 191737 bp and putative M2L is encoded by 663 bp. The protein is 220 AA. According to Applicant’s claims, any partial deletion of any of those bases will result in a defective m2 protein that cannot bind CD80/CD86. But Applicant hasn’t disclosed which specific bases are responsible for that change in function.
Applicant argues that the Spec. adequately describes techniques and strategies that can be used to identify an M2L locus within a poxvirus genome or determine whether or not an m2 protein translated from a lesioned M2L locus binds or fails to bind CD80/CD86. Examination of the cited passages reveals that they do not provide detail about structures that must be changed or altered in order to obtain the claimed outcome of a lack of CD80/CD86 binding. Altogether, Applicant hasn’t sufficiently disclosed how a person of ordinary skill would alter M2L such that the resultant defective protein doesn’t bind CD80/CD86. The Spec. does not divulge any requisite structure that will render the m2 protein defective and unable to bind CD80/86 costimulatory ligands, and the Spec. does not divulge what specific nucleotides should or should not be modified to produce a sufficiently defective m2 poxvirus protein function.
Applicant argues that the Spec. discloses one region whose deletion results in loss of expression of m2 protein. That is insufficient to provide adequate written description support for the breadth of the claims because the claims recite partial deletions that cause synthesis of a defective m2 protein that can’t bind CD80/CD86.
Applicant’s arguments on pp. 24-25 further assert that there is sufficient disclosure that a person of ordinary skill can determine and then verify inactivation of m2 protein. That argument is not persuasive because the written description requirement is that Applicant should reasonably convey that, at the time the application was filed, they had possession of the claimed invention and Applicant hasn’t provided that for the full breadth of the claims: partial deletion of M2L locus that results in a defective m2 protein that is unable to bind CD80/CD86.
Applicant hasn’t met that burden, as discussed here and below.
Applicant argues that (pp. 23-27) an artisan would readily determine the region to modify in a poxvirus of interest and verify its m2 protein function. That is not found persuasive because the teachings of Brennan indicate that poxviruses undergo rapid change and have great nucleotide variation. Furthermore, that argument is not found persuasive because Applicant’s claims encompass partial deletions to the M2L locus, mutations that result in defective m2, tk, and rr activities, and a virus that expresses any cytokine, chemokine, antibody, etc.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
Description of how to determine whether a protein does or doesn’t bind CD80/CD86 fails to meet the written description requirement because that description does not demonstrate that Applicant was in full possession of the breadth of the claims. The claims encompass any partial deletion within the M2L locus. A partial deletion could be any amount of deletion, even as little as a single nt.
Written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) MPEP 2163 §I(A)
But Applicant’s claims are very broad (as discussed, they read on any partial deletion) and Applicant’s Spec. does not allow an artisan to immediately envisage the claimed product.
Other ways of establishing possession of a claimed invention may include unique cleavage by particular enzymes, isoelectric points of fragments, detailed restriction enzyme maps, a comparison of enzymatic activities, or antibody cross-reactivity. See Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966 (Stating that the written description requirement may be satisfied by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention."). Conversely, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. … An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). MPEP 2163 §II(A)(3)(a)
The case described above is similar to the instant situation: While there is a description of assays for screening m2 proteins to identify those that lack the ability to bind CD80/CD86, there is no disclosure about the physical structure required for that binding or the physical structure that must be absent so that binding does not occur.
Regarding Claims 38-42 and 51-56, those claims are directed to broad genera of cytokines, chemokines, ligands, antibodies, and immune checkpoint proteins. Claim 39 is directed to an engineered poxvirus that expresses the cytokine IL-12. Those claims still broadly recite that the poxvirus can expression any cytokine, chemokine, ligand, and antibody and Applicants have not demonstrated possession of poxviruses comprising a representative number of those species. Applicant has not demonstrated possession of a virus that expresses any ligand, antibodies, or any antibody that specifically binds an immune checkpoint molecule.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). … ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) MPEP 2163 §II(A)(3)(a)(i-ii)
While the Spec. discusses (Example 4) secretion of IL-2, there is nothing that demonstrates possession of a virus that expresses IL-12. No example discusses a chemokine. While there are examples describing viruses encoding antibodies (Ab) to PD-L1 and CTLA4, Ab are highly variable molecules and possession of a single species of Ab does not represent possession of the broad range of Ab—even Ab to a single antigen. Similarly, cytokines, chemokines, immune checkpoint proteins, and “ligands” are all broad genera that encompass diverse species, each with different physical structures. The recitation ligand is particularly broad because it can be interpreted to encompass any molecule.
