DETAILED ACTION
Disposition of Claims
Claims 1, 5-11, 13, 16-18, 26, 28-29, 32-34, and 39-40 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20220409684A1, Published 12/29/2022.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 05/13/2022, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
The examiner of your application in the Patent and Trademark Office has been reassigned. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Rachel Gill, Art Unit 1671.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Election/Restrictions
Applicant’s election without traverse of Group I, and species of HSV-1 VP5/VP5 promoter, modified HSV-2 ICP4 IE promoter, gK variant gene, dominant-negative TGF-β mutant sequence, and intergenic region between UL26 and UL27 in the reply filed on 04/03/2026 is acknowledged.
After further consideration and review, the restriction/election requirement set forth in the Office action mailed 10/08/2025 is withdrawn. All pending claims and species will be examined on their merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/15/2025, 09/27/2024, 05/10/2024, and 08/16/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements 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.
Claim Objections
Claim 5 is objected to because of the following informalities: the definition of the abbreviation “TGF-β” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … transforming growth factor-beta (TGF-β)...).
Also, to place the claim in better form, “the gene sequence of (f) is a dominant-negative Transforming growth factor-beta (TGF-β) mutant sequence” should read on “the gene sequence of (f) encodes a dominant-negative Transforming growth factor-beta (TGF-β) mutant sequence” [emphasis added] as the gene sequence itself does not have the activity, but the resulting protein does.
Appropriate correction is required.
Claim 7 is objected to because of the following informalities: the definition of the abbreviation “HCMV” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … human cytomegalovirus (HCMV)...).
Appropriate correction is required.
Claim 17 is objected to because of the following informalities: the definition of the abbreviations “PD-1”, “PD-L1”, “CTLA-4”, “TIM-3”, and “TIGIT” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)...).
Appropriate correction is required.
Claim 40 is objected to because of the following informalities: to place the claim in better form, it is suggested it be amended to read on a “solid tumor cancer” [emphasis added] because the claim is attempting to further limit the type of cancer which is treated by the oncolytic HSV, and cancers are generally classified into the subtypes of “solid tumor cancers” and “non-solid or liquid tumor cancers”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 1 and dependent claims 5-11, 13, 16-18, 32-34, and 39-40 thereof 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.
The term “variant gene” in claim 1 is a relative term which renders the claim indefinite. The term “variant gene” 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. Because the “variant gene” is being compared to a “wild type” version of the gene, and because the “base” sequence of the oncolytic HSV and genes encoded therein has not been identified, it is unclear how a skilled artisan is to determine if the “variant gene” varies without providing what the “wild type” version of said gene or genome is as a frame-of-reference.
Similar issues arise with the term “modified”, as said term is relative and it is unclear how to determine if a promoter has been “modified” if a base or reference sequence is not provided for comparison.
In part c) of claim 1, the antecedent basis of “the ICP0 loci” is unclear as the HSV genome comprises two ICP0 loci, so it is unclear if one or both are being referenced and if it is only one, which loci (e.g. the terminal repeat copy or internal repeat copy.)
In part f), the claim provides for “a gene sequence operably linked to a modified HSV promoter, wherein the gene is located in an intergenic region of a set of genes selected from the group consisting of: UL26 and UL27 genes; UL21 and UL22 genes; and UL26, UL27, UL21 and UL 21 genes,”, but it is unclear what is meant by the intergenic region of “and UL26, UL27, UL21 and UL 21 genes” as UL21 is repeated twice and it is unclear what “intergenic region” is encompassed by this grouping.
Finally, the claim appears to define the tetracycline operator (tetO) sequence by its position relative to the VP5 promoter TATA element and the VP5 gene. Applicant should clarify whether the recited 3’ positioning is intended to refer to the coding/transcriptional orientation of the VP5 gene rather than a genome-coordinate orientation, particularly because HSV genomes may exist as different isomers.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 1 is rejected on the grounds of being indefinite. Claims 5-11, 13, 16-18, 32-34, and 39-40 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claims 1 and 26 and dependent claims 5-11, 13, 16-18, 28-29, 32-34, and 39-40 thereof 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 1 and 26 claim that the oncolytic HSV (oHSV) does not encode functional ICP0, and does or does not encode a functional ICP34.5. Claim 26 further states the oHSV encodes a functional mmTGF-β2-7 M.
First, with respect to ICP0 and ICP34.5, these genes are duplicated within the HSV genome. The language regarding the genes should clarify if one or both copies are affected, as this materially affects the structure, pathogenicity, and oncogenic features of the resulting oHSV.
