Notice of Pre-AIA or AIA Status
The present application is being examined under the AIA first-to-invent provisions.
DETAILED ACTION
Election Restrictions
Applicant’s election without traverse of Group II invention (claims 276, 292, and 306-353) as well as the species of recombinant oncolytic vaccinia virus comprising a heterologous nucleic acid encoding an inducible apoptosis protein, wherein said apoptosis protein comprising a DED, a Fas, or a caspase, in the reply filed on 02/17/2026 is acknowledged.
Claims 327-341 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/17/2026.
Status of the Claims
Claims 1-275, 277-291, 293-305 are canceled.
Claims 306-326 and 342-353 are new.
Claims 327-341 are withdrawn.
Claims 276, 292, 306-326 and 342-353 are under examination for their merits.
Information Disclosure Statement
Two information disclosure statements (IDS), as submitted on 05/02/2024 and 02/17/2016, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS are being considered by the examiner. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/368,029, filed July 8, 2022. The disclosure of Provisional Patent Application (pages 1-247) had 613 paragraphs, seven tables (E1 through Table E7) and , 20 figures (FIG. 1 through FIG. 20), which did not provide full support for the 10/18/2023 disclosure (pages 1-270): the “Substitutive Specification – Clean” section now has 853 paragraphs, 11 tables (E1 through E11) and 22 figures (FIG. 1 through FIG. 22), so contents beyond ¶[0613], Table E7, FIG. 20 did not qualify for the 07/08/2022 filing date. Among SEQ ID NOs: 1, 7-9, 27-29, 56 and 86 cited in claims 276, 292, 306-326 and 342-353, SEQ ID NO: 86 was not present in the Provisional Patent Application, so claim 325 now receives an effective filing date of 10/18/2023, while claims 276, 292, 306-324, 326 and 342-353 receive the effective filing date of July 8, 2022.
Objection to Drawings
The drawings are objected to because of multiple ambiguities with nomenclatures. 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.
The drawings for this application are objected to as “PSE” promoter in FIG. 13 does not have a full spelling in the annotation or elsewhere in the specification, while “WiDr” in FIG. 19G is inconsistent for the nomenclature of a cancer cell line cited in specification (¶[0171) and ¶[0815]). Applicant is advised to define claimed abbreviations and present consistent listing of cancer cell lines such that the drawings are free of ambiguities. For compact prosecution, examiner accepts WiDR as the correct name, as supported by specification (¶[0171) and ¶[0815]). As for the “PSE” promoter, the first reference to this element (¶[0286]) has no full spelling and is treated as an ambiguous term/limitation. Examiner recommends a full spelling for PSE in the figure legend.
Objections to Specification
The disclosure for this application is objected to because of the following informalities:
“Prostate cancer” is listed twice in ¶[0134] (page 34, VERSION WITH MARKINGS TO SHOW CHANGES MADE).
Multiple cancer cell lines (e.g., LS123, LS174T, WiDR in FIG. 19 and ¶[0171) are listed without indicating the cancer types that they represent, being inconsistent with other cancer cell lines for which cell origins are given.
Cancer cell line WiDR in ¶[0171) and ¶[0815] is cited as “WiDr” in FIG. 19G, which is another internal inconsistency between sections.
FKBP variant F36V is first cited as “FKBP-F36V” in ¶[0058], ¶[0442] and ¶[0448] and then as “F36V-FKBP” in ¶[0441], ¶[0451] and ¶[0452], being internally inconsistent.
The genotype of VIR40, VIR41 and VIR42 has an “SSE” promoter, yet the claimed promoter is PSE (cited in ¶[0286], ¶[0451] and ¶[0463]).
In ¶[0486], the amount of “pfu” cited for virus titer is incorrect, as “1 x 106 pfu” and “1 x108 pfu/mL” cited here should be “1 x 106 pfu” and “1 x108 pfu/mL”, respectively.
“COLO205” cited in ¶[0469] and ¶[0815], “COLO-205” in ¶[0738] and “COLO205 MSS colon cancer” in ¶[0815] are inconsistent for the nomenclature of an MSS cancer cell line.
Applicant is advised to avoid redundancy and to provide consistent listing of claimed virus clones/strains or promoter sequences such that the disclosure is clear and readable. For compact prosecution, examiner treats the examples of cancer types as mere possibilities that add no weight to the claim limitation. As for the “PSE” promoter, the first reference to this element (¶[0286]) is accepted as the basis for examination. COLO205 is accepted as an MSS colon cancer line.
Claim Objections
Claims 307, 316, 344 and 353 are objected to as having redundant information – “Cervical cancer” and “prostate cancer” are cited twice in claims 307 and 344 (lines 2, 4 and 5 in each claim), and A56R gene is first cited as “hemagglutinin (HA)” (line 3) and then as “A56R (hemagglutinin)” in claim 316 (lines 3-4). Claim 353 (lines 1-2) cites that “wherein the proliferative disorder is a cancer that cancer is Microsatellite Stable (MSS) colorectal cancer,” which should read as “wherein the proliferative disorder is Microsatellite Stable (MSS) colorectal cancer.” Applicant is advised to delete the redundant information.
Claims 311-312, 322 and 342 are objected to as containing abbreviations that lack full spelling: “FKBP” in claim 311 (line 2), “DED” in claim 312, “PSE” in claim 322 (line 3) and “pfu” in claim 342 (line 2) are not preceded by full spelling. Applicant is advised to provide a proper, full nomenclature for each of these terms. For compact prosecution, examiners lifts information from the specification or cited literature: (i) FKBP is a “FK506-binding proteins (Kolos et al. 2018. Front. Pharmacol. 9:1425), (ii) DED stands for “death effector domain” (¶[0059]); (iii) pfu (PFU) stands for plaque-forming units for virus titer (Kirn 2004, WO 2004/014314 A2, last paragraph on page 66). PSE is not fully defined anywhere of record; examiner treats “PSE” as the “synthetic early promoter” cited in Stritzker et al. 2014 (Journal of Virology 88(19): 11556–11567; of record on IDS and cited in ¶[0286] of the instant application), which “was active early during the infection cycle” when tested in a “set of rVACV strains” (Stritzker et al., page 11559, last paragraph on the left).
Claim 346 is objected to as having a nomenclature that differs from specification: FKBP-F36V is referred to as “F36V-FKBP” in ¶[0441], ¶[0446], ¶[0447] and elsewhere in the specification (e.g., ¶[0451] and ¶[0452]).
Claim 348 is objected to as containing a typographical error: “… iDED is inserted into the genome of the vaccinia virus at the B2R, J2R, A35R, A56R or F14.5L gene loci” should read “… … iDED is inserted into the genome of the vaccinia virus at the B2R, J2R, A35R, A56R or F14.5L gene locus” because a single fusion gene sequence like iDED is meant to be inserted into a single viral locus, as defined in the specification for SEQ ID NO: 8 (Table E5). Appropriate correction is required.
Claim 353 is objected to as containing improper language: “The method of claim 352, wherein the proliferative disorder is a cancer that cancer is Microsatellite Stable (MSS) colorectal cancer” should read “… is a cancer and that cancer is Microsatellite Stable (MSS) colorectal cancer” or simply “is a Microsatellite Stable (MSS) colorectal cancer.” Appropriate correction is required.
Claim Rejection under 35 U.S.C. §112(b)
The following is a quotation of 35 U.S.C. §112(b) which forms the basis for indefiniteness rejections set forth in this Office action:
(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.