Applicant’s arguments (p. 25) that various members of the Orthopoxvirus genus that are defective for and/or tk activities are known in the art is not persuasive because Applicant hasn’t disclosed structures whose absence results in defects. Applicant does not refer to any part of the Spec. or any reference that describes how to make the recited loci (J2R, I4L, and/or F4L) defective, which is what the claims recite. Regarding the rr and tk mutations, Applicant’s arguments that those were well known and sequenced is not persuasive because Applicant hasn’t presented evidence of how much of each locus should be modified to cause defective tk or rr function.
Regarding Applicant’s arguments on pp. 26-27, none of those demonstrates that Applicant was in possession of the full breadth of the claimed invention. The post-filing date publication (Azar) doesn’t demonstrate that Applicant was in possession of the full breadth of the claimed invention at time of filing.
Applicant’s arguments (pp. 27-28) aren’t persuasive because none of those points to anything in the Spec. that teaches specific structures that render any of the claimed proteins defective. Applicant isn’t just claiming a virus wherein the m2, tk, and rr proteins are absent. Their claims recite defective versions of those proteins yet they haven’t disclosed what structural deficiencies (i.e., in terms of mutated/absent nucleic acids or amino acids) render any of those proteins “defective”. Even on p. 26 Applicate mentions Example 2 in which a partial deletion in the M2L locus results in suppressed expression of m2 protein. That Example doesn’t demonstrate possession because it shows a poxvirus comprising an absent m2 protein, not a defective m2 protein, wherein said defective m2 protein is unable to bind CD80/CD86.
Applicant argues the claimed subject matter is not functionally defined but fails to explain how that is the case when the claims recite (functional language emphasized):
An engineered poxvirus that is different from a non-engineered poxvirus in its native form, wherein the non-engineered poxvirus genome comprises an M2L locus encoding a functional m2 poxviral protein that binds CD80 or CD86 co-stimulatory ligands or both CD80 and CD86 co-stimulatory ligands; wherein the engineered poxvirus is modified in the M2L locus, leading:
- to the synthesis of a defective m2 protein, wherein said defective m2 protein is unable to bind said CD80 and CD86 co-stimulatory ligands; or
- to the lack of m2 protein synthesis;
wherein the inability to bind said CD80 and CD86 co-stimulatory ligands originates from a genetic lesion within the M2L locus, wherein the genetic lesion comprises:_
a partial deletion within the M2L locus, wherein the partial deletion is a partial deletion within the m2-codinq sequence and/or in an m2 promoter; or
a total deletion of the m2-coding sequence or of an m2 promoter; or
a total deletion of the M2L locus;
wherein the engineered poxvirus is not a Pseudocowpox virus (PCPV), an MVA virus, or a NYVAC virus; wherein the engineered poxvirus is obtained by engineering a poxvirus of the Orthopoxvirus genus; wherein the engineered poxvirus is oncolytic; and wherein the engineered poxvirus is further engineered in the J2R locus, and in the 14L locus and/or in the F4L locus, resulting in an engineered poxvirus defective for m2, tk and rr activities.
That claim very clearly recites functional language: the defective m2 protein that can’t bind CD80/CD86 and the partial deletion that causes the defect(s) and the defective m2, tk, and rr activities. Yet nothing in the Spec. explains what structures are responsible for the functions of being defective.
Then Applicant mischaracterizes the rejection and their own disclosure:
[The claims] recite a specific viral construct comprising a structurally defined M2 protein variant. The limitation in Claim 29 that the engineered poxvirus is obtained by engineering a poxvirus of the Orthopoxvirus genus, which includes m2 proteins with at least 72% sequence identity to Cop m2 protein, is an objective structural constraint that directly defines the amino acid composition of the viral protein.
Amino acid sequence identity is an objective, measurable structural parameter that directly defines molecular structure.