Second, ICP0, ICP34.5, and mmTGF-β2-7 M all have multiple functions, so claiming that these resulting proteins are “functional” or not is unclear, because it does not clarify if the gene is present or not in the oHSV genome, and if said gene is present, what functions are present in said resulting protein and what are absent. For instance, “does not encode functional ICP0” could mean no full-length ICP0, no ICP0 protein at all, no transactivation function, no E3 ubiquitin ligase activity, no ability to counter intrinsic immunity, no ICP0 expression from either repeat locus, or some other loss of activity. For ICP34.5, “functional” could mean retaining neurovirulence-related activity, PKR/eIF2-alpha antagonism, autophagy antagonism, replication support in certain cells, or merely being expressible as a recognizable ICP34.5 protein. As these proteins are claimed functionally in the claims and specification and not specifically defined by sequence, deletion boundaries, biological activity, or other means, the metes and bounds of these limitations are unclear.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 1 and 26 are rejected on the grounds of being indefinite. Claims 5-11, 13, 16-18, 28-29, 32-34, and 39-40 are also rejected since they depend from claim 1 or 26, but do not remedy these deficiencies of claims 1 or 26.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 is drawn to the oncolytic HSV of claim 1, wherein the promoter of (f) is a modified HSV immediate-early promoter, an HCMV immediate-early promoter, or a human elongation alpha promoter. However, the promoter of (f) is recited as “a modified HSV promoter”, and the “HCMV immediate-early promoter” and “a human elongation alpha promoter” are not “HSV promoters”. It is suggested that claim 1 either be amended to remove the recitation of “HSV” before promoter or recite that said promoter may be a HSV or heterologous promoter to provide proper antecedence to claim 7.
For at least these reasons, the metes and bounds of claim 7 are unclear.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 is drawn to the oncolytic HSV of claim 1, wherein the recombinant DNA is part of the HSV-1 genome or part of the HSV-2 genome. However, the antecedent basis of “the HSV-1 genome” and “the HSV-2 genome” is unclear, as neither genome was recited in claim 1. One suggestion is to replace the definite article “the” with the indefinite article “a/an” before both “HSV-1” and “HSV-2”.
For at least these reasons, claim 13 is rejected on the grounds of being indefinite.
Claim 16 and dependent claim 17 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 is drawn to the oncolytic HSV of claim 1, further encoding at least one polypeptide that can increase the efficacy of the oncolytic HSV to induce an anti-tumor-specific immunity. However, the term “increase the efficacy… to induce an anti-tumor-specific immunity” in claim 16 is a relative term which renders the claim indefinite. The term 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. Since there is no point of comparison (e.g. a non-oncolytic HSV upon which this recombinant oHSV is based, the general “base” oHSV upon which this oHSV is based, the same oHSV lacking this additional polypeptide, the species or system in which the tumor system is being tested, etc.) it is unclear how a skilled artisan is to determine if there has been an “increase” in efficacy to induce said anti-tumor-specific immunity.
For at least these reasons, the metes and bounds of claim 16 are unclear. Claim 17 is rejected for depending upon claim 16, but not clarifying the metes and bounds of claim 16.
Claims 18 and 28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 is drawn to the oncolytic HSV of claim 1, wherein the oncolytic HSV the further encodes fusogenic activity. The wording of the claim makes it unclear what is being claimed, as it appears something is missing from the claim, such as “…wherein the oncolytic HSV further encodes an additional protein that comprises fusogenic activity.”
Claim 28 is rejected for similar reasoning, because it is unclear exactly what in the oncolytic HSV further encodes fusogenic activity. Again, it is suggested that the claim be amended to read on encoding a protein wherein said protein comprises the claimed fusogenic activity.
For at least these reasons, claims 18 and 28 are rejected on the grounds of being indefinite.
Claim 32 and dependent claim 33 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 is drawn to “A composition comprising a virus of claim 1.” However, with the use of the indefinite article “a” before “virus”, the antecedent basis of said virus is unclear. It is suggested the “a” be replaced with the definite article “the” to provide clear antecedent basis in the claim.
For at least these reasons, the metes and bounds of claim 32 are unclear. Claim 33 is also rejected for depending upon claim 32, but not clarifying the metes and bounds of claim 32.
Claim 34 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 34 recites the limitation "any of the viruses of claim 1" in line 1. There is insufficient antecedent basis for this limitation in the claim, as claim 1 recites one virus. It is suggested the claim be amended to read along the lines of the following (taking into account the 35 USC 101 rejection infra):
“An isolated cell comprising the virus of claim 1.”