Claims 307, 342, 344 and 351-352 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.
Claims 307 and 344 are rendered indefinite by contents placed in parentheses that differ in scope from their respective terms preceding them. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 307 and 344 recites the broad term of “bile duct cancer” (line 6 in both claims) and the claim also recites “cholangiocarcinoma,” which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The phrase "for example" (“e.g.”) in claims 307 and 344 also renders these claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention or not. See MPEP § 2173.05(d).
The term “about” in claims 342 (line 2), 351 (line 2) and 352 (line 3) is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specification discloses an explanation that “as used herein, ranges and amounts can be expressed as ‘about’ a particular value or range. About also includes the exact amount. Hence ‘about 5 bases’ means ‘about 5 bases’ and also ‘5 bases’” (§[0731]. However, the explanation here is not a definition of “about”, so its application to claims 342, 352 and 353 falls short of specifying the actual dosage of viruses administered to a patient. See MPEP §2173.05(b), which sates the following: the court held that claims reciting "at least about" were invalid for indefiniteness where there was close prior art and there was nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term "about." Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991).
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 311, 318-321, 324-325, 343, 346-347, 350 and 352-353 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. These claims 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.
Specifically, claims 311, 343 and 352 recite the phrase “an FKBP variant.” Claim 318 extends claim 311 by reciting “the FKBP variant is FKBP comprising the mutation F36V” but reads on adding limitless other mutations not listed. Claims 320 inherits the issue of claim 311 without any remedy, while claims 319 and 346 specify the “FKBP variant” as FKBP-F36V (SEQ ID NO: 56), but in each case a “95% identity” to SEQ ID NO: 56 reads on a genus.
Claims 321, 324-325, 347, 350 and 352 recite additional sequences that bear “95% identity” to SEQ ID NOs: 1, 7-9, 26-28 and 86, with each case again reading on a genus. Claims 353 extends claim 352, with an inherent issue for taking a genus of sequence identity.
For each of the nucleotide and amino acid sequences cited in claims 311, 318-321, 324-325, 343, 346-347, 350 and 352-353, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. 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 each genus, one must describe a sufficient variety of species to reflect the variation within 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. “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.”
According to MPEP 2163.04, “¶[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.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
When there is substantial variation within the genus, as here in which the DNA and amino sequence variants can have any sequence in the range of “at least 95% identity”, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of ordinary skill in this art cannot envision the structure of any recombinant DNA sequence or its corresponding protein/polypeptide with the required or preferred function other than SEQ ID NOs: 1, 7-9, 26-28, 56 and 86 provided by the Applicant or other relevant ones from prior art, as the specification merely cites the definition of identify (¶[0719]) and methods for calculating sequence identity (¶[0720]). Therefore, without any other representative sequence variants in the form of Tables/Figures or GenBank accession numbers, each of the DNA or amino acid species of SEQ ID NOs: 1, 7-9, 26-28, 56 and 86 is not sufficient enough to represent their respective genus, so the claims encompassing the same SEQ ID NOs clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“¶[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”).
Even when several species are disclosed (e.g., SEQ ID NOs: 1 and 7-9 for vaccinia virus strains before and after modification), these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus”). Thus, when there is substantial variation within the virus strains and/or recombination events, as SEQ ID NOs: 1, 7-9 and 86 entail, one must describe a sufficient variety of each anticipated variant species to reflect the spectrum of variation within the genus to provide a "representative number” of species with comparable structure and/or function for a practical application. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures/functions of the entire genus. A single sequence for each virus strains or several sequences for each influenza virus lineage/subtype (A or B) is certainly inadequate.
Overall, at the time the invention was filed, the level of skill for preparing variant forms of recombination vaccinia viruses for in vitro testing and in vivo anti-cancer function and then packaging them into a pharmaceutically acceptable formulation toward therapy with desired oncolytic properties was high. And even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify such variants with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Without details mapping of DNA sequence variations, a skilled artisan generally would not be able to visualize or otherwise predict, a priori, what nucleotide position(s) with a particular set of functional properties (coding or noncoding) would look like structurally. As taught by Kirn 2004 (WO 2004/014314 A2, published 02/19/2004), “sequence variants… can be substitutional, insertional or deletion variants” (page 33, first paragraph). “Deletion variants lack one or more residues of the native or wild-type protein. Individual residues can be deleted or all or part of a domain (such as a catalytic or binding domain) can be deleted. A stop codon may be introduced (by substitution or insertion) into an encoding nucleic acid sequence to generate a truncated protein. Insertional mutants typically involve the addition of material at a non-terminal point in the polypeptide. This may include the insertion of an immunoreactive epitope or sin1ply one or more residues. Terminal additions, called fusion proteins, may also be generated” (page 33, second paragraph). In contrast, “substitutional variants typically contain the exchange of one amino acid for another, at one or more sites within the protein, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar shape and charge. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Alternatively, substitutions may be non-conservative such that a function or activity of the polypeptide is affected. Non-conservative changes typically involve substituting a residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa” (page 33, third paragraph). Applying these nuances to the nine SEQ ID NOs claimed in the instant application would require numerous iterative efforts at the cut-off of 95% identity. For example, SEQ ID NO. 86 (VIR109) has 198,639 nucleotides, and 95% identity leads to a minimum of 9,932 point mutations, with each position having three possible nucleotide substitutions, plus various possibilities for insertion/deletion, leading to an astronomical number of sequence variants for experimental validation.
Applicant may show that the invention of claims 311, 318-321, 324-325, 343, 346-347, 350 and 352-353 is complete by (i) naming a specific FKBP variant (by SEQ ID NO) required for each claim pertinent to the invention, (ii) sufficiently disclosing details beyond the listing of one single DNA molecule (SEQ ID NO) per genus of FKBP variant, apoptosis protein, fusion protein, vaccinia virus strain or their combination that is expected to serve their respective function, (iii) providing relevant identifying characteristics to illustrate that applicant was in possession of the claimed invention, i.e., complete or partial sequence with expected physical and/or biochemical properties, and (iv) revealing functional characteristics when coupled with a known or disclosed correlation between structure and function, or some combination of such characteristics. (see Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.)
Claims 311, 318-321, 324-325, 343, 346-347, 350 and 352-353 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inherent or named amino acid sequences corresponding to SEQ ID NOs: 1, 7-9, 26-28, 56 and 86, does not reasonably provide enablement for their respective variants that bear 95% identity to these sequences. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the species of fusion proteins toward inducible apoptosis in the invention commensurate in scope with these claims.
Claims 319, 321, 346-347 and 352 recite iCasp 9 polypeptide (SEQ ID NO: 26), iDED polypeptide (SEQ ID NO: 27), iFas polypeptide (SEQ ID NO: 28) and FKBP-F36V (SEQ ID NO: 56), which are expected to function as a fusion protein to induce cell apoptosis after dimerization (in the presence of AP1903/Rimiducid). Claims 324-325, 350 and 352 further require recombinant vaccinia virus strains (corresponding to SEQ ID NO: 1, 7-9 and 86) that carry inherent open reading frames for protein products, as shown in GenBank accession number KJ125439.1 (from Qin et al., 2015. J. Virol. 89(3), 1809-1824). The disclosure enables the use of (i) specific polypeptides defined by the SEQ ID NOs 26-28 and 56 when their corresponding nucleotide sequences (not cited for these claims); (ii) a vaccinia virus backbone (SEQ ID NO: 1) for inserting heterologous sequences (transgenes) encoding polypeptides of interest; (iii) four recombinant vaccinia viruses (SEQ ID NOs: 7-9 and 86) that carry transgene inserts encoding these polypeptides (Tables E5 and E9). However, the disclosure fails to provide any example of fusion peptides or protein products deviating from those corresponding to SEQ ID NOs: 26-28 and 56 or encoded by SEQ ID NOs: 1, 7-9 and 86, so the claimed invention reads on a genus for each fusion polypeptide and each vaccinia virus strain (before and after recombination) without providing sufficient variants or their combinations to enable the scope of broad fusion peptide species and broad vaccinia virus strains with native protein species.