But the problem is exactly that the claimed m2 protein variants are absolutely not structurally defined! The claims recite defects that render m2 unable to bind CD80/CD86 and render tk and rr activities “defective”. Yet, no structure responsible for those defects has been disclosed. Applicant discusses 72% identity as if they have disclosed what portion(s)—or in their own terms partial deletion[s]—of that 72% render m2, tk, and rr defective (which is what they have claimed). But the absolutely haven’t and Applicant’s arguments don’t point to where they do. Applicant’s Remarks mention (p. 29) guidance regarding substitutions and sequence variation but guidance on what AA changes produce defective m2, tk, and rr proteins is simply not in the Spec., no matter how much Applicant asserts, erroneously, that it is. Applicant mentions (p. 30) defined structural homology to a sequence but there is a disconnect between the genus and genera Applicant has claimed (i.e., engineered poxviruses modified in the M2L locus such that they synthesize a defective m2 protein, wherein said defective m2 protein is unable to bind said CD80 and CD86 co-stimulatory ligands… wherein the inability to bind said CD80 and CD86 co-stimulatory ligands originates from a partial genetic lesion within the M2L locus, wherein the partial deletion is a partial deletion within the m2-coding sequence and/or in an m2 promoter and wherein the engineered poxvirus is further engineered in the J2R locus, and in the I4L locus and/or in the F4L locus, resulting in an engineered poxvirus defective for m2, tk and rr activities) and the genus they have actually defined (i.e., Genbank reference numbers for a few species of wildtype Orthopoxviruses).
Applicant mentions structural homology but they haven’t actually shown any structural homology or discussed what structures are actually present (or absent) such that the defective m2 protein is unable to bind said CD80 and CD86 co-stimulatory ligands or such that m2, tk, and rr activities are defective. Not just absent but defective and defective due to partial deletions. Applicant is merely being asked to show data demonstrating they were in possession of the full breadth of their claims: a representative number of viruses modified such that the virus is defective as claimed or to disclose the structures that render the virus defective as claimed. Not only is it unclear what they are actually wanting patent protections for (since they don’t disclose what makes an m2 protein unable to bind CD80/CD86 or what partial deletions render the m2 protein defective in that way, and since they also don’t disclose what makes tk and rr activities defective), but they are not meeting their statutory burden of exchange.
Applicant argues (p. 26) that the Examples show what is claimed. But that is not found persuasive because while the Examples show some part of what is claimed, the claims encompass much greater breadth that is not evidenced by the Examples. While Applicant states that Example 1 shows that the engineered m2-defective poxviruses inhibit the interaction of CTLA4 with CD80 or CD86, Applicant is claiming any engineered m2-defective poxviruses (besides for those excluded by the Claims) and Applicant never discloses what specific structural failing—a partial genetic lesion or deletion—makes an M2L locus “defective”. While Applicant states that Example 2: shows that an M2L partial deletion extending from 64 nucleotides upstream the m2 ORF to the 169 first codons results in a suppressed expression of m2 protein (m2-), that shows only one specific partial deletion, it does not disclose any other partial genetic lesion or deletion—not the full breadth of what is claimed. While Applicant states Example 3: shows that tk-rr-m2- oncolytic vaccinia virus express luciferase and the modification of the VV M2L locus has no impact on the oncolytic activity, the antitumoral effect and the expression of the transgene, that Example does not demonstrate possession of the entirety of what is claimed because the Spec. does not disclose what makes any of those proteins defective. Applicant’s statements about Examples 4 and 5 do not clearly relate to any of the claims.
Applicant argues (p. 25):
One of ordinary skill in the art, based on the disclosures in Applicants' Specification, would readily determine the region to modify in a poxvirus of interest, and verify that the chosen modification functionally inactivates m2 protein, by comparing the unmodified m2 and the mutated m2 protein of this poxvirus for their ability to bind CD80 and/or CD86, as illustrated in the Example section of Applicants' Specification
But that is not persuasive because the statute requires that written description must allow an artisan to envision the claimed structure.
If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that inventor was in possession of the claimed invention.
(1) Determine whether the application as filed describes the complete structure (or acts of a process) of the claimed invention as a whole. The complete structure of a species or embodiment typically satisfies the requirement that the description be set forth "in such full, clear, concise, and exact terms" to show possession of the claimed invention. 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph; cf. Fields v. Conover, 443 F.2d 1386, 1392, 170 USPQ 276, 280 (CCPA 1971) (finding a lack of written description because the specification lacked the "full, clear, concise, and exact written description" which is necessary to support the claimed invention). If a complete structure is disclosed, the written description requirement is satisfied for that species or embodiment, and a rejection under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, for lack of written description must not be made.