For at least these reasons, claim 34 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA comprises:
a) a gene comprising a 5' untranslated region (UTR) and a HSV-1, or HSV-2, VP5 gene that is operably linked to an VP5 promoter comprising a TATA element;
b) a tetracycline operator (tetO) sequence positioned between 6 and 24 nucleotides 3' to said TATA element, wherein the VP5 gene lies 3' to said tetracycline operator sequence;
c) a gene sequence encoding tetracycline repressor (TetR) operably linked to an HSV immediate- early promoter, wherein the gene sequence is located at the ICP0 locus;
d) a variant gene that increases syncytium formation as compared to wild type, wherein the HSV-1, or HSV-2, variant gene is selected from the group consisting of: a glycoprotein K (gK) variant; a glycoprotein B (gB) variant; a UL24 variant; and UL20 gene variant;
e) a gene sequence encoding a functional ICP34.5 protein; and
f) a gene sequence operably linked to a modified HSV promoter, wherein the gene is located in an intergenic region of a set of genes selected from the group consisting of: UL26 and UL27 genes; UL21 and UL22 genes; and UL26, UL27, UL21 and UL 21 genes,
wherein said oncolytic HSV does not encode functional ICP0 and does not contain a ribozyme sequence located in said 5' untranslated region of VP5.
Further limitations on the oncolytic HSV of claim 1 are wherein the gene sequence of (f) encodes a dominant-negative transforming growth factor-beta (TGF-β) mutant sequence or is a LacZ gene sequence (claim 5), wherein the dominant-negative TGF-β mutant sequence is a mmTGF-β2-7M fragment sequence (claim 6); wherein the promoter of (f) is a modified HSV immediate-early promoter, a human cytomegalovirus (HCMV) immediate-early promoter, or a human elongation alpha promoter (claim 7); wherein the variant gene is a gK variant gene that encodes an amino acid substitution selected from the group consisting of: an Ala to Thr amino acid substitution corresponding to amino acid 40 of SEQ ID NO: 2; an Ala to "x" amino acid substitution corresponding to amino acid 40 of SEQ ID NO: 2, wherein "x" is any amino acid; an Asp to Asn amino acid substitution corresponding to amino acid 99 of SEQ ID NO: 2; a Leu to Pro amino acid substitution corresponding to amino acid 304 of SEQ ID NO: 2; and an Arg to Leu amino acid substitution corresponding to amino acid 310 of SEQ ID NO: 2 (claim 8); wherein the tetracycline operator sequence comprises two Op2 repressor binding sites (claim 9); wherein the VP5 promoter is an HSV-1 or HSV-2 VP5 promoter (claim 10); wherein the immediate-early promoter is an HSV-1 or HSV-2 immediate-early promoter, and wherein the HSV immediate-early promoter is selected from the group consisting of: ICP0 promoter, ICP4 promoter, and ICP27 promoter (claim 11); wherein the recombinant DNA is part of a HSV-1 genome or part of a HSV-2 genome (claim 13); further encoding at least one polypeptide that can increase the efficacy of the oncolytic HSV to induce an anti-tumor-specific immunity (claim 16), wherein the at least one polypeptide encodes a product selected from the group consisting of: interleukin 2 (IL-2), interleukin 12 (IL-12), interleukin 15 (IL-15), an anti-PD-1 antibody or antibody reagent, an anti-PD-L1 antibody or antibody reagent, an anti-OX40 antibody or antibody reagent, a CTLA-4 antibody or antibody reagent, a TIM-3 antibody or antibody reagent, a TIGIT antibody or antibody reagent, a soluble interleukin 10 receptor (IL10R), a fusion polypeptide between a soluble IL10R and IgG-Fc domain, a soluble TGFβ type II receptor (TGFβRII), a fusion polypeptide between a soluble TGFBRII and IgG-Fc domain, an anti-IL10R antibody or antibody reagent, an anti-IL10 antibody or antibody reagent, an anti- TGFβRII antibody or antibody reagent, and an anti-TGFβRII antibody or antibody reagent (claim 17); wherein the oncolytic HSV further encodes an additional protein which comprises fusogenic activity (claim 18).
Claim 26 is drawn to an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA does not encode functional ICP0 or ICP34.5 genes; and encodes a functional mmTGF-Β2-7M fragment sequence.
Further limitations on the oncolytic HSV of claim 26 are wherein the HSV encodes a protein which comprises fusogenic activity (claim 28); and wherein the HSV is tetracycline or doxycycline-regulatable (claim 29).
Claim 32 is drawn to a composition comprising the virus of claim 1.
Further limitations on the composition of claim 32 are wherein the composition is further comprising a pharmaceutically acceptable carrier (claim 33).
Claim 34 is drawn to an isolated cell comprising the virus of claim 1.
Claim 39 is drawn to a method for treating cancer, the method comprising administering the virus of claim 1 to a subject having cancer.
Further limitations on the method of claim 39 are wherein the cancer is a solid tumor cancer (claim 40).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 34 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). It is suggested the claim be amended to read upon “An isolated cell..” in order to overcome this rejection.