Prior art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111: 2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity, while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibition or activation). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, pp. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
Amino acid substitutions need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, pp. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (Journal of Biological Chemistry, Vol. 272, No. 43, pp. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, pp. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, pp. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (Journal of Biological Chemistry, Vol. 272, pp. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (page 21205, column 2, first full paragraph).
Since prior art teaches that it is unpredictable whether or not peptide variants will function as their wild-type version and it is also unpredictable that even a known function in vitro may not be maintained in vivo, and the specification in the instant application does nothing to ameliorate these concerns about polypeptide/fusion peptide variants, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed. Thus, the fusion polypeptide variants in claims 319, 321, 346-347 and 352 fall beyond the scope of the claimed invention.
Claims 307 and 344 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating experimentally evaluated cancers (breast cancer, colon adenocarcinoma, colorectal adenocarcinoma, lung cancer, melanoma, MSI colon cancer, MSS colon cancer and prostate cancer, as discussed below) with four recombinant VCVA strains (VIR40-VIR42 and VIR109), does not reasonably provide enablement for treating a broad range of heterogenous cancers listed in claims 307 and 344. The specification does not adequately teach one of ordinary skill in the art how to use the claimed invention commensurate in scope with the breadth of the claims. See MPEP §2164 et seq.; In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988). See also Amgen Inc. v. Sanofi, 598 U.S. 594, 143 S.Ct. 1243, 1254–56 (2023).
Nature of the invention/Breadth of the claims. The claims are drawn broadly to treating “proliferative disorder” using several “recombinant oncolytic vaccina virus” strains with a genetically engineered “suicide switch.” The invention claims that “wherein the proliferative disorder is a cancer that is a pancreatic cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer, cervical cancer, breast cancer, rectal cancer, renal (kidney) cancer, gastric cancer, esophageal cancer, hepatic (liver) cancer, endometrial cancer, bladder cancer, brain cancer, head and neck cancer, oral cancer (e.g., oral cavity cancer), cervical cancer, uterine cancer, thyroid cancer, testicular cancer, prostate cancer, skin cancers, such as melanoma, e.g., malignant melanoma, cholangiocarcinoma (bile duct cancer), thymic epithelial cancer, e.g., thymoma, leukemia, lymphoma, or multiple myeloma” (claims 307 and 344). These cancer types cover a broad range of heterogenous origins and differ in accessibility (a barrier to therapy).
State of the prior art/Predictability of the art. In the context of “oncolytic virus-based immunotherapy”, the state of the art (Lathwal et al. 2020. Virology 548: 109–116) shows “300 recombinant… viral strains” against “124 cancer types and 427 cancer cell lines” (abstract and Table 1), with just a single example of “FDA approved… oncolytic virus T-vec for the treatment of melanoma” (abstract and page 110, first paragraph under Figure 1). For vaccinia virus, “deletion of TK gene” and “defective in I4L, F4L and J2R genes) are common (Table 3 on page 114), and “mode of delivery” includes “intratumoral, intravenous and subcutaneous” injections (Table 2, page 114). Lathwal et al cautioned that “a major factor that needs to be considered for successful OV therapy is the induction of the right immune response” (page 114, first paragraph on the right). Xu et al. 2024 (Front. Immunol. 14:1324744) cautioned further that “challenges remain in the clinical application of engineered oncolytic VACVs. Firstly, failure of the phase III trial about JX-594 reminds us the importance of selecting proper combination therapy, and ensuring the administration sequence and timing. In addition, the two sides of oncolytic VACV-mediated antiviral immunity should be overall considered during the construction of VACV backbones and gene engineering of oncolytic VACVs. Another challenge is repeated intravenous injection of oncolytic VACVs with lower dosages”, as “repeated administration can activate strong antiviral immunity to eliminate VACVs” (page 12, section 8 “Conclusions and prospect”). Xiao et al. 2026 (Signal Transduction and Targeted Therapy 11: 45) expressly acknowledges that “strategies to overcome barriers to viral replication”, “optimal dosing schedule and sequence”, and “type of tumor” are critical parameters and must be addressed for OV treatments (Fig. 6 on page 25).
Working examples. For three recombinant VCVA strains (SEQ ID NOs: 7-9, VIR40-VIR42 in Table E5 and FIG. 13) based on VIR3 (after “J2R deletion”), working examples disclose in vitro and in vivo oncolytic properties against breast cancer (BT-549 in FIG. 15A and FIG 18A, Hs578T in FIG. 15B and FIG. 18B, 4T1 in FIG. 15B and FIG. 18C, as well as MCF-7 in FIG. 15C and ¶[0167]), lung cancer and melanoma (A549 in FIG. 18F, M14 in FIG. 15D & FIG. 18G), colon adenocarcinoma (SL-4 in FIG. 20), MSI colon cancer (HCT-15 in FIG. 15E, HCT-16 in FIG. 15F, KM12 in FIG. 15G and FIG. 18J, COLO 320DM in FIG. 18H, HCT-116 in FIG. 18I, SW48 in FIG. 18K, as well as HCC-2998 in FIG. 19B), MSS colon cancer (COLO205 in FIG. 16A and FIG. 19A), HCC-2998 (FIG. 16B & FIG. 19B), colorectal adenocarcinoma (HT-29 in FIG. 16C & FIG. 19C), prostate cancer (DU-145 in FIG. 18D, PC-3 in FIG. 18E, LS123 in FIG. 19D, LS174T in FIG. 19E, SW620 in FIG. 19F and WiDR in FIG. 19G). Judging from “PFUs per million cells”, the in vitro results are highly heterogenous, especially in the presence of Rimiducid (AP1903, an inducer of protein dimerization and apoptosis) (e.g., FIG. 16C for VIR40-VIR42). The in vivo outcomes (body weight, survival, tumor volume, tumor size) are not readily available for the three virus strains, as tests are selective (e.g., VIR40-VIR42 in FIG. 19G versus VIR41 alone in FIG21A).
A fourth recombinant vaccinia virus (VIR106, SEQ ID NO: 86 in Table E9) was “evaluated in vivo using the SL-4 GFP mouse colon adenocarcinoma model (¶[0840]). Female C57BL/6 mice that were 5-6 weeks old were implanted with 5 x 105 SL-4 GFP cells in 100 μL of PBS in the right flank of the mice. Here, mice were treated once with an intravenous dose of 1 x 108 PFU of each indicated virus. Tumor volume and body weight were measured twice per week using vernier calipers and an electronic scale, respectively” (¶[0840]). The results, as measured by tumor volume (FIG. 22D and ¶[0841]), confirm oncolytic function of VIR106, but VIR40-VIR42 are not included in this experiment.
In short, the working examples as discussed supra fail to cover pancreatic cancer, ovarian cancer, cervical cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, endometrial cancer, bladder cancer, brain cancer, head and neck cancer, oral cancer, uterine cancer, thyroid cancer, testicular cancer, cholangiocarcinoma, thymic epithelial cancer, leukemia, lymphoma and multiple myeloma as cited in claims 307 and 344.