(2) If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize inventor was in possession of the claimed invention. For example, in the biotech art, if a strong correlation has been established between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). MPEP 2163 §II(A)(3)(a)(i)
Altogether, Applicant’s arguments are not persuasive because the claims are very broad, much broader than what is disclosed in the Spec. The Spec. never discloses what genetic lesions will and will not render an m2 protein unable to bind CD80/CD86, or what genetic lesions make m2, tk, and/or rr defective, or what even is considered a defective tk or rr protein or “activity”.
Note that: The written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term. MPEP 2163 §I In this case, the Spec. does not meet that burden because the claims are very broad. Therefore the WD rejection is maintained.
This rejection can be overcome if Applicant specifies the nt or AA changes that will render the virus defective for m2 such that it can’t bind CD80/CD86, the nt or AA changes that will render the tk and rr defective for their activities, and demonstrates possession of a representative number of viruses that express cytokines, cytokines, and antibodies. Specifying the nt or AA changes that will render the virus defective for m2 such that it can’t bind CD80/CD86 and the nt or AA changes that will render the tk and rr defective for their activities would disclose to an artisan what partial deletions would produce the claimed virus whose m2, tk, and rr proteins are defective.
102
A new 102 rejection over Claim 57 is applied because Hinthong discloses an engineered poxvirus that meets all the limitations of the Claim. Hinthong’s ΔM2L vaccinia virus (strain WR) is (§Results-The M2L product is expressed early during vaccinia virus infection ¶2; Fig. 1) different from WR in that it lacks m2 protein synthesis. Therefore it could not bind CD80/CD86 (evidence from Kleinpeter demonstrates that). Guo provides evidence that WR is oncolytic which by definition means it selectively replicates in tumor cells which are dividing cells. Guo specifies that WR is a tumor-selective replicating vaccinia virus.
103
Applicant argues that reliance on 4 publications evidences lack of obviousness. That is not found persuasive because the level of a person of ordinary skill in the art is high and an artisan knows that it is common in the art of biotechnology to synthesize or contemplate teachings from tens, hundreds, or even thousands of pieces of art.
In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). The requirement for 103 is what would have been obvious to a person of ordinary skill in view of what exists in the prior art. In this case, benefits of oncolytic viruses lacking m2, tk, and rr proteins were known, and the rejection only synthesizes what was already known. A person of ordinary skill is a person of ordinary competence and creativity.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In addition to the factors above, Office personnel may rely on their own technical expertise to describe the knowledge and skills of a person of ordinary skill in the art. The Federal Circuit has stated that examiners and administrative patent judges on the Board are "persons of scientific competence in the fields in which they work" and that their findings are "informed by their scientific knowledge, as to the meaning of prior art references to persons of ordinary skill in the art." In re Berg, 320 F.3d 1310, 1315, 65 USPQ2d 2003, 2007 (Fed. Cir. 2003). In addition, examiners "are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art ." PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 86 USPQ2d 1385 (Fed. Cir. 2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1360, 220 USPQ 763, 770 (Fed. Cir. 1984). See MPEP § 2141.03 for a discussion of the level of ordinary skill.
MPEP §2141(II)(c)
Regarding the arguments in §C (pp. 36-43), Applicant should note that the rejection is now clarified to explain that since Hinthong teaches the m2 protein inhibits NF-kB and since Li teaches attenuated NF-kB downregulates DC, thereby causing DC dysfunction (which underlies immune escape), an artisan would have wanted to use an oncolytic virus that does not express m2. They would have wanted to do so because in using an oncolytic virus to treat cancer, they would have wanted to use an oncolytic virus that doesn’t (1) downregulate NF-kB or (2) exacerbate immune escape. Eliminating m2 protein from the oncolytic virus would have been a straightforward way to accomplish that. Therefore Applicant’s arguments directed to any reactivation of the NF-kB signaling pathway are no longer relevant.
Applicant argues that signaling pathways are complex, which is clearly true. But what is being synthesized in the rejection is that Li teaches NF-kB downregulation has clear negative effects on anticancer immune function and Hinthong teaches that m2 protein downregulates NF-kB. There is no reach or handwaving to come to the obvious conclusion that an artisan would want to use an oncolytic virus that doesn’t downregulate NF-kB.
Applicant declares that Li is nonanalogous art but that is not persuasive because Li is directed to treating cancer and Guo is directed to oncolytic viruses. Furthermore, it is common in the art of biotechnology for an artisan formulating hypotheses or designing experiments to synthesize teachings from tens, hundreds, or even thousands of pieces of art. That doesn’t mean that such synthesis is nonobvious.
Applicant argues (p38 full ¶3) comparative data provided in the Spec. demonstrate the superiority of the m2- tk- rr- triple mutant and show it would not have been obvious that a poxvirus engineered as defined in the claims would be oncolytic… but that is not persuasive because viruses deficient in each of those proteins were known to be oncolytic, as demonstrated by Hinthong, Guo, and Potts and by McCart and Li 2011. Applicant’s discussion of unexpected results isn’t found persuasive because data in Potts show (Fig. 3C) a double mutated tk- rr- virus reduces tumor volume to a similar if not greater degree than what’s shown in Spec. Figs. 9 and 12. Potts shows (Fig. 5G) their double mutated tk- rr- virus increases percent survival to a similar if not greater degree than what’s shown in Spec. Fig 13. Potts shows (Fig. 4) the virus titer is still high in tumor tissues at Day 19 post infection (i.e., to compare with Spec. Fig. 8). Regarding toxicity, Guo and McCart describe (as discussed in the rejection) that their tk- virus has reduced toxicity and better safety and Potts teaches (§Abstract) their virus has enhanced safety. Then an artisan would have expected even better results when the teachings of Potts were combined with those of Hinthong to produce an oncolytic virus wherein m2 protein was eliminated and the virus loses its ability to inhibit NF-kB activation.
Regarding Applicant’s other allegations of superiority and applicant's arguments (pp. 39-41) that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., any effect on IL-2 secretion, anything regarding an interference factor IF or the B7-mediated costimulatory pathway) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's arguments against the references individually (i.e., pp. 40-41), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the rejection describes a reasonable explanation for why an artisan would have wanted to modify Hinthong’s m2-deficient virus with other modifications known in the art for the benefit of producing an oncolytic virus that would not produce a protein known to downregulate NF-kB (i.e., m2 protein), since NF-kB downregulation had a known detrimental effect on cancer treatment. As explained at length, the rejection is based only upon a synthesis of the references and knowledge held by a person of ordinary skill in the art. The rejection is over what would have been obvious in view of a combination of references.
Regarding argument (pp. 41-42): Applicant’s arguments about any teaching about m2’s property of binding CD80/CD86 costimulatory ligands are not relevant because an artisan would have been motivated to produce an m2-deficient virus and that virus would have inherently possessed the property of not binding CD80/CD86 costimulatory ligands. Regarding m2 deficient virus not being oncolytic, Guo teaches that the vaccinia virus strain WR is inherently oncolytic. The lack of m2 virus doesn’t make the vaccinia virus oncolytic and an artisan would have known, based on the teachings of Guo, that the virus was oncolytic.
Regarding the arguments (pp. 42-43), the rejection has been modified to clarify that an artisan would have wanted to use Hinthong’s m2-deficient virus to avoid expressing a protein known to downregulate the NF-kB pathway. Given a choice of an oncolytic virus that expresses a protein (i.e., m2) that downregulates NF-kB (and would therefore contribute to detrimental effects on DC activation and cancer treatment outcomes) or that same virus lacking that NF-kB–downregulating protein, an artisan would have wanted to use a virus lacking the protein. Whether or not Li discusses oncolytic viruses is irrelevant to what would have been obvious to an artisan based on Li and Hinthong: it’s better to use a cancer treatment that doesn’t downregulate NF-kB. An oncolytic virus is a cancer treatment, so it’s clearly better to use an oncolytic virus that doesn’t downregulate NF-kB. That would have led the artisan to the virus of Hinthong.
Regarding Applicant’s allegation (p. 43) that the rejection shouldn’t use a motivation to combine references that comes from the invention itself, that is not persuasive because nothing in the rejection relied on anything in the Spec.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): Hinthong teaches an m2-deficient vaccinia virus strain WR and that m2 protein downregulates NF-kB. Li discusses the fact that NF-kB downregulation suppresses DCs and, therefore, their cancer-fighting capability. Guo and Potts discuss that tk- and rr-deficient WR are superior at treating cancer.
Regarding (2): Based only on those teachings, it would have been obvious to modify Hinthong’s m2-deficient strain of WR with the tk- and rr-deficiencies of Guo and Potts (and McCart and Li 2011) to produce a triple mutant WR lacking m2, tk, and rr. There were only a finite number of solutions because the references teach that m2 had known inhibitory effects on NF-kB and Li teaches reasons why NF-kB downregulation is undesirable in cancer treatment. Hinthong discloses an m2-deficient virus and describes in detail how they made it. The other references discuss reasons to modify the other loci.
Regarding (3): the combination of prior art demonstrates it was routine and conventional to remove genes from a known oncolytic virus and that the specific claimed genes had been removed from the vaccinia virus. That indicates that a person of ordinary skill could have pursued the finite number of known potential solutions with a reasonable expectation of success.
The arguments against Potts (pp. 44-45) are not persuasive because of the reasons explained above.
Applicant argues against Twumasi (pp. 45-47) and asserts that Twumasi provides no experimental evidence. That is not found persuasive because the rejection discusses what was known in the art at time of filing and Twumasi suggested using oncolytic viruses that augment anti-tumor immunity. In fact, as described in the 103 rejections, Twumasi wasn’t the first to suggest using oncolytic viruses to augment anti-tumor immunity via expression of various molecules. McCart teaches (as cited in the rejection) that as early as December 2001 (its publication date), it was routine and conventional to produce a vaccinia virus modified to carry various antigens, cytokines, immunostimulatory molecules, etc. for the benefits of treating cancer.
Therefore those claim limitations fall under an “obvious to try” rationale. That rationale has been explained above. In this case, using oncolytic viruses to deliver immunostimulatory molecules (such as chemokines, ligands, or cytokines including the cytokine IL-12) or proteins that augment immunotherapy (including antibodies that bind immune checkpoint proteins such as anti-PD-1, anti-PD-L1, anti-CTLA-4), was well known in the art.
Applicant argues against Liu and Suarez (pp. 47-49) but those arguments aren’t found persuasive because it was known in the art to use oncolytic viruses to deliver immunostimulatory proteins, including checkpoint inhibitors. Liu teaches using anti-PD-L1 therapies and Suarez demonstrates that it was possible to genetically encode anti-PD-L1. An artisan would have used Twumasi and McCart’s teachings about oncolytic viruses modified to express checkpoint inhibitors and/or immunostimulatory molecules with Suarez’s sequence to modify an oncolytic virus to express the anti-PD-L1 antibodies. Again, this falls under an “obvious to try” rationale as explained above. In this case, using oncolytic viruses to deliver immunostimulatory molecules was well known in the art and an artisan would have readily used Liu’s teachings and Suarez’s sequence encoding an anti-PD-L1 antibody to modify the oncolytic virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi.
Similarly, Applicant’s arguments against Dias (pp. 49-50) are not persuasive because an artisan would have used Twumasi and McCart’s teachings about oncolytic viruses modified to express checkpoint inhibitors and/or immunostimulatory molecules with Dias’s teachings about an antibody specific for CTLA-4 to encode the antibody in the oncolytic virus of Hinthong (as evidenced by Kleinpeter, Guo, and Wikipedia), Guo, Li, Potts, McCart, and Twumasi.
The 103 rejections are maintained for those reasons.
NSDP
Applicant argues against the NSDP rejections over US080, US619, and US981 because those patents don’t disclose modifying the m2 protein or M2L locus. Those arguments aren’t persuasive for the same reasons the arguments against the 103 rejections weren’t persuasive: an artisan would have had reason to produce an oncolytic virus lacking m2 protein. Hinthong and Li describe the role of m2 protein in downregulating NF-kB and that such downregulation has detrimental effects in cancer treatment. Those teachings would have motivated an artisan to produce an oncolytic vaccinia virus lacking the m2 protein. Applicant argues their claimed virus produces superior results but as explained in the arguments against the 103 rejections, the results are not superior to what would have been expected from the combination of prior art. The NSDP rejections over US080, US619, and US981 are maintained for those reasons.
Applicant argues that US581 and US702 are directed to methods of producing or purifying poxviruses but that isn’t correct because those patents are directed to medicaments comprising poxvirus compositions. Then, modifying the poxviruses in those compositions in ways known in the prior art would have been obvious and would have been motivated to produce known benefits, as discussed in the preceding paragraph. The NSDP rejections over US581 and US702 are maintained for those reasons.
Regarding the rejection over App073, any rejection over late-filed applications will be withdrawn only after allowable subject matter has been indicated.
Therefore all remaining NSDP rejections are maintained.
Conclusion
Claims 29, 32, 34, 37-42, and 51-58 are rejected.
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636