Claim Rejections - 35 USC § 112(a); First Paragraph
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 1, 5-11, 13, 16-18, 26, 28-29, 32-34, and 39-40 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 the disclosed QREO5-F-derived HSV-1 constructs exemplified by QREOF-lacZ and QREO-DNT, does not reasonably provide enablement for the broader genus of oncolytic HSV-1 and HSV-2 viruses having any tet-regulated VP5 expression, no functional ICP0, functional ICP34.5, any fusogenic variant gene selected from gK, gB, UL24, or UL20, and any inserted payload cassette at the recited HSV intergenic loci. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to regulatable, fusogenic, oncolytic herpes simplex virus (oHSV) recombinant DNA constructs. Claim 1 broadly encompasses HSV-1 and HSV-2 constructs having a tetracycline operator (tetO) positioned relative to the VP5 TATA element, a tetracycline repressor (TetR) at any ICP0 loci (note there are two ICP0 loci in the HSV genome), no functional ICP0, functional ICP34.5, and any fusogenic variant gene selected from gK, gB, UL24, and UL20, wherein the HSV comprises a gene sequence operably linked to any modified HSV promoter inserted into a variety of intergenic regions. Functional ICP34.5 means that said oHSV is still neurovirulent, and can still actively replicate within the central nervous system (CNS). Further dependent claims narrow the fusogenic variant to gK but still vary as to how said gK is modified, and further dependent claims note the use of different promoters in the oHSV which have different regulatable elements (e.g. the ICP0 promoter, ICP4 promoter, and ICP27 promoter are all IE promoters, but regulated differently in that they diverge in their dependence on neighboring Cis-Regulatory Modules (CRMs), Sp1 binding sites, physiological stress loops, and autoregulation. For instance, ICP0 is transactivated by its own product and synergizes with ICP4, while the ICP4 promoter is repressed by its own product to shut off IE transcription, and the ICP27 promoter is modulated by ICP27 as a repressor or enhancer depending on the context. With respect to HSV immediate-early promoter, an HCMV immediate-early promoter, or a human elongation alpha promoter, the HSV IE promoters are highly responsible to transactivation, while the HCMV IE and human EF1-alpha promoter are constitutively active promoters that are susceptible to regulation depending on the cell type they are within.) The claims are also drawn to methods of using said oHSV to treat cancer in a subject, namely solid-tumor cancers.
The specification describes specific HSV-1 constructs, including QREOF-lacZ and QREO-DNT, generated in a QREO5-F-derived background. The examples describe insertion at the HSV-1 UL26/UL27 intergenic region, use of LacZ or codon-optimized mmTGF-β2-7M, plaque purification, confirmation of insertion, doxycycline-regulated expression, and expression of the dominant-negative TGF-β protein in infected U2OS cells (which are used to compensate for the loss of ICP0 in the HSV)(¶[0353-0359]). No in vivo testing of these constructs appears to have been performed.
However, the claims are not limited to the disclosed embodiments. The claims also encompass the use of either HSV-1 or HSV-2 as the oHSV, multiple insertion locations for the heterologous cassette, multiple fusogenic HSV genes which can be rendered variants in a variety of ways, any dominant-negative TGF-β mutant sequences broader than the specific mmTGF-β2-7M construct tested. The claims encompass treatment of any cancer type in any subject through any route of administration. The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, tet-regulated HSV engineering was known. Yao (US20150337319A1) describes HSV-1 vectors in which a tetO is positioned 6-24 nucleotides 3’ to a TATA element and a TetR is expressed from an HSV IE promoter. Yao also recognizes that HSV may contain more than one ICP0 or ICP4 gene copy, and that regulatory cassette placement is part of the construct design, and that the HSV should be replication deficient so that it will only replicate in cells providing missing factors in trans, to reduce the cytotoxicity of the HSV. Yao notes that tetO sequences occur in different forms depending upon the presence or absence of two well recognized tetR binding sites designated as Op-1 and Op-2, and that the most preferred form of operator for use in the present invention has two Op-2 sites. This art shows that individual regulatory elements were known, but it does not make every HSV-1/HSV-2 configuration with different insertion loci and payloads predictable.