Guidance in the specification. For therapeutic use of VIR40-VIR42 and VIR106, the disclosure provides guidance towards tumor cell killing in vitro (¶[0747]-¶[0750]), assessment of immune evasion and oncolytic activity (¶[0763]-¶[0766], ¶[0773]-¶[0774] and ¶[0796]-¶[0805]), apoptosis-mediated inhibition of virus replication (¶[0806]-¶[0810]), apoptosis-mediated inhibition of virus cytotoxicity (¶[0811]-¶[0815]), assessment of tumor growth inhibition in mice (¶[0816]-¶[0818]), and assessment of clinical outcomes (FIG. 18 through FIG. 24 and ¶[0819]-¶[0827]). Experimental data for the first three recombinant VACV strains (VIR40-VIR42) far exceed those for the fourth recombinant VACV strain (VIR109) cited in claims 307 and 344. In other words, the four claimed recombinant VACV strains (SEQ ID NOs: 7-9 and 86) for cancer therapy have not been tested in the same way when presented as one invention.
Amount of experimentation necessary. Therapeutic outcomes in cancer/tumor treatment are highly unpredictable, as heterogeneity of tumor cells, tumor types, staging, prognosis and patient characteristics are known to dictate outcomes (Xiao et al., Fig. 6). Multiple figures (e.g., FIG. 18 and FIG. 19) in the instant application already attest to this phenomenon. Xiao et al. 2026 explicitly teaches that “tumor heterogeneity remains a substantial obstacle for the widespread application of OVT” (page 25, last paragraph on the left). Thus, to fully determine therapeutic feasibility and efficacy, especially tumor regression, progression-free survival or other clinically relevant outcomes, additional research is required to establish the proper use of each candidate VACV strain for a given indication, including dosing regimen, duration of therapy, methods of delivery and sampling intervals needed to determine clinical endpoints that can be tailored to various settings (Xiao et al., Fig. 6).
Under MPEP §2164.01(a), the specification must enable the full scope of the claimed invention. However, for reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed recombinant VACV strains and methods for cancer treatment. Accordingly, claims 307 and 344 are not enabled under 35 U.S.C. 112(a).
Although actual clinical data are not necessarily required to establish enablement (see MPEP §2164.02), the specification must nonetheless provide sufficient guidance and representative examples to enable a person of ordinary skill in the art to practice the full scope of the claims. In view of the breadth of the claims for cancer types and highly variable performance of four recombinant VACV strains during in vitro and in vivo tests, the limited guidance for actual application to each indication in the specification, and the unpredictability of the art, a person of ordinary skill in the art would be required to undertake extensive experimentation to determine a proper formulation of recombinant VACV strains toward the treatment of a broad range of heterogenous cancer types, especially in terms of regimens, treatment schedules, and cancer contexts (e.g., staging and barrier to delivery). Such experimentation would require a research program rather than routine experimentation (see MPEP §2164.03).
Claim Rejections under 35 U.S.C. §103
The following is a quotation of 35 U.S.C. §103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the Claimed invention to a person having ordinary skill in the art to which the Claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. §103 are summarized as the following:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the Claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 276, 292, 306-315, 318-320, 323, 342-346 and 351 are rejected under are rejected under 35 U.S.C. §103 as being unpatentable over Kirn 2004 (WO 2004/014314 A2, published 02/19/2004) in view of Bell et al 2022 (US 2022/0056480 A1, published 02/24/2022) and Spencer et al. 2016 (PGPub 2016/0166613 A1, published 06/16/2016).
Kirn 2004 taught “methods and compositions concerning poxviruses and cancer” (title), as “poxviruses can be engineered to be more effective or more efficient at killing cancer cells and/or be less toxic or damaging to non-cancer cells. More specifically, poxviruses may be mutated to modify gene products such that the modifications render the viruses better able to infect the host, better able to infect cancer cells” (page 20, first paragraph) and “for treating a cancer cell” (claim 50 on page 113). A variety of viral loci suitable for manipulation were cited in claim 50 (page 113) and claim 82 (page 116). After attenuation, their oncolytic viruses “may also have deletions in the viral genome to accommodate heterologous nucleic acid sequences” (page 7, last paragraph), and “the heterologous therapeutic polypeptide can be an apoptosis inducer” (page 15, second paragraph), which is the equivalent of apoptosis-inducible protein. In terms of virus backbones, Kirn’s methods were applicable to “any of the poxviruses discussed” (page 13, fourth paragraph) and “specifically including vaccinia viruses” (page 1, “Field of the invention”) or “vaccinia virus of any strain” (page 3, “SUMMARY OF THE INVENTION”), including “an attenuated vaccinia virus that is the IHD-J strain” (FIG. 1 and page 15, third paragraph), which replicated efficiently in a human ovarian carcinoma (A2780) (FIG. 1A). IHD-J strain was further recited in claim 85 (page 116, a dependent of claim 50). Kirn’s claim 50 then taught a method for “treating a cancer cell” using attenuated vaccinia viruses after incorporation of heterologous elements (claims 82-83 on page 116), “wherein attenuated vaccinia virus is administered to the patient directly, … intratumorally, intravenously” (claim 70 on page 115). Gauged by “plaque forming units (pfu)”, Kirn further taught “unit doses” as “ranging from 103, 104, 105, 106, 107, 108, 109, 1010, 1011, 1012, … pfu and higher” (page 66, last paragraph), but “treatment regimens may vary… often depend on tumor type, tumor location, disease progression, and health and age of the patient” (page 66, second paragraph).
Bell et al., on the other hand, taught methods for genetically engineering vaccinia virus IHD-J strain genome (¶[0288]) for “the treatment of various cancers” (abstract). One of their “efficacy studies” was to “determine the anticancer activity of the modified vaccinia viruses (SKY)… injected intravenously (IV) and/or intratumorally (IT) in athymic nude mice implanted subcutaneously (SC) with either Mia PaCa-2 human pancreatic tumor cells, PC-3 human prostate tumor cells…, COLO-205 human colon tumor cells, NCIH460 human lung tumor cells or HT29 human colon adenocarcinoma cells” (¶[2222]). The results indicated ”a significant increase in percent survival (p <0.0001) in… all 8 xenograft models when administered with SKY IV and/or IT compared to control mice treated with PBS alone, as shown in FIGS. 48A-48H” (¶[2226]). According to disclosure in the instant application (¶[0171] and FIG. 19A), “COLO205” is an “MSS colon cancer” cell line tested against “apoptosis-inducing viral clones VIR13, VIR40, VIR41 and VIR42” (¶[0171]).
The combined teachings of Kirn 2004 and Bell et al 2022 would allow a person of ordinary skill in the art to arrive at recombinant oncolytic vaccinia viruses suitable for the treatment of colon cancer and MSS colon cancer, because both references taught the flexibility of using an IHD-J strain genome as a backbone to carry payloads (transgenes) that promote oncolytic activity and apoptosis, and Bell’s in vivo test results was promising (FIG. 48). In addition, Bell’s attenuated, recombinant vaccinia viruses were ready for “large scale manufacturing" (Bell et al, ¶[0006]). These two references also taught delivery routes (IV and/or IT) and dosage (103 to 1012 pfu and higher), but they fell short of teaching the use of an inducible apoptosis protein that is capable of dimerization following activation by AP1903 (Rimiducid).
The deficiencies left by Kirn 2004 and Bell et al 2022 are overcome by Spencer et al. 2016, who taught “methods for controlled elimination of therapeutic cells” (title) through “an alternative suicide gene strategy that is based on human proapoptotic molecules fused with an FKBP variant… optimized to bind a chemical inducer of dimerization (CID)” (¶[0129]). Specifically, transfection of T-cells with vectors encoding a fusion peptide consisting of a FKBP variant (FKBP12-F36V) and Caspase 9 (FIG. 2 and pasted below) coupled with administration of a small molecule called AP1903 results in cross-linking and activation of Casp9-induced cell apoptosis. The inducible system also worked “using Fas or the death effector domain (DED) of the Fas-associated death domain-containing protein (FADD) as proapoptotic molecules”, as “up to 90% of T cells transduced with these inducible death molecules underwent apoptosis after administration of CID (¶[0129]). AP1903 (rimiducid) in Spencer et al. is a “high specificity, efficient dimerizer” that “has two identical, protein-binding surfaces arranged tail-to-tail, each with high affinity and specificity for a mutant of FKBP12: FKBP12(F36V) (¶[0007]). Spencer’s FKBP variant (SEQ ID NO 394, TABLE 7, page 110) is a 100% match with SEQ ID NO. 56 of the instant application, so the FKBP12(F36V) variant is the same as FKBP-F36V of the instant application.
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FIG. 2 from Spencer et al. 2016 (see ¶[0036] for description).
Mapping the collective teachings of Kirn 2004, Bell et al 2022 and Spencer et al. 2016 to individual claims in the instant application is straightforward:
For claims 276, 310-311, 318-320, 323 and 346, the oncolytic vaccinia virus backbone can come from either Kirn 2004 or Bell et al 2022, as both taught genetically engineered/recombinant IHD-J strain genome for cancer therapy; the “one heterologous nucleic acid encoding… an apoptosis inducible protein” is found in Spencer et al., as their FKBP12 variant (FKBP12-F36V) is “optimized to bind a chemical inducer of dimerization (CID)” (¶[0129]) and fused with an apoptosis inducer (e.g., Casp-9 in FIG. 2) to facilitate AP1903 (rimiducid)-activated (controllable) apoptosis (a safety switch). Together, these teachings meet the limitations of claims 276, 310-311 and 323. According to the instant application, FKBP12 (human FK506 binding protein) is synonymous for FKBP (see ¶[0441]), while Spencer’s SEQ ID NO 394 (TABLE 7, page 110) is the same as the FKBP-F36V variant (a mutant insert, cited as SEQ ID NO. 56) in claims 318-319 and 346 of the instant application. Thus, a simple substitution of the apoptosis inducer taught by Kirn with one FKBP-F36V fusion protein (e.g., FKBP-F36V + Casp9 or FKBP-F36V + FADD) from Spencer could allow an IHD-J strain-based, recombinant oncolytic vaccinia virus strain with a controllable apoptosis inducer (the equivalent of Spencer’s safety switch) facilitated by specific interaction between FKBP-F36V and AP1903 (rimiducid) (the CID cited in claims 311 and 320).
For claim 292, virus inhibition is an inherent function of oncolytic vaccinia virus (VCVA) with or without attenuation/recombination, as taught by Kirn (FIG. 1 and page 15, third paragraph, lines 1-5). The AP1903 (rimiducid)-induced apoptosis mechanism provides a safety switch, as taught by Spencer.
Among other claims that depend on claim 276 and/or claims 310-311, the limitations of claims 306-309 are met by Kirn and Bell, as both taught the use of recombinant oncolytic vaccinia virus in treating cancer cells, and Bell specifically targeted colon cancer and MSS colon cancer through IV and/or IT delivery; inserting an apoptosis-mediated safety switch into oncolytic vaccinia virus will not alter oncolytic function, as Kirn taught methods for inserting a heterologous sequence encoding apoptosis inducer. For claim 311, the apoptosis protein fused with an FKBP variant that is able to bind a chemical inducer of dimerization (CID) is found in Spencer et al. ¶[0129]. The apoptosis protein DED cited in claim 312, apoptosis protein caspase and caspase 9 (Cas9) cited in claim 313-314, as well as apoptosis protein Fas cited in claim 315 are all found in Spencer et al. (¶[0129], ¶[0312] and FIG. 2).
For claims 342-343 and 351, Kirn further taught “unit doses” as “ranging from 103, 104, 105, 106, 107, 108, 109, 1010, 1011, 1012, … pfu and higher” (page 66, last paragraph), and Spencer et al. taught that “one heterologous nucleic acid encoding one or more heterologous gene product… encoding an inducible death effector domain (iDED).. of the Fas-associated death domain-containing protein fused with an FKBP variant that is able to bind AP1903 (Rimiducid) (¶[0129]). Additional limitations for claims 344-345, which depend on claim 343, are taught by Bell et al., as they targeted various cancer types, including colon cancer and MSS colon cancer (¶[2222]).
A person of ordinary skill in the art could follow the teachings of Kirn 2004 and Bell et al. 2022 to first arrive at a recombinant strain and then adopt the teaching of Spencer et al. 2016 to insert a heterologous sequence encoding a pro-apoptotic fusion protein into an IHD-J strain virus backbone. The resulting rVACV strain would express an inducible apoptosis switch controlled by the binding of AP1903 (rimiducid) to FKBP12-F36V, as shown in Spencer’s FIG. 2. When rVACV viruses are used in a pharmaceutical composition (as taught by Kirn and Bell) for IV/IT injection, their oncolytic properties (as taught by all three references) are coupled with inducible apoptosis (as taught by Spencer et al) to first facilitate cancer therapy and then to induce apoptosis of recombinant VACV-infected cells with AP1903 (rimiducid). The fusion protein construct in Spencer et al (FIG. 2) is straightforward, which would ensure a reasonable success when coupled with the knowledge that recombinant oncolytic vaccinia viruses, such as attenuated IHD-J strain, can be genetically engineered to express heterologous nucleic acid sequences as transgenes (Kirn, page 7, last paragraph). The motivation is also obvious in that the concept of having an apoptosis-mediated “safety switch”, as taught by Spencer et al. 2016 for T-cell-based cancer therapy, is desirable in situations where rVACV persists to cause adverse outcomes. Moreover, the dimerization activator “AP1903… has proven safe in healthy volunteers (Kirn, ¶[0129]). Thus, the invention of claims 276, 292, 306-315, 318-320, 323, 342-346 and 351 as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time of the invention: as an example of rationale A of MPEP 2143 (combing prior art elements according to known methods to yield predictable results) and rationale B of MPEP 2143 (simple substitution of one known element for another to obtain predictable results).
Claims 276, 310 and 316-317 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al. 2016 (supra) and Spencer et al. 2016 (supra) as applied to the rejection of claims 276, 292, 306-315, 318-320, 323, 342-346 and 351, further in view of Wu et al. 2001 (Journal of Immunology, 166: 4773–4779)).