The prior art also shows that fusogenic HSV mutations were known, but not interchangeable. HSV mutations in gK, gB, UL24, and UL20 generate highly fusogenic (syncytial) viruses by removing the virus's intrinsic negative regulation of membrane fusion and allowing the principal fusogen, which is glycoprotein B (gB), to trigger prematurely or traffic inappropriately to cell surfaces (Ruel N, et. al. Virology. 2006 Mar 1;346(1):229-37. Epub 2005 Dec 2.) Campadelli et. al. (US20160074448A1) describes mutations in HSV glycoproteins that promote cell syncytia, including mutations in gK and gB (¶[0082]). Melancon et. al. (Melancon JM, et. al. Virol J. 2007 Nov 8;4:120.) notes that UL20 protein (UL20p) and glycoprotein K (gK) are both important determinants of cytoplasmic virion morphogenesis and virus-induced cell fusion, and that different UL20 mutations produced different biological effects. In fact, gB and gK syncytial mutations require the presence of functional UL20 to drive cell-to-cell fusion (Foster TP, et. al. J Virol. 2004 May;78(10):5347-57.) The art therefore indicates that increased syncytium formation could not be assumed merely from selecting any variant in gK, gB, UL24, or UL20.
The prior art regarding dominant-negative forms of TGF-β, such as mmTGF-β2-7M, was also sequence and context dependent. Hinck et. al. (US20190359667A1) describes an engineered TGF-β monomer containing seven substitutions, expression in E. coli inclusion bodies, testing with the binding to the native receptor, and inhibition of TGF-β signaling, which supports the testing of a particular engineered TGF-β monomer. mmTGF-β2-7M is an engineered, “mini-monomer” dominant-negative monomer of the Transforming Growth Factor Beta-2 (TGF-β2) cytokine. Designed by researchers, it acts as a high-affinity "ligand trap" that binds to the Type II receptor but is unable to recruit the Type I receptor, effectively shutting down TGF-β signaling in a localized area.
Other dominant-negative forms of Transforming Growth Factor-beta (TGF-β) primarily include truncated TGF-β receptor type II (dnTGF-βRII), kinase-deficient ALK5 (TGF-β type I receptor) mutants, and dominant-negative Smad proteins (e.g., mutated Smad6/7 or phosphorylation-deficient R-Smads). Their major drawback is the systemic disruption of the TGF-β pathway, leading to life-threatening multiorgan inflammation, loss of tumor suppression, and impaired DNA repair if not tightly regulated; for instance, non-selective global application can inadvertently promote tumor progression by creating a highly metastatic microenvironment (Bierie B, et. al. Nat Rev Cancer. 2006 Jul;6(7):506-20.) Therefore, the art does not establish that the broadly varied dominant-negative TGF-β mutant sequences, when encoded by the claimed oHSV, would be properly expressed, secreted, folded, and active in the desired format (e.g. against only a specific cancer/tumor) without further experimentation.
While oHSV was widely known as a vector that could accommodate large payloads, it remained that insertion of genes into HSV could still trigger genomic instability, heterologous transgene silencing, disruption of neighboring viral promoters, and reduced oHSV replication fitness, as well as its use therapeutically encountered significant issues with pre-existing immunity, potential for wild-type revertants, and quality control issues. Even post-filing art notes the continued technical challenges in the oHSV art, including the ability to optimize the targeting of the oHSV therapy, the administration of the oHSV and being neutralized by pre-existing antibodies, the contamination of oHSV with adventitious viruses (Zheng Y, et. al. Vaccines (Basel). 2025 Aug 20;13(8):880.) Miao et. al. notes that arming oHSV with therapeutics is known in the art, but most transgenes were placed under ubiquitous viral promoters, with such promoters not being tumor-selective (Miao L, et. al. Br J Cancer. 2014 Jan 7;110(1):94-106. Epub 2013 Nov 5.). Longo et. al. (Longo SL, et. al. Cancer Gene Ther. 2011 Feb;18(2):123-34. Epub 2010 Oct 8.) notes a gene that is essential for viral replication, infected cell polypeptide 4 (ICP4), was placed under the regulation of a hypoxia-inducible factor (HIF)-responsive promoter and then introduced into the thymidine kinase locus (U(L)23) of HSV d120, which contains partial deletions in the two endogenous ICP4 genes. Unexpectedly, this HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia, which was noted due to reversion of the oHSV to wild-type, suggesting that the oHSV was genetically unstable and can activate a tumor-related promoter in a non-specific manner. Herrlinger notes that tet-regulated gene expression in HSV systems, such as HSV still expressing ICP4, ICP27, ICP0, or VP16, can activate the tetO promoter and interfere with tet-regulated transgene expression (Herrlinger U, et. al. J Gene Med. 2000 Sep-Oct;2(5):379-89.) These findings support that the oHSV art was still highly unpredictable, and required empirical validation to ensure the stability and safety of the oHSV, especially if said oHSV was intended for use in the treatment of clinical subjects.
The art was not sufficiently predictable to support extrapolation from the disclosed QREO-DNT construct to the full scope of the claims. Accordingly, the results obtained using one HSV-1 background, one principal fusogenic construct, one tested payload, and one demonstrated insertion strategy would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with recombinant HSV construction, homologous recombination, plaque purification, Western blotting, viral growth assays, syncytial assays, and other assays required in the formation and testing of oHSV both in vitro and in vivo. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional HSV-1 or HSV-2 constructs, fusogenic variants of the claimed proteins, intergenic insertion sites, and which dominant-negative TGF-β mutants would satisfy the claimed limitations, especially in methods of treating any cancer type.
Working examples. The specification provides working examples directed to QREOF-LacZ and QREO-DNT. These examples show construction and testing of specific HSV-1 recombinant viruses in a HSV-1 F strain background. QREOF-lacZ is a QREO5-F derived recombinant that encodes the lacZ gene under the control of the HSV-2 ICP0 immediate-early promoter at the intergenic region of the HSV-1 UL26 and UL27 genes (¶[0351]). pQUL2627-TGF-DN was constructed by replacing the HSV-2 ICP0/lacZ gene-containing DNA fragment in pQUL2627-lacZ with a synthesized DNA fragment consisting of the codon optimized mmTGF-β2-7M with the HSV-1 gD signal peptide under the control of the tetO-containing HSV-2 ICP4/TO promoter (¶[0355]), and QREO-DNT is a QREOF-lacZ-derived recombinant virus in which the lacZ gene under the control of the modified HSV-2 ICP0 promoter is replaced by the DNA fragment encoding the codon optimized codon optimized mmTGF-β2-7 M under the control of the HSV-2 ICP4/TO promoter sequence (¶[0357]). Further in vitro testing confirmed the ability of the virus to express the dominant-negative mmTGF-β2-7 M in the presence of doxycycline (¶[0358-0359]). The specification does not provide working examples directed to any other HSV-1 strain, background, or construct, nor does the specification generate any oHSV-2 with any of the claimed structural features. The oHSV used comprises the gK A40T mutant in order to promote syncytial formation; no other gK mutants or other gB, UL20, or UL24 mutants were tested in the oHSV. No other HSV with any of the other claimed heterologous payloads were generated and tested. No in vivo studies with the generated oHSV were performed in any animal models or any clinical subjects showing any effect on cancer or solid tumor treatment. As the oHSV is claimed to have functional ICP34.5, this means the virus is still neurovirulent, and can actively replicate within the CNS, potentially causing disease. While ICP0 is noted as being “non-functional”, as set forth in the 35 USC 112b rejection supra, it is unclear what this means and how it affects the replication capability of the virus, especially if said virus has increased fusogenicity and has the capability to spread more rapidly between adjacent cells. Overall, the combination of structural and functional limitations within the oHSV were not tested in vivo, so it is unclear how said virus would replicate in a host and whether or not said system would be capable of eliciting any type of anti-cancer therapeutic effect. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the construction of the disclosed QREOF-LacZ and QREO-DNT oHSV and for testing expression of the mmTGF-β2-7M payload. However, the specification does not provide sufficient guidance regarding selection and validation of the broader claimed combinations of oHSV. In particular, the specification does not explain which gK, gB, UL24, or UL20 variants will produce the required fusogenic phenotype while preserving regulated viral replication and functional ICP34.5 activity in both HSV-1 and HSV-2 contexts. The specification fails to explain what cancer types the disclosed oHSV could be used in, how specifically the treatment method is to happen (e.g. delivery route, when the tetracycline/doxycycline/etc. is to be administered, what types of cancers are susceptible to said oHSV, etc.)
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to prepare and test additional HSV-1 and HSV-2 oncolytic constructs, insert payload cassettes at different intergenic loci, introduce different fusogenic variants, confirm loss of functional ICP0, confirm retention of ICP34.5, and determine whether the resulting viruses remain regulatable, safe, and capable of expressing the heterologous payload in vivo in such a manner as to effectuate a therapeutic response against the cancer being treated in said subject. Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed functional requirements. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional oHSV-1 and oHSV-2 to determine which embodiments satisfy the claimed fusogenic and therapeutic functions.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes specific QREO5-F-derived HSV-1 constructs, including QREOF-LacZ and QREO-DNT, but the claims also encompass a much broader class of oHSV-1 and oHSV-2 constructs having different fusogenic variant genes, different insertion loci, different payloads, different dominant-negative TGF-β, and different methods of treatment for different types of cancer in different subjects. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in the instant claims without undue experimentation.
Claims 1, 5-11, 13, 16-18, 26, 28-29, 32-34, and 39-40 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claims 1, 5-11, 13, 16-18, 26, 28-29, 32-34, and 39-40 recite oHSV recombinant DNA constructs having tet-regulated VP5 expression, a tet repressor sequence at an ICP0 loci, no functional ICP0, functional ICP34.5, a fusogenic variant gene selected from gK, gB, UL24, and UL20, and an inserted gene cassette at recited HSV intergenic regions. The claims further require a dominant-negative TGF-β mutant sequence linked to a modified HSV-2 IE promoter. The claims are also drawn to methods of using said oHSV to treat cancer in a subject, namely a solid tumor cancer.
The specification describes specific QREO5-F-derived HSV-1 constructs. In particular, the specification describes QREOF-LacZ, in which LacZ under a modified HSV-2 ICP0 promoter, is inserted at the HSV-1 UL26/UL27 intergenic region in the HSV-1 genome (¶[0353-0354]). The specification also describes QREO-DNT, in which the lacZ cassette of QREOF-lacZ is replaces with a codon-optimized mmTGF-β2-7M cassette under the HSV-2 ICP4/TetO promoter (¶[0355-0359]). The summary similarly describes construction of a shuttle vector for insertion into the HSV01 UL26/UL27 intergenic region and construction of a tetracycline-regulatable fusogenic HSV-1 virus encoding mmTGF-β2-7M (¶[0005]).
However, the scope of the claims is not limited to the embodiments described in the specification. The claims broadly encompass constructs that differ in viral type (e.g. HSV-1 vs. HSV-2), fusogenic gene (e.g. gK, gB, UL20, UL24 variants that increase syncytium formation), insertion locus (e.g. UL26/UL27, UL21/UL22 intergenic loci), and inserted gene cassette (e.g. see instant claim 17, wherein said gene can be any one of interleukin 2 (IL2), interleukin 12 (IL12), interleukin 15 (IL15), an anti-PD-1 antibody or antibody reagent, an anti-PD-L1 antibody or antibody reagent, an anti-OX40 antibody or antibody reagent, a CTLA-4 antibody or antibody reagent, a TIM-3 antibody or antibody reagent, a TIGIT antibody or antibody reagent, a soluble interleukin 10 receptor (IL10R), a fusion polypeptide between a soluble IL10R and IgG-Fc domain, a soluble TGF3 type II receptor (TGFBRII), a fusion polypeptide between a soluble TGFBRII and IgG-Fc domain, an anti-IL10R antibody or antibody reagent, an anti-IL10 antibody or antibody reagent, an anti- TGFBRII antibody or antibody reagent, and an anti- TGFBRII antibody or antibody reagent.) The claims also encompass constructs retaining functional ICP34.5 (retention of neurovirulence genes) while lacking “functional ICP0” (as set forth supra in the 35 USC 112b rejection, it is unclear what one or more functions are lost or if all copies of ICP0 are completely deleted from the HSV genome.) The claims are also drawn to the use of said oHSV in methods of treating cancer in a subject. The specification does not describe representative species across that scope
The specification does not describe a sufficient number of species representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional gK, gB, UL20, and UL24 fusogenic variants, heterologous genes, mutated HSV promoters, tetO sequences, tetR sequences, location of said tetO sequence, ICP0 mutants to knock out the function, intergenic regions, and HSV-1 or HSV-2 genomes not described in the specification and determine whether those additional embodiments satisfy the recited limitations.
The claimed oHSV constructs are defined, at least in part, by the recited function of ICP0 and the ability of said virus to formulate more syncytium. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the additional oHSV variants, gene mutants, and constructs falling within the scope of the claim. For instance, with respect to increased fusogenic capability, the specification describes the oHSV-1 comprising an A40T mutation in gK, but does not identify structural features common to the broader claimed genus which would allow one skilled in the art to recognize other members of the genus. The disclosure discussed a desired fusogenic result without representative species or common features across gK, gB, UL24, and UL20 variants in both HSV-1 and HSV-2 that would result in said functional result. Likewise, the specification describes “ICP0 null mutations” in order to have a oHSV that does not comprise functional ICP0, but the specification fails to explicitly identify what exactly these ICP0 null mutations encompass (e.g. partial deletion of one or both ORF, full deletion of one or both ORF, insertion/substitution mutations within one or both ORF, etc.), the specification does not identify other mutants or methods of rendering one or both copies of ICP0 non-functional, or if only one function of ICP0 must be obliterated or if all functions of ICP0 must be knocked out. The disclosure of the desired functions, without a sufficient description of the claimed genera, does not demonstrate possession of the full scope of the claim.
The specification also does not identify structural features common to the broader claimed genus which would allow one of skill in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional HSV-1 or HSV-2 backbones, select different fusogenic variant genes, place the regulatory and payload cassettes at different loci, and determine whether the resulting constructs satisfy the claimed limitations.
The claims broadly encompass any method of treating any subject with any cancer, specifically any solid tumor cancer. The specification does not describe representative embodiments across that scope or otherwise demonstrate possession of the broader claimed method. No in vivo studies with any representative species of the claimed oHSV were performed in any subject, and it is not clear how said oHSV would be used in any method of treatment, as it is unclear how said virus should be delivered and in what dosage regimen, if said virus can be used in subjects that are HSV-1 and/or HSV-2 seropositive, when said subject should receive the tetracycline to turn on/off the HSV replication machinery, and whether said virus can be used to effectively treat any specific type of cancer. The disclosure does not reasonably convey possession of methods using the clamed oHSV, especially in methods of treatment of any cancer in any subject.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in the claims at the time the application was filed.
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.
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Claims 1, 5-11, 13, 16-18, 26, 28-29, 32-34, and 39-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,509,662 in view of Hinck et. al. (US20190359667A1; Priority 11/18/2016; hereafter “Hinck”) and Russell et. al. (Russell TA, et. al. J Virol Methods. 2015 Mar;213:18-25. Epub 2014 Dec 3.; hereafter “Russell”.) Both sets of claims are drawn to an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA comprises:
a) a gene comprising a 5′ untranslated region and a HSV-1, or HSV-2, VP5 gene that is operably linked to an VP5 promoter comprising a TATA element;
b) a tetracycline operator sequence positioned between 6 and 24 nucleotides 3′ to said TATA element, wherein the VP5 gene lies 3′ to said tetracycline operator sequence;
c) a gene sequence encoding tetracycline repressor operably linked to an HSV immediate-early promoter, wherein the gene sequence is located at the ICP0 locus;
d) a variant gene that increases syncytium formation as compared to wild type, wherein the HSV-1, or HSV-2, variant gene is selected from the group consisting of: a glycoprotein K (gK) variant; a glycoprotein B (gB) variant; a UL24 variant; and UL20 gene variant; and
e) a gene sequence encoding a functional ICP34.5 protein;
wherein said oncolytic HSV does not encode functional ICP0 and does not contain a ribozyme sequence located in said 5′ untranslated region of VP5. Both sets of claims are drawn to the same gK variant genes, and both sets of claims are drawn to wherein the tetracycline operator sequence comprises two Op2 repressor binding sites. Both sets of claims are drawn to wherein the VP5 promoter is an HSV-1 or HSV-2 VP5 promoter, and wherein the immediate-early promoter is an HSV-1 or HSV-2 immediate-early promoter, such as an ICP0 promoter or ICP4 promoter. Both sets of claims are drawn to wherein the recombinant DNA is part of the HSV-1 genome or part of the HSV-2 genome. Both sets of claims are drawn to said oHSV further encoding at least one polypeptide that can increase the efficacy of the oncolytic HSV to induce an anti-tumor-specific immunity, wherein said at least one polypeptides are the same (e.g. IL-2, IL-12, anti-PD1, etc.) Both sets of claims are drawn to the oHSV comprising additional proteins with further fusogenic activity, and both are drawn to compositions comprising the oncolytic HSV. Both sets of claims are drawn to methods for treating cancer, the method comprising administering the oncolytic HSV to a subject having cancer, namely a solid tumor cancer.
The main difference is that the instant claim specify the insertion site of the payload is between UL26 and UL27, and that said oHSV encodes a mmTGF-β2-7M, which is a dominant-negative form of TGF-β. However, such elements were known in the art at the time of filing, and would have been obvious optimizations to the claims of ‘662 as the UL26/UL27 intergenic region was a known foreign DNA insertion site in HSV-1 that was known as a site that could be used without disrupting vital lytic genes or compromising viral replication, as evidenced by the teachings of Russell (entire document; see abstract). The dominant-negative mmTGF-β2-7M was a known TGF-β monomer that could successfully block TGF-β signaling, which is known to promote the progression of certain types of cancers, as evidenced by the teachings of Hinck (entire document; see abstract; ¶[0006]; Example 1 starting at ¶[0116].) Hinck teaches said TGF-β monomer can be delivered via viral vectors (¶[0106]). Therefore, using the vector of the ‘662 claims to deliver a known anti-cancer therapeutic and inserting said gene into a known intergenic region that is useful for heterologous DNA insertions would be an obvious optimization of the ‘662 claims, given the teachings of Hinck and Russell, and thus the instant claims and ‘662 claims are not patentably distinct.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Chouljenko VN, et. al. J Virol. 2009 Dec;83(23):12301-13. Epub 2009 Sep 30. Teaches A40V/T mutations in gK. Not utilized as rejection would be redundant to those set forth supra.
Rider PJF, et. al. Sci Rep. 2019 Oct 10;9(1):14625. Teaches mutations in gK important for functionality. Not utilized as rejection would be redundant to those set forth supra.
Avitabile E, et. al. J Virol. 2003 Jun;77(12):6836-44. Teaches mutations in gK that allow for syncytia formation. Not utilized as rejection would be redundant to those set forth supra.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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