Kirn, Bell et al. and Spencer et al. taught the elements of claims 276 and 310, including methods for VCVA virus composition and cancer therapy and inducible apoptosis; Kirn 2004 also taught the use of a heterologous sequence encoding apoptosis inducer that can be inserted into a VCVA “IHD-J strain” backbone (page 15, third paragraph and claim 85 on page 116) but fell short of specifying J2R as a site for insertion. This deficiency was overcome by Wu et al. 2001, as they taught the insertion of heterologous plasmid DNA into the “J2R region” of vaccinia virus (VV), “disrupting the VV TK gene” (FIGURE 1 on page 4774). Thus, the J2R locus was a known insertion site for heterologous sequences prior to the filing of the claimed invention. Indeed, the I4L locus that is cited as an alternative site in claim 316 was also chosen as a second insertion site for heterologous sequences for recombination (Wu et al., FIGURE 1 on page 4774), so the invention of claims 276, 310 and 316-317 as a whole was rendered prima facie obvious to one of ordinary skill in the art at the time the invention: as an example of rationale A of MPEP 2143 (combing prior art elements according to known methods to yield predictable results).
Claims 276, 310 and 322 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al. 2016 (supra) and Spencer et al. 2016 (supra) as applied to the rejection of claims 276, 292, 306-315, 318-320, 323, 342-346 and 351, further in view of Stritzker et al. 2014 (Journal of Virology 88(19): 11556–11567).
As discussed supra, Kirn, Bell et al. and Spencer et al. taught the elements of claims 276 and 310, including methods for recombinant VACV (rVACV) virus composition and insertion of a safety switch for inducible apoptosis. The heterologous sequences (DNA inserts) in Bell’s recombinant VACV strains also “comprise at least one promoter operably linked to the first nucleotide sequence” (¶[0008]), but their teachings still fell short of naming the promoter as PSE (a “synthetic early promoter”). This deficiency is overcome by Stritzker et al. 2014 (of record on IDS and cited in ¶[0286] of the instant application), as they taught the use of a PSE promoter that “was active early during the infection cycle” when tested in a “set of rVACV strains” (page 11559, last paragraph on the left). One of ordinary skill in the art at the time of invention could substitute the promoter taught by Bell with PSE from Stritzker et al. to arrive at the invention of claim 322. The motivation is also obvious, as Stritzker et al. established that the PSE promoter “was active early during the infection cycle,” which is what an attenuated, rVACV strain needs for immediately gene expression after transfection. Thus, the invention of claims 276, 310 and 322 as a whole was rendered prima facie obvious by four references, as an example of rationale B of MPEP 2143 (simple substitution of one known element for another to obtain predictable results).
Claims 276, 326, 343 and 348-349 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al. 2016 (supra) and Spencer et al. 2016 (supra) as applied to claims 276, 292, 306-315, 318-320, 323, 342-346 and 351, further in view of Deng et al. 2022 (PGPub 20220056475 A1, published 02/24/2022).
Kirn, Bell et al. and Spencer et al. collectively taught the elements of claims 276 and 343, including methods for preparing recombinant VACV strains using an IHD-J strain-based backbone and then apply these products in a pharmaceutical formulation to treat cancer cells and to induce apoptosis through specific interaction between FKBP-F36V (part of a fusion protein) and AP1903 (Rimiducid, a dimerization activator/CID cited in claims 311 and 320 of instant application). However, these references fell short of specifying B2R and J2R as two chosen sites for inserting a heterologous sequence encoding the FKBP-F36V fusion protein into an IHD-J strain backbone. This deficiency is overcome by Deng et al. 2022, as they taught methods for “cancer immunotherapy” (title) using genetically engineered, recombinant vaccinia virus (VACV) strains. Several VACV strains “express a specific gene of interest…” (¶[0003]), and “each of… heterologous sequences of human origin “is expressed from within a viral gene selected from the group consisting of the thymidine kinase (TK) gene” and other loci (¶[0110]). The TK gene locus is labeled as open reading frame 096, (VACCP-J2R) in GenBank sequence KJ125439.1 (from Qin et al. 2015. J. Virol. 89 (3), 1809-1824), which is the same as J2R cited in claim 348; and Deng specifically taught that “homologous recombination between plasmid DNA… vector and… viral genomic DNA” allowed the insertion of a transgene… into the TK (J2R) gene locus” (¶[0156]). Deng also taught recombinant VACV strain with a “B2R mutant” that “includes a heterologous nucleic acid sequence in place of all or a majority of the B2R gene sequence” (¶[0492]). Thus, J2R and B2R genes in VACV are known to be suitable sites for accommodating heterologous gene sequences, meeting the limitations of claims 326 and 348-349.
It would have been obvious to one of ordinary skill in the art to follow the teachings of Kirn and Bell et al. to generate an IHD-J-based recombinant oncolytic vaccinia virus and insert an inducible apoptosis element (such as an iDED) taught by Spencer et al. into B2R, J2R or another suitable locus taught by Deng et al. 2022 (e.g., C7 locus on page 2, ¶[0006]). The end result would be a recombinant oncolytic vaccinia virus with a tunable (inducible) apoptosis switch to ensure that virus replication can be inhibited through chemically induced apoptosis of rVACV-infected cells. The motivations are also obvious, as various transgenes have been successfully generated for “gain-of-function mutations”, as taught by Kirn (page 40, first paragraph under section “1. Random Mutagenesis”). Thus, the invention of claims 276, 326, 343 and 348-349 as a whole was rendered prima facie obvious to one of ordinary skill in the art at the time of invention: as an example of rationale (A) of MPEP 2143 (Combing prior art elements according to known methods to yield predictable results) rationale (G) of MPEP 2143 (Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
Claims 276, 310, 321, 343 and 347 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al 2022 (supra) and Spencer et al. 2016 (supra), as applied to claims 276, 292, 306-315, 318-320, 323, 342-346 and 351, further in view of two GenBank sequences (DQ449938.1 as submitted in 2006 and SJL87468.1 as submitted in 2017) and Fan et al. 1999 (Human Gene Therapy 10: 2273–2285).
As discussed supra, the collective teachings of Kirn 2004, Bell et al 2022 and Spencer et al. 2016 render claims 276, 310 and 343 obvious, and Spencer further taught multiple heterologous sequences encoding a fusion protein (FKBP-F36V + an apoptosis domain) for inducible apoptosis (a safety switch for immunotherapy), including “an alternative suicide gene strategy that is based on human proapoptotic molecules fused with an FKBP variant that is optimized to bind a chemical inducer of dimerization (CID)” (¶[0129]). Spencer’s SEQ ID NO 394 (TABLE 7, page 110) is the equivalent of FKBP-F36V (SEQ ID NO: 56 in claims 319 and 346 of instant application), being 100% identical to the 107 amino acids of SEQ ID NO: 56 (see mapping below), and their “inducible system… using Fas or the death effector domain (DED) of the Fas-associated death domain–containing protein (FADD)” was effective: “Up to 90% of T cells transduced with these inducible death molecules underwent apoptosis after administration of CID” (¶[0129]). However, the combined teachings from three references still fall short of disclosing a heterologous polynucleotide insert encoding a fusion protein that matches SEQ ID NO: 27 in claims 321 and 437 at the 95% identity level.
The 335 amino acids (aa) in “SEQ ID NO: 27” correspond to the following “inducible death effector domain (iDED)” polypeptide:
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From N-terminus to C-terminus, SEQ ID NO: 27 has a 14-aa leader sequence (in superscript), two tandem FKBP polypeptide repeats of 107 amino acids each (underlined, starting with GVQV and ending with LKLE), a linker sequence (SGSGGGS in italics), followed by a 100-aa FADD sequence of human origin.
The 14-aa leader peptide has a 100% match with GenBank Sequence ID SJL87468.1 for a mammalian expression vector pCMF2E-hFADD-DED (De Schamphelaire et al., submitted 02/02/2017). The FKBP component (cited as SEQ ID: 56 in claims 319 and 346) has a 100% match with Spencer’s SEQ ID NO: 394 (TABLE 7 on page 110). Next, the linker sequence shows a single mismatch with Spencer’s linker SEQ ID NO 285 (Gly-Ser-Gly-Gly-Gly-Ser linker in ¶[0312]), and the FADD portion of SEQ ID NO: 27 has a 100% match with the first 100 amino acid residues of “FAS-associated death domain protein [Homo sapiens]” under GenBank accession number NP_003815 (Boldin et al. 1995. J Biol Chem 270 (14): 7795-7798). Overall, leader peptide, FKBP, linker sequence and FADD that collectively make up SEQ ID: 27 all match records in prior art and GenBank sequences, with a combined percentage match of 99.7% (334 out of 335 amino acids).
Structurally, Fan et al. 1999 taught the design of fusion protein for multiple “AP1903-responsive” apoptosis systems (FIG. 1B on page 2276 and pasted below).
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FIG. 1B from Fan et al., 1999 (Human Gene Therapy 10: 2273–2285). Schematic of CID-regulated proapoptotic molecules showing the CID-binding domain (i.e., Fv 5 FKBP12V36), intracellular targeting sequences (i.e., M [myristoylation-targeting sequence], [nuclear localization sequence], and Mas7034 [mitochondria-targeting sequence]), proapoptotic molecules (i.e., caspase 1, 3, 8, and 9; Fas cytoplasmic domain [residues 179–319]; FADD125 [death effector domain], and hemagglutinin epitope tag (E). Arrows point to elements found in SEQ ID NOs: 26-28 and 56 of the instant application.
As for SEQ ID NO: 27 in the instant application, Fan et al. placed a leader peptide before “FKBP(V36F)” to direct the fusion protein to various cellular compartments (nuclear, mitochondrial, etc.), followed by FKBP(V36F) (the equivalent of FKBP-V36F), a “GS-linker” (FIG. 1B on page 2276), and a pro-apoptosis domain (FADD, Casp9 and others). FKBP(V36F) was present in monomeric, dimeric or trimeric form to facilitate inducible apoptosis, while the “death effector domain” (DED) was mapped to the “amino-terminal” of FADD (page 2274, last paragraph on the left). Among three versions of fusion proteins with truncated FADD (FADD125, FADD80 and FADD100), “FADD100 is sufficient for FK1012-mediated cytotoxicity (FIG. 3 on page 2278); cell-based testing indicated that “oligomerization of the death effector domain of the Fas-associated protein, FADD, is sufficient to trigger apoptosis (abstract) and that “cross-linking the DED of FADD is sufficient to trigger the Fas pathway” (page 2280, first paragraph on the left). Annotation for GenBank sequence NP_003815 (supra) defines the “death effector domain” of FADD as “residues <24..82.” Thus, it would be obvious to use residues 1-100 of GenBank sequence NP_003815 as the death effector domain for fusion with FKBP-V36F, as taught by Fan. The advantage of FADD100 (residues 1-100) is also obvious, as “FADD100 still function better than… FADD80 even after normalizing transfections for steady state protein levels” (Fan et al., page 2880, last paragraph on the right). In other words, the structure and function of pro-apoptotic fusion proteins with four elements (including FKBP-V36F repeats) for cellular targeting and AP1903-inducible apoptosis are a well-known art before the filing of SEQ ID NO: 27.
A skilled artisan could follow the teachings of Spencer, Fan et al. and two GenBank sequences (SJL87468.1 and NP_003815) to arrive at a pro-apoptotic fusion protein construct (iDED comprising of FKBP-V36F + FADD) that matches SEQ ID NO: 27 with 99.7% sequence identity. Insertion of the corresponding nucleotide sequence into a vaccinia virus backbone, as taught by Kirn and Bell would arrive at the invention of claims 321 and 347. Thus, the invention of claims 276, 310, 321 and 347 as a whole is rendered prima facie obvious by four references and two GenBank sequences discussed supra, as an example of Rationale (G) of MPEP 2143 (Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention). The motivation for a fusion protein linked to a FKBP variant is also obvious, as Spencer et al. (FIG. 2) and Fan et al. (FIG. 1 on page 2276) used the same design to achieve the same results of induced apoptosis.
Claims 276, 324-325, 343 and 350 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al 2022 (supra) and Spencer et al. 2016 (supra), as applied to claims 276, 292, 306-315, 318-320, 323, 342-346 and 351, further in view of Qin et al. 2015 (J. Virol. 89 (3), 1809-1824).
As discussed supra, the collective teachings of Kirn 2004, Bell et al 2022 and Spencer et al. 2016 render the invention of claims 276 and 343 obvious in terms of recombinant oncolytic vaccinia virus with a inducible safety switch (AP1903/Rimiducid-triggered apoptosis), but these references fall short of disclosing a sequence that has a least 95% identify with SEQ ID NO:1, 7-9 and 86 cited in claims 324-325 and 350. This deficiency is overcome by the teaching of Qin et al., as their genomic sequence for a “vaccinia virus IHD-W clone” (195821 nucleotides, under GenBank accession number KJ125439) (page 1811, right column) shares 99.9% identity with SEQ ID NO: 1. After accounting for an insert of a heterologous sequence encoding an inducible apoptosis system (335-400 amino acids, as in SEQ ID NOs: 26-27) and mutation in the B2R or J2R locus (insertion site), the genome size change for each of the four recombinant VACV strains (SEQ ID NOs: 7-9 and 86) ranges from 673 nucleotides (SEQ ID No: 1 versus SEQ ID NO: 8, 0.3% difference) to 3065 nucleotides (SEQ ID No: 1 versus SEQ ID NO: 86, 1.5% difference). The 0.3%-1.5% difference falls within the 5% cited for claims 324-325 and 350. Thus, a fully functional vaccinia virus from Qin et al. not only has 99.9% identity to SEQ ID NO: 1 (VIP02 in Table E5 of the instant application) but also renders four other claimed recombinant viruses (SEQ IDs. 7-9 and 86) as a close match (>95% sequence identity) despite genetic manipulations (mutation and insertion of heterologous sequence). In other words, Qin’s virus defined by GenBank accession number KJ125439 met the SEQ ID elements of claims 324-325 and 350. The collective teachings of Kirn, Bell, Spencer and Qin render the invention of claims 276, 324-325, 343 and 350 as a whole obvious to one of ordinary skill in the art at the time of invention: as an example of Rationale (A) of MPEP 2143 (combining prior art elements according to known methods to yield predictable results) and Rationale (G) of MPEP 2143 (some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
Claims 276, 343 and 352-353 are rejected as being unpatentable over Kirn 2004 (supra), Bell et al 2022 (supra), Spencer et al. 2016 (supra) and Deng et al (supra), as applied to claims 276, 292, 306-315, 316-320, 323, 342-346 and 351, further in view of Qin et al. 2015 (supra), Fan et al. 1999 (supra) and two GenBank sequences – accession numbers DQ449938.1 (2006) and SJL87468.1 (2017).
As discussed supra, Kirn 2004, Bell et al 2022 and Spencer et al. 2016 render claims 276 and 343 obvious in the context of making recombinant VACV virus with a heterologous sequence (transgene) encoding a tunable safety switch/apoptosis inducer (iDED fused with a FKBP variant, shown in Spencer’s FIG. 2 and ¶[0129] and supported by similar constructs in Fan et al., FIG. 1), while Deng further taught that “each of… heterologous sequences of human origin “is expressed from within a viral gene selected from the group consisting of the thymidine kinase (TK) gene” and other loci (¶[0110]). The TK gene locus is labeled as open reading frame 096 (VACCP-J2R) in GenBank sequence KJ125439.1 (from Qin et al. 2015), which is the same as J2R cited in claim 352. The VACV virus backbone (SEQ ID NO: 1) in the instant application (VIP02 in Table E5 of the instant application) is named by Kirn (IHD-J strain in FIG. 1A), while the sequence of “vaccinia virus IHD-W clone” (195821 nucleotides, GenBank sequence KJ125439) taught by Qin et al. (page 1811, right column in Qin et al. 2015) shares 99.9% sequence identity with SEQ ID NO: 1. As for the heterologous sequence insert encoding an iDED, the four elements of SEQ ID NO: 27 (leader peptide, FKBP-V36F, linker and FADD100) are mapped to two SEQ IDs in Spencer (FKBP-V36F linker) and two sequences in GenBank (SJL87468.1 and NP_003815) (leader peptide and FADD100), allowing a combined sequence identity of 99.7% (as discussed supra) when aligned with the 355 amino acids in SEQ ID NO: 27 of the instant application. Moreover, Fan et al. taught the structural and functional basis for the effective use of various fusion proteins that facilitate induced apoptosis (FIG. 1 on page 2276). For cancer therapy using rVACV strains, Kirn further taught “unit doses” as “ranging from 103, 104, 105, 106, 107, 108, 109, 1010, 1011, 1012, … pfu and higher” (page 66, last paragraph), but “treatment regimens may vary… often depend on tumor type, tumor location, disease progression, and health and age of the patient” (page 66, second paragraph. For MSS colorectal cancer treatment using the invention of claim 352, Bell et al. taught further that “efficacy studies” using “COLO-205 human colon tumor cells, NCIH460 human lung tumor cells or HT29 human colon adenocarcinoma cells” (¶[2222]) had “a significant increase in percent survival (p <0.0001) in… all 8 xenograft models” when two recombinant oncolytic vaccinia virus strains were tested (FIGS. 48A-48H and ¶[2226]). According to specification (¶[0171] and FIG. 19A) of the instant application, “COLO205” is an “MSS colon cancer” cell line being tested against “apoptosis-inducing viral clones VIR13, VIR40, VIR41 and VIR42” (¶[0171]), so “COLO-205 human colon tumor cells” from of Bell et al 2022 is the equivalent of “MSS colon cancer” cited in claim 353.
A person of ordinary skill would be motivated to treat MSS colon cancer with recombinant oncolytic vaccinia virus strains because the in vivo test results from Bell et al 2022 was promising (FIG. 48). The teachings from five references and two GenBank sequences render other limitations of claims 276, 343 and 352-353 obvious as discussed supra. Thus, the invention of claims 276, 343 and 352-353 as a whole is rendered prima facie obvious to one of ordinary skill in the art at the time of invention: an example of Rationale (A) of MPEP 2143 (combining prior art elements according to known methods to yield predictable results) and Rationale (G) of MPEP 2143 (some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention), with clear motivations for efficacy and safety.
Conclusion
No claims are allowed.
Additional Prior Art Cited but Not Applied
Thorne 2016 (PGPub 2016/0235793 A1, published 08/18/2016). Immuno-Oncolytic Therapies.
This prior art taught the use of “oncolytic vaccinia viruses which have been modified to promote anti-tumor immunity and/or reduce host immunity and/or antibody response against the virus” (abstract) toward “treating a subject with a cancer” by “administering… an effective amount of” genetically modified oncolytic vaccinia virus (claim 21) or in combination with “one or more… anti-cancer agents” (claim 23), effectively providing the rationale and multiple strategies for modifying oncolytic vaccinia virus toward a pharmaceutically viable agent for cancer therapy.
Buijs et al. 2015. Oncolytic viruses: From bench to bedside with a focus on safety. Human Vaccines & Immunotherapeutics 11(7): 1573-1584.
This prior art taught that “several viruses have undergone evaluation in clinical trials in the last decades… about to be approved to be used as a novel cancer therapy modality” (abstract). Oncolytic viruses taught by Buijs et al. included vaccinia virus with “1-3 transgenes” (Table 5, page 1574), suggesting that oncolytic vaccinia virus strains can accommodate various transgenes. They also cautioned against “possible safety issues like toxicity, environmental shedding, mutation and reversion to wildtype virus” (abstract), which justifies the addition of a chemically inducible “safety switch”, as disclosed in the instant application.
Mendlein & Grayson 2011 (WO 2011/035018 A2, published 03/24/2011). Suicide ready cells.
This prior art taught methods “of providing cell-based compositions comprising features that increase both the safety and therapeutic efficacy of regenerative therapy” (page 1, lines 7-9). To ensure safety, Mendlein & Grayson taught the use of genetically modified cells that express a heterologous inducible apoptosis protein, which is encoded by “a suicide transgene… selected from the group consisting of: caspase-3, caspase-8, caspase-9, caspase-12, apoptosis inducing factor, BAD, and BIM” (page 4, lines 13-15). They also taught the use of “FAS-FK506 binding protein (FKBP) fusion protein, FADD-FK506 fusion protein… caspase-9 death domain-FK506 fusion protein” as a suicide transgene (page 4, lines 19-23 and claim 13 on page 125). A heterologous nucleic acid sequence encoding such suicide-inducing polypeptide is inserted into a viral vector, including a vaccinia virus, for delivery into a host cell (page 62, lines 25-28), because viral delivery systems “offer several attractive features” (page 63, line 1). The expression of one or more transgenes is either “inducible” (claim 115 on page 144) or “constitutive” (claim 116 on page 144), and “a homodimerizer, such as AP1903 (rimiducid), directly induces dimerization or multimerization of chimeric caspase polypeptides comprising an FKBP12 multimerizing region, which are expressed in a modified cell, leading to apoptosis” (page 3, lines 11-15). They also taught “formulations… suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration” (page 82, line 24-26), and “oral, intravenous, intracerebroventricular and subcutaneous doses… range from about 0.000001 to about 1000 mg per kilogram” (page 91, lines 7-10). These teachings are complementary to those from Spencer et al. 2016 and confirm the inventive concept for a AP1903 (rimiducid)-controlled safety switch facilitated by inducible apoptosis.
Rollins et al. 2000. A ligand-reversible dimerization system for controlling protein-protein interactions. Proc Natl Acad Sci U S A. 97(13):7096-101.
Supporting the use of FKBP12-F36V as part of a fusion protein in Spencer et al. 2016 (FIG. 2), this prior art taught that “chemically induced dimerization provides a general way to gain control over intracellular processes. Typically, FK506-binding protein (FKBP) domains are fused to a signaling domain of interest, allowing crosslinking to be initiated by addition of a bivalent FKBP ligand”, while “a single point mutation in the ligand binding site (Phe-36→ Met) converts the normally monomeric protein into a ligand-reversible dimer” (abstract). They also taught that “most dimerizer applications to date have used the 12-kDa FK506-binding protein (FKBP12; herein called FKBP) and its ligands” (page 7096, last paragraph on the left). Their sequence for FKBP12-F36V, as submitted to GenBank (access number 1EYM_A), was a 100% match with SEQ ID NO: 56 cited in claims 319 and 346 of the instant application. Thus, the name FKBP12-F36V is often abbreviated as FKBP-F36V in prior art.
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/JIANMING TANG/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights