DETAILED ACTION
Disposition of Claims
Claims 1-10, 12-18, 20-21, and 24 are pending. Claims 11, 19, 22-23, and 25-26 have been cancelled.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250057931A1, Published 02/20/2025.
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.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/12/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See “www.medicenna.com“, “www.synthekine.com” ¶[0875][0880][0882].
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows: Sequences are present in the specification that do not have a corresponding SEQ ID NO: (see e.g. ¶[0975-0976][0993], “KSPWFTTL”, “FQPQNGQFI”
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 1, 4-6, 13, and 18 are objected to because of the following informalities: only one period can be present per claim (See MPEP § 608.01(m)). It is suggested that the claims be amended to have a colon instead of a period bracketing the lower-case letters/roman numerals to be in line with how the rest of the claims are formatted (i.e. “(a)” instead of “a.”). Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the definitions of the abbreviations “L segment”, “S segment”, “NP”, “Z protein”, “L protein”, “GP”, and “UTR” 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. … nucleoprotein (NP)...).
Appropriate correction is required.
Claim 12 is objected to because of the following informalities: “arenavirus particles” in line 3 should be “arenavirus particle”. 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.
Claims 1, 5, 10, 12, 16, and 18 and dependent claims 2-4, 6-9, 13-15, 17, 20-21, and 24 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 “functionally inactivated” in claims 1, 5, 10, 12, 16, 18 is a relative term which renders the claim indefinite. The term “functionally inactivated” 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. As the “functional inactivation” is in relation to any arenavirus open reading frame (ORF), it is unclear what function is meant to be inactivated, how one of skill would measure such an inactivation, and what degree of inactivation is required (e.g. full, partial, percentage compared to wild type protein, etc.)
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1, 5, 10, 12, 16, and 18 are rejected on the grounds of being indefinite. Claims 2-4, 6-9, 13-15, 17, 20-21, and 24 are also rejected since they depend from claims 1, 5, 10, 12, 16, or 18, but do not remedy these deficiencies of claims 1, 5, 10, 12, 16, or 18.
Claims 1, 5, 12, and 18 and dependent claims 2-4, 6-10, 13-17, 20-21, and 24 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 “wild-type position” in claims 1, 5, 12, and 18 is a relative term which renders the claim indefinite. The term “wild-type position” 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. As the “wild-type position” is in relation to any arenavirus open reading frame (ORF), it is unclear what “base” viral sequence or structure is meant to be the reference point, how one of skill would measure whether the ORF is no longer at the “wild-type position”, and what degree of movement/change is required for it to be considered located at a position other than the native “wild-type position” (e.g. insert of heterologous non-coding elements between the native ORF, shifting of a certain number of nucleotides, complete excision of the entire ORF and placement 5’ or 3’ of another ORF, etc.)
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1, 5, 12, and 18 are rejected on the grounds of being indefinite. Claims 2-4, 6-10, 13-17, 20-21, and 24 are also rejected since they depend from claims 1, 5, 12, or 18, but do not remedy these deficiencies of claims 1, 5, 12, or 18.
Claims 2 and 3 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 2 and 3 depend upon claim 1, which recites that the subject is administered “(i) an arenavirus particle, and (ii) an immune checkpoint modulator and/or a cytokine”. Claims 2 and 3 refer to “the cytokine”, which, with the use of “and/or” in part (ii), is optional in the claim. Therefore, the antecedent basis of “the cytokine” is not absolutely clear with respect to the claim construction of claim 1. Further confusion arises with the optional cytokine in claim 1 being “IL-12”, while the cytokines referenced in claims 2-3 are mainly “IL-2”.
Further, claim 2 uses the term “specifically binds”, which is a relative term which renders the claim indefinite. The term “specifically binds” 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. No definition has been provided by the specification or claim to allow a skilled artisan to determine what is, or is not, “specific” binding to a target, such as the use of a dissociation constant (Kd) or other measurable parameter.
Finally, in claim 3, the limitation “an IL-2-immunoglobulin fusion protein, a modified IL-2 molecule having abrogated binding to CD25, ANV419, XTX202, AB248, MDNA11, STK-012, and combinations thereof” is confusing from the punctuation, because it is unclear if “a modified IL-2 molecule having abrogated binding to” is meant to only have abrogated binding to CD25, or abrogated binding to “CD25, ANV419, XTX202, AB248, MDNA11, STK-012, and combinations thereof”, the latter of which is confusing, because ANV419, XTX202, AB248, MDNA11, and STK-012 are all engineered IL-2 variants. Even further, some of these engineered IL-2 variants are examples of “an IL-2-immunoglobulin fusion protein”, such as ANV419 and AB248, so it is unclear if this is a broad followed by narrow limitation that further renders the metes and bounds of the claim unclear.
For at least these reasons, the metes and bounds of claims 2-3 are unclear.
Claims 9 and 15 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.
It is unclear if the recited elements within parentheses (See e.g. "(“GP”)", “(“NP”)”, “(“Z protein”)”, “(“L protein”)”) are required elements of the claim, as the quotation marks around the internal recitation make it unclear what is being recited and whether it is a required element. As it appears as though Applicant is attempting to provide abbreviations for the longer names of the proteins, it is suggested the quotation marks within the parentheses be deleted for clarity (e.g. “…the glycoprotein (GP), the nucleoprotein (NP), the matrix Z protein (Z protein), or the RNA dependent RNA polymerase L protein (L protein) of the arenavirus particle.”)
Claim 15 is rejected for similar reasoning.
For at least these reasons, the metes and bounds of the claims are unclear
Claim 20 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 20 contains the trademark/trade name “DUOBODY®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a bispecific antibody platform and, accordingly, the identification/description is indefinite.
Additionally, claim 20 depends upon claim 1, which recites that the subject is administered “(i) an arenavirus particle, and (ii) an immune checkpoint modulator and/or a cytokine”. Claim 20 refers to “the immune checkpoint modulator”, which, with the use of “and/or” in part (ii), is optional in the claim. Furthermore, the antecedent basis of “the additional immune checkpoint modulator” is unclear, as claim 1 refers to such an additional modulator, but said modulator is optional. Therefore, the antecedent basis of both “the immune checkpoint modulator” and “the additional immune checkpoint modulator” is not clear with respect to the claim construction of claim 1. It is suggested that claim 20 be amended to clearly recite that in this further limitation, both are present and required elements, and then to describe the further limitations with respect to these modulators.
For at least these reasons, the metes and bounds of claim 20 are unclear.
Claim 21 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.
The term “anti-tumor efficacy” in claim 21 is a relative term which renders the claim indefinite. The term “anti-tumor efficacy” 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. The claim fails to identify the parameter or objective standard by which anti-tumor efficacy is to be determined. Although the claim identifies a general base for comparison, namely administration of a control arenavirus particle expressing the tumor antigen, tumor-associated antigen, or antigenic fragment thereof alone, the claim does not state what measured outcome must be “higher” in order for the recited method to have the higher “anti-tumor efficacy”. The specification also fails to provide an objective standard for comparison; at ¶[0948] the specification states the method described has a higher anti-tumor or anti-infection efficacy as compared to administration of a control arenavirus particle expressing the tumor antigen, tumor associated antigen, antigen of a pathogen that causes an infectious disease, or antigenic fragment of any of the foregoing, alone. That same paragraph states that a control arenavirus particle can be any arenavirus particle deemed suitable by a skilled artisan to serve as a control arenavirus vector for the comparison, while merely expressing preferences that the control particle be derived from the same arenavirus species or have the same backbone. At ¶[0977], the specification states any assay known to the skilled artisan can be used to measure anti-tumoral or anti-infection effect and survival benefit, and the exemplary assay in the Examples measures tumor diameter and volume and evaluates survival by a Kaplan-Meier analysis. The working examples also describe “anti-tumor efficacy” using different outcomes; in Example 6, they characterize reduced tumor growth as demonstrating anti-tumor efficacy and separately identifies a survival benefit, while Examples 7 and 8 discuss median survival, tumor-free animals, tumor elimination, and protection against tumor rechallenge.
These measurements are related, but not interchangeable. The specification and claims fail to explain which of these outcomes controls the determination that a treatment has “higher anti-tumor efficacy”, whether improvement in ANY outcome is sufficient, or how conflicting results among different measures are to be evaluated.
For at least these reasons, the metes and bounds of claim 21 are unclear.
Claims 21 and 24 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.
The term “increased concentration/ratio” in claims 21 and 24 is a relative term which renders the claim indefinite. The term “increased concentration/ratio” 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. There is no determination of a baseline in the claim itself or in the specification against which the “increase” in the concentration or ratio can be determined.
For at least these reasons, claims 21 and 24 are rejected on the grounds of being indefinite.
Claim 24 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.
The term “near cells infected with the pathogen” in claim 24 is a relative term which renders the claim indefinite. The term “near cells infected with the pathogen” 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. There is no apparent objective boundary provided for in the claim or the specification for determining what qualifies as “near”. The claim nor the disclosure establishes whether the T cell must be immediately adjacent to an infected cell, within a defined distance (e.g. measurable distance or number of cell diameters away), within a specified microscopic field, within the same tissue/organ compartment, or merely present in infected tissue.
For at least these reasons, the metes and bounds of claim 24 are unclear.
Claim 24 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.
The term “anti-infection efficacy” in claim 24 is a relative term which renders the claim indefinite. The term “anti-infection efficacy” 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.
The claim fails to identify the parameter or objective standard by which anti-infection efficacy is to be determined. Although the claim identifies a general base for comparison, namely administration of a control arenavirus particle expressing the viral antigen or antigenic fragment thereof alone, the claim does not state what measured outcome must be “higher” in order for the recited method to have the higher “anti-infection efficacy”. The specification also fails to provide an objective standard for comparison; at ¶[0948] the specification states the method described has a higher anti-tumor or anti-infection efficacy as compared to administration of a control arenavirus particle expressing the tumor antigen, tumor associated antigen, antigen of a pathogen that causes an infectious disease, or antigenic fragment of any of the foregoing, alone. That same paragraph states that a control arenavirus particle can be any arenavirus particle deemed suitable by a skilled artisan to serve as a control arenavirus vector for the comparison, while merely expressing preferences that the control particle be derived from the same arenavirus species or have the same backbone. At ¶[0977], the specification states any assay known to the skilled artisan can be used to measure anti-tumoral or anti-infection effect and survival benefit, and the exemplary assay in the Examples measures tumor diameter and volume and evaluates survival by a Kaplan-Meier analysis.
Different infectious diseases can be evaluated using materially different endpoints. For example, infection may be assessed by pathogen burden, viral load, bacterial colony counts, parasitemia, lesion burden, symptom severity, duration of disease, time to pathogen clearance, tissue pathology, morbidity, or mortality. These measurements are not interchangeable. The specification and claims fail to explain which of these outcomes controls the determination that a treatment has “higher anti-infection efficacy”, whether improvement in ANY outcome is sufficient, or how conflicting results among different measures are to be evaluated.
For at least these reasons, the metes and bounds of claim 24 are unclear.
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 a method for treating or preventing a neoplastic disease or an infectious disease in a subject in need thereof, wherein the method comprises administering to the subject:
(i) an arenavirus particle, and
(ii) an immune checkpoint modulator and/or a cytokine, optionally wherein the cytokine is IL-12; wherein:
(a) the arenavirus particle comprises an arenavirus genome comprising a heterologous ORF encoding an antigen or an antigenic fragment thereof, and
(b) (i) at least one arenavirus open reading frame (ORF) of the arenavirus genome is either functionally inactivated or deleted, or (ii) at least one arenavirus ORF is located in a position other than the wild-type position of said at least one arenavirus ORF, or (iii) a fragment of at least one arenavirus ORF is located in a position other than the wild-type position of said fragment of the at least one arenavirus ORF,
optionally wherein the method further comprises administering an additional immune checkpoint modulator that is different from the immune checkpoint modulator; and
further optionally wherein the arenavirus particle is derived from lymphocytic choriomeningitis virus (LCMV) or Pichinde virus.
Further limitations on the method of claim 1 are wherein the method further comprises administering to the subject an antibody that specifically binds to the cytokine, wherein the antibody is administered with the cytokine in the same composition, optionally wherein the cytokine is IL-2 and the antibody is an anti-IL-2 antibody (claim 2); wherein the cytokine is selected from the group consisting of an IL-2-immunoglobulin fusion protein, a modified IL-2 molecule having abrogated binding to CD25, ANV419, XTX202, AB248, MDNA11, STK-012, and combinations thereof (claim 3); wherein the arenavirus particle is tri-segmented and replication-competent and comprises one L segment and two S segments, wherein one of the two S segments is selected from the group consisting of:
(a) an S segment, wherein the ORF encoding the NP is under control of an arenavirus genomic 5′ UTR;
(b) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 5′ UTR;
(c) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 5′ UTR;
(d) an S segment, wherein the ORF encoding the GP is under control of an arenavirus genomic 3′ UTR;
(e) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 3′ UTR; and
(f) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 3′ UTR (claim 4); wherein the arenavirus particle is administered via intravenous injection or via intratumoral injection (claim 8); wherein the at least one arenavirus ORF encodes the glycoprotein (GP), the nucleoprotein (NP), the matrix protein Z (Z protein) or the RNA dependent RNA polymerase L (L protein) of the arenavirus particle (claim 9); wherein the at least one arenavirus ORF is either functionally inactivated or deleted and wherein the arenavirus particle has the ability to amplify and express its genetic information in cells infected with the arenavirus particle but is unable to produce further infectious progeny particles in normal, non-complementing cells (claim 10); wherein the immune checkpoint modulator of any one of claims 1-18 and/or the additional immune checkpoint modulator of claim 19 is an agonist of 4-1BB costimulatory pathway, an agonist of OX40 costimulatory pathway, an antagonist of NKG2A coinhibitory pathway, or a combination thereof;
optionally wherein
(i) the agonist of 4-1BB costimulatory pathway is an agonistic antibody of 4-1BB or 4-1BBL, optionally wherein the agonist of the 4-1BB costimulatory pathway is selected from the group consisting of utomilumab (PF-05082566), INBRX-105, ABL503, ATOR-1017, FS222, RG7827 (FAP 4-1BBL FP), RG6076 (CD19-4-1BBL), urelumab (BMS-663513), CHU CD137 agonist switch antibody, AGEN-2373, CTX-471, FS-120, LVGN-6051, MCLA-145, AMG-506, PRS-343, STA-551, ADG-106, DSP-107, DuoBody-CD40x4-1BB (BNT-312, GEN1042), DuoBody-PD-L1x 4-1BB (GEN-1046, BNT-311), ALG.APV-527, CB307, ABP-300, NM21-1480, EU101, RO7227166, ABL111, HERA-4-1BBL, SL-279137 (PD-1-Fc-4-1BBL), and combinations thereof;
(ii) the agonist of OX40 costimulatory pathway is an agonistic antibody of OX40, optionally wherein the agonist of the OX40 costimulatory pathway is selected from the group consisting of INBRX-106, PF-04518600, BMS-986178, BGB-A445, MEDI0562, MOXR-0916 (pogalizumab, RG 7888), anti-FAP/anti-OX40 bispecific agonistic antibody, anti-FAP/OX40L agonist fusion protein, INCAGN01949, MEDI6469, GSK3174998, HERA-OX40L, SL-279252 (PD1-Fc-OX40L), and combinations thereof, and/or
(iii) the antagonist of the NKG2A coinhibitory pathway is an antagonistic antibody of NKG2A (claim 20); wherein the method is for treating or preventing a neoplastic disease, and the antigen is a tumor antigen, tumor associated antigen, or antigenic fragment thereof;
optionally wherein the neoplastic disease is a solid tumor and wherein the method results in an increase of the concentration of T cells within the solid tumor, optionally wherein the method results in an increased concentration of CD8+ T cells, an increased concentration of CD4+ T cells, an increased concentration of tumor antigen specific T cells, an increased concentration of T cells producing IFN-gamma, an increased concentration of T cells producing granzyme B, and/or an increased ratio of effector T cells/regulatory T cells within the solid tumor;
further optionally wherein the method has a higher anti-tumor efficacy as compared to administration of a control arenavirus particle expressing the tumor antigen, tumor associated antigen, or antigenic fragment thereof, alone; and/or the method results in an increase in the survival rate of subjects treated with the method, compared to subjects having the same neoplastic disease in the absence of such treatment (claim 21); and wherein the method is for preventing or treating an infectious disease, and the antigen is an antigen of a pathogen that causes the infectious disease, or antigenic fragment thereof;
optionally wherein the method results in an increase of the concentration of T cells near cells infected with the pathogen, optionally wherein the method results in an increased concentration of CD8+ T cells, an increased concentration of CD4+ T cells, an increased concentration of tumor antigen specific T cells, an increased concentration of T cells producing IFN-gamma, an increased concentration of T cells producing granzyme B, and/or an increased ratio of effector T cells/ regulatory T cells, near cells infected with the pathogen;
further optionally wherein the method has a higher anti-infection efficacy as compared to administration of a control arenavirus particle expressing the antigen of a pathogen that causes the infectious disease, or antigenic fragment thereof, alone; and/or the method results in an increase in the survival rate of subjects treated with the method, compared to subjects having the same infectious disease in the absence of such treatment (claim 24).
Claim 5 is drawn to a method for treating or preventing a neoplastic disease or an infectious disease in a subject in need thereof, wherein the method comprises administering to the subject an arenavirus particle, wherein
(a) the arenavirus particle comprises an arenavirus genome comprising:
(i) a first heterologous ORF encoding an antigen; and
(ii) a second heterologous ORF encoding an immune checkpoint modulator or a cytokine, optionally wherein the cytokine is IL-12; and
(b) (i) at least one arenavirus ORF of the arenavirus genome is either functionally inactivated or deleted, or
(ii) at least one arenavirus ORF is located in a position other than the wild-type position of said at least one arenavirus ORF, or
(iii) a fragment of at least one arenavirus ORF is located in a position other than the wild-type position of said fragment of the at least one arenavirus ORF;
optionally wherein the method further comprises administering an additional immune checkpoint modulator that is different from the immune checkpoint modulator; and
further optionally wherein the arenavirus particle is derived from lymphocytic choriomeningitis virus (LCMV) or Pichinde virus.
Further limitations on the method of claim 5 are wherein the arenavirus particle is tri-segmented and replication-competent and comprises one L segment and two S segments, wherein one of the two S segments is selected from the group consisting of:
(a) an S segment, wherein the ORF encoding the NP is under control of an arenavirus genomic 5′ UTR;
(b) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 5′ UTR;
(c) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 5′ UTR;
(d) an S segment, wherein the ORF encoding the GP is under control of an arenavirus genomic 3′ UTR;
(e) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 3′ UTR; and
(f) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 3′ UTR (claim 6), and wherein (i) a first S segment is engineered to carry an arenaviral ORF encoding GP in a position under control of an arenavirus genomic 3′ UTR and the first heterologous ORF in a position under control of an arenavirus genomic 5′ UTR, and a second S segment is engineered to carry an arenaviral ORF encoding NP in a position under control of an arenavirus genomic 3′ UTR and the second heterologous ORF in a position under control of an arenavirus genomic 5′ UTR; or (ii) a first S segment is engineered to carry an arenaviral ORF encoding NP in a position under control of an arenavirus genomic 3′ UTR and the first heterologous ORF in a position under control of an arenavirus genomic 5′ UTR, and a second S segment is engineered to carry an arenaviral ORF encoding GP in a position under control of an arenavirus genomic 3′ UTR and the second heterologous ORF in a position under control of an arenavirus genomic 5′ UTR; or (iii) an S segment is engineered to carry both the first and the second heterologous ORFs (claim 7).
Claim 12 is drawn to a method for treating or preventing a neoplastic disease or an infectious disease in a subject in need thereof, wherein the method comprises administering to the subject a first and a second arenavirus particles, wherein
(a) the first arenavirus particle comprises a first arenavirus genome comprising: a first heterologous ORF encoding an antigen; and (i) at least one first arenavirus ORF of the first arenavirus genome is either functionally inactivated or deleted, or (ii) at least one first arenavirus ORF is located in a position other than the wild-type position of said at least one first arenavirus ORF, or (iii) a fragment of at least one first arenavirus ORF is located in a position other than the wild-type position of said fragment of the at least one first arenavirus ORF; and
(b) the second arenavirus particle comprises a second arenavirus genome comprising: a second heterologous ORF encoding an immune checkpoint modulator or a cytokine, optionally wherein the cytokine is IL-12; and (i) at least one second arenavirus ORF of the second arenavirus genome is either functionally inactivated or deleted, or (ii) at least one second arenavirus ORF is located in a position other than the wild-type position of said at least one second arenavirus ORF, or (iii) a fragment of at least one second arenavirus ORF is located in a position other than the wild-type position of said fragment of the at least one second arenavirus ORF;
optionally wherein the method further comprises administering an additional immune checkpoint modulator that is different from the immune checkpoint modulator.
Further limitations on the method of claim 12 are wherein the first arenavirus particle, the second arenavirus particle, or both the first and second arenavirus particles are tri-segmented and replication-competent and comprise one L segment and two S segments, wherein one of the two S segments is selected from the group consisting of:
(a) an S segment, wherein the ORF encoding the NP is under control of an arenavirus genomic 5′ UTR;
(b) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 5′ UTR;
(c) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 5′ UTR;
(d) an S segment, wherein the ORF encoding the GP is under control of an arenavirus genomic 3′ UTR;
(e) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 3′ UTR; and
(f) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 3′ UTR (claim 13); wherein the first and/or the second arenavirus particles are administered via intravenous injection or via intratumoral injection (claim 14); wherein the at least one first arenavirus ORF encodes the glycoprotein (GP), the nucleoprotein (NP), the matrix protein Z (Z protein) or the RNA dependent RNA polymerase L (L protein) of the first arenavirus particle; and/or the at least one second arenavirus ORF encodes the glycoprotein (GP), the nucleoprotein (NP), the matrix protein Z (Z protein) or the RNA dependent RNA polymerase L (L protein) of the second arenavirus particle (claim 15); wherein the at least one first arenavirus ORF is either functionally inactivated or deleted and wherein the first arenavirus particle has the ability to amplify and express its genetic information in cells infected with the first arenavirus particle but is unable to produce further infectious progeny particles in normal, non-complementing cells; and/or wherein the at least one second arenavirus ORF is either functionally inactivated or deleted and wherein the second arenavirus particle has the ability to amplify and express its genetic information in cells infected with the second arenavirus particle but is unable to produce further infectious progeny particles in normal, non-complementing cells (claim 16); and wherein the first arenavirus particle, the second arenavirus particle, or both the first and second arenavirus particles are derived from lymphocytic choriomeningitis virus (LCMV) or Pichinde virus (claim 17).
Claim 18 is drawn to a method for treating or preventing a neoplastic disease or preventing or treating an infectious disease in a subject in need thereof, wherein the method comprises administering to the subject an arenavirus particle; wherein
(a) the arenavirus particle comprises an arenavirus genome comprising a heterologous ORF encoding:
(i) a cytokine, optionally the cytokine is IL-12, or
(ii) an immune checkpoint modulator, optionally the immune checkpoint modulator is a ligand of 4-1BB; and
(b)
(i) at least one arenavirus ORF of the arenavirus genome is either functionally inactivated or deleted, or
(ii) at least one arenavirus ORF is located in a position other than the wild-type position of said at least one arenavirus ORF, or (iii) a fragment of at least one arenavirus ORF is located in a position other than the wild-type position of said fragment of the at least one arenavirus ORF;
optionally wherein the method further comprises administering an additional immune checkpoint modulator that is different from the immune checkpoint modulator.
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 1-10, 12-18, 20-21, and 24 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 certain exemplified murine oncology embodiments using LCMV- or Pichinde-based arenavirus vectors in combination with particular 4-1BB, OX40, NKG2A, IL-12, or IL-2 interventions, does not reasonably provide enablement for the substantially broader claimed scope of treatment or prevention across broad classes of neoplastic and infectious diseases using altered arenavirus particles together with immune checkpoint modulators or cytokines that are defined largely by biological function, and further encompass materially different ways of delivering those immunomodulators. 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 or 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 methods of treating or preventing neoplastic or infectious disease using an altered arenavirus particle in conjunction with an immune checkpoint modulator and/or cytokine. Depending on the claim, the antigen and immunomodulator may be delivered separately, encoded by the same arenavirus particle, divided between separate arenavirus particles, or the arenavirus particle may encode the cytokine or immune checkpoint modulator without requiring a disease antigen (¶[0640-0642][0713-0715][0858-0860][0871-0873]).
The specification provides fifteen oncology directed working examples. Examples 1-5 evaluate tumor-antigen arenavirus vectors with 4-1BB, CD40, and OX40 stimulation; Examples 6-8 evaluate vector-encoded IL-12 or 4-1BBL; and Examples 9-14 further examine NKG2A modulation, 4-1BB agonism, IL-12 expression, administration route, and dose in murine tumor models. Example 15 evaluates an artLCMV-E7E6 vector with an IL-2/anti-IL-2 immune complex in the TC-1 tumor model (¶[0995-1057]). These experiments provide meaningful support for a limited group of cancer-treatment embodiments. The tested tumor antigens principally include GP70, TRP2, and HPV E7/E6, with GFP also used as a control, and the experimental checkpoint or cytokine interventions are concentrated around 4-1BB, OX40, NKG2A, IL-12, and one particular IL-2 immune-complex approach. The examples do not establish that the same results extend throughout the materially broader genera recited in the claims.
The specification itself describes that broader scope, in that the immune checkpoint discussion encompasses agonism of numerous costimulatory pathways and antagonism of numerous coinhibitory pathways, and further permits antibodies, fragments, multispecific molecules, ligands, aptamers, and variants (¶[0853-0869]). The cytokine disclosure extends beyond IL-2 and IL-12 to interleukins generally, interferons, tumor necrosis factors, lymphokines, monokines, and variants or complexes thereof (¶[0870-0873]). The disease scope is similarly broad, as the neoplastic disease disclosure reaches many biologically distinct malignancies and tumor antigens (¶[0728-0732]). More significantly, the infectious disease breadth encompasses acute and chronic infections caused by bacteria, viruses, fungi, parasites, helminths, and protists, with numerous unrelated diseases and pathogens expressly contemplated (¶[0745-0748]). No infectious-disease working example is provided.
The narrower dependent claims do not cure this problem. Claims directed to particular IL-2 embodiments retain the broader disease scope and are supported experimentally by only the particular IL-2 immune complex embodiment of Example 15. Limitations directed to tri-segmented vectors, routes of administration, particular altered viral ORFs, or LCMV/Pichinde species narrow the vector in certain respects, but do not supply enablement for the remaining breadth of disease, antigen, cytokine, and checkpoint-modulator combinations. Likewise, narrowing a checkpoint modulator to 4-1BB, OX40, or NKG2A does not establish that modulation of that pathway will provide the claimed therapeutic method throughout the full range of neoplastic and infectious diseases encompassed by the claim.
Claims 12-17 present an additional problem, as these claims require the antigen and the immune checkpoint modulator or cytokine to be divided between a first and second altered arenavirus particle. Although the specification describes this arrangement conceptually, see ¶[0858][0871-0872], the working examples do not demonstrate the claimed split-payload treatment in which one arenavirus particle provides the antigen and a second arenavirus particle provides the checkpoint modulator or cytokine. The optional limitations added to the independent claims do not materially reduce this breadth. For example, recitation that an additional, different immune checkpoint modulator may optionally be administered does not require that additional treatment. Similarly, the further optional recitation of an LCMV- or Pichinde-derived particle in claims 1 and 5 does not confine those claims to LCMV or Pichinde virus. The optional efficacy or immunological result language added to instant claims 21 and 24 likewise does not require those results in every claimed embodiment and therefore does not resolve the underlying full-scope enablement problem.
State of the prior art and predictability of the art. At the time of filing, arenavirus vectors were known to be useful platforms for inducing antigen-specific T-cell responses, but their behavior was not independent of vector selection and treatment design. Bonilla et. al. (Bonilla WV, et. al. Cell Rep Med. 2021 Mar 3;2(3):100209.), reported that the magnitude of the tumor-directed CTL response “requires combining two genealogically distantly related arenaviruses.” The authors further reported that immunodominance can favor responses against the viral vector backbone at the expense of self-antigen-directed CTLs, showing that changing the vector context can materially alter the immune response rather than merely provide an interchangeable delivery vehicle.
The infectious disease checkpoint literature likewise did not establish a generally predictable relationship between checkpoint modulation and therapeutic benefit across infections. Attanasio et. al. (Attanasio J, et. al. Immunity. 2016 May 17;44(5):1052-68.), explained that these pathways regulate immune responses differently in “acute and chronic infections” and reviewed distinct effects resulting from manipulation of individual pathways. Their discussion reflects that checkpoint signaling occurs in the context of pathogen persistence, antigen exposure, T-cell differentiation, tissue environment, and exhaustion, rather than functioning as a uniform therapeutic switch that can be predictably transferred from a cancer model to an unrelated infection.
The cytokine art also demonstrated substantial context dependence. Lasek et. al.(Lasek W, et. al. Cancer Immunol Immunother. 2014 May;63(5):419-35. Epub 2014 Feb 11.) explained that encouraging animal studies were followed by “very modest antitumor effects” in early clinical trials that were often associated with unacceptable adverse events. The review discusses efforts to alter route, localization, and delivery format to obtain useful IL-12 activity, including gene therapy, local delivery, vaccines, and tumor-targeted immunocytokines. Accordingly, knowledge that IL-12 could stimulate an antitumor immune response did not make the therapeutic performance of a different IL-12 delivery system, dose, disease setting, or immune context predictable.
Even within a single checkpoint pathway, different therapeutic molecules did not behave equivalently. Chester et. al.(Chester C, et. al. Blood. 2018 Jan 4;131(1):49-57. Epub 2017 Nov 8.), reported that clinical development of urelumab was limited by dose-dependent inflammatory liver toxicity, whereas utomilumab had a “superior safety profile, but is a less potent 4-1BB agonist.” The authors attributed differences between these agents to characteristics including intrinsic agonistic activity, antibody subclass, Fc-receptor interactions, epitope selection, and interference with endogenous ligand binding. Thus, even where the checkpoint target itself was fixed, selection of a particular molecule and administration regimen remained material to whether useful immune activation could be obtained at an acceptable exposure.
The prior art therefore does not provide the missing predictability. Rather, it confirms that immune responses to arenavirus vectors, checkpoint modulation, and cytokine therapy can change with vector backbone, molecular format, disease environment, administration route, dose, and timing. The art was not sufficiently predictable to support extrapolation from the limited murine tumor embodiments of ¶[0996-1057] to the full claimed scope, particularly the broad infectious-disease embodiments and the untested checkpoint, cytokine, and split-vector combinations. The unpredictability is also reflected in the applicant's own data. For example, the specification reports unexpected results when comparing intratumoral IL-12-expressing arenavirus vectors carrying the tumor antigen with an IL-12 vector carrying an irrelevant GFP antigen (¶[1021-1024][1048-1051]). Dose and route also affected immune responses, antitumor activity, and body-weight changes in the IL-12 experiments (¶[1048-1053]). These results do not negate enablement of the tested embodiments, but they weigh against assuming that an untested immunomodulator, vector arrangement, disease, and dose would predictably provide a useful treatment simply because another combination worked.
Accordingly, the results obtained using the disclosed tumor models 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 preparation and propagation of arenavirus vectors, recombinant nucleic-acid techniques, tumor and infectious-disease models, flow cytometry, antigen-specific T-cell assays, cytokine measurements, and standard methods for evaluating immune modulating antibodies, as the level of skill in this field was rather substantial. That substantial level of skill would guide a researcher to construct additional vectors and test candidate combinations; however, it would not tell the researcher in advance which additional cytokines or checkpoint modulators would remain active when expressed from a particular arenavirus configuration, which separately administered combinations would produce a therapeutically useful response, or which interventions would be effective rather than ineffective or detrimental in a particular acute or chronic infection. The existence of techniques capable of answering those questions experimentally is not the same as having an enabling teaching that supplies the answers.
Working examples. The specification provides fifteen working examples directed to oncology-related embodiments (¶[0995-1057]). These examples employ a relatively small number of antigens and tumor models and principally test 4-1BB, OX40, NKG2A, IL-12, and an IL-2 immune-complex intervention. No working example is directed to treatment or prevention of any infectious disease of any etiology. There is no working example involving a bacterial, fungal, parasitic, or other non-viral infection, and no working example showing that checkpoint or cytokine modulation by the claimed arenavirus methods is therapeutic in either an acute or chronic viral infection. The specification at ¶[0745-0748] discusses the substantially broader infectious disease scope contemplated. The examples also do not test most of the checkpoint pathways and cytokine classes identified at ¶[0853-0873], nor do they provide a working example of the particular two-particle, split-payload arrangement required by claims 12-17. The disclosed examples therefore do not establish enablement across the full scope of claims 1-10, 12-18, 20-21, and 24.
Guidance in the specification. The specification provides substantial descriptive guidance regarding arenavirus construction and identifies candidate tumor antigens, pathogen antigens, checkpoint targets, cytokines, routes, and treatment arrangements (¶[0728-0748][0853-0873]). It also provides detailed protocols for the particular tumor experiments in Examples 1-15. The specification does not, however, provide a general rule that permits one skilled in the art to determine which combinations within the much larger claimed genera will provide a therapeutic or prophylactic effect. Naming a checkpoint pathway or cytokine does not explain whether stimulation of that pathway will enhance immunity in a particular disease, whether the same intervention should instead be avoided because of the existing immune state, or how the result changes when the immunomodulator is expressed locally from an arenavirus rather than administered systemically. This deficiency is particularly apparent for infectious disease, as the specification identifies many pathogens and diseases but does not explain which checkpoint pathways or cytokines should be paired with a given pathogen antigen, whether the infection should be acute or persistent when the treatment is used, or how to select a dose and timing that enhances pathogen-directed immunity without causing excessive inflammation or other detrimental immune effects (¶[0745-0748]).
The same problem applies to the broader encoded immunomodulator embodiments, in that the disclosure does not provide sufficient guidance to predict which antibody fragments, ligands, multispecific checkpoint molecules, cytokine variants, or cytokine complexes can be expressed at a biologically useful level and in an appropriate form from the claimed arenavirus configurations while retaining the activity needed for treatment. For claims 12-17, additional decisions are required because the antigen and immunomodulator reside in separate viral particles, yet no working example establishes how the relative doses, timing, particle backbones, or expression levels should be selected for that arrangement.
Quantity of experimentation necessary. To practice the full scope of claims 1-10, 12-18, 20-21, and 24, one skilled in the art would need to select additional disease antigens, checkpoint modulators or cytokines, and arenavirus configurations; construct or obtain the corresponding treatment components; and then determine experimentally whether the resulting combination provides the claimed treatment or prevention. For many embodiments, the worker would further need to determine an appropriate route, dose, sequence of administration, and expression level before knowing whether the candidate combination produces useful immunity rather than insufficient activity or unacceptable immune stimulation. For the infectious-disease embodiments, this is not simply routine confirmation of combinations already taught to work. The skilled worker would have to screen combinations across biologically different pathogens and immune settings to determine whether the selected checkpoint or cytokine intervention enhances clearance, has little effect, or interferes with the immune response. The specification supplies no working infectious-disease embodiment from which those selections can be predictably extrapolated.
For claims 12-17, one skilled in the art would additionally need to establish whether two independently administered arenavirus populations provide compatible antigen and immunomodulator expression at the relevant place and time and then optimize their relative administration. The specification describes that architecture but does not demonstrate it experimentally. 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 actually provide treatment or prevention across the claimed scope. Although the individual methods used to construct vectors, administer immunotherapies, and measure immune or disease responses were known, the relevant inquiry is not whether one skilled in the art could perform those experiments; instead, 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.
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 particular murine tumor-antigen vaccines combined with selected 4-1BB, OX40, NKG2A, IL-12, and IL-2 interventions, and it demonstrates particular same vector cytokine or checkpoint ligand embodiments. The claims, however, extend to far broader checkpoint and cytokine genera, numerous untested neoplastic settings, a wide range of acute and chronic infectious diseases, and multiple materially different arrangements for providing the antigen and immunomodulator. The specification does not identify a general quality or provide sufficient guidance that would permit one skilled in the art to move from the demonstrated species to that broader claimed scope without determining experimentally which combinations work. The disclosure instead provides examples that must be expanded through further selection, construction, screening, and optimization before the operative members of the broader claimed classes can be identified.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to use the full scope of the invention recited in claims 1-10, 12-18, 20-21, and 24 without undue experimentation.
Claims 1-10, 12-18, 20, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 1-10, 12-18, 20, and 24 encompass methods for treating or preventing an infectious disease using an altered arenavirus particle in combination with, or encoding, an immune checkpoint modulator or cytokine. Depending on the claim, an antigen and the immune-modulating agent may be provided separately, encoded by the same arenavirus particle, or encoded by different arenavirus particles. Claim 18 is broader in this respect because it does not require the arenavirus particle to encode a pathogen antigen.
The specification expressly contemplates treatment and prevention of infectious disease. The specification at ¶[0724] states generally that the disclosed methods may be used for treating or preventing an infectious disease, and ¶[0725] directs the reader to Sections 5.2, 5.4-5.12 for the contemplated diseases, vectors, checkpoint modulators, cytokines, methods of use, and assays. At ¶[0726] it likewise describes an arenavirus particle encoding an immune checkpoint modulator or cytokine. The infectious-disease disclosure begins at ¶[0745], and the specification states that infectious disease can include an acute or chronic infection and broadly encompasses disease caused by any bacteria, viruses, fungi, parasites, helminths, or protists. The specification then identifies a very large number of unrelated pathogens and infectious diseases (¶[0746-0747]). At ¶[0748], the specification states generally that the antigen encoded by the arenavirus particle may be associated with or specific to one of the listed infectious diseases.
The specification further characterizes a pathogen antigen principally by its desired immunologic property. For example, the disclosure describes the antigen as an immunogenic protein expressed in, on, or by the pathogen and describes an antigenic fragment in terms of its ability to elicit an antibody response and/or a specific T-cell response (¶[0748-0752]). The disclosure therefore identifies a broad desired class of pathogen antigens, but does not identify a representative set of pathogen-antigen/checkpoint-modulator or pathogen-antigen/cytokine combinations that were possessed as methods for treating or preventing the claimed infectious diseases. The checkpoint-modulator disclosure is similar in its description by its desired immunologic property. At ¶[0853], the specification defines an immune checkpoint modulator as an agonist of a costimulatory pathway or an antagonist of a coinhibitory pathway, while ¶[0854-0856] extend this definition across numerous unrelated receptor systems and molecular formats. The disclosure thereafter identifies particular 4-1BB and OX40 agonists among many other agents (¶[0866-0869]).
The cytokine disclosure likewise states that the cytokines include interleukins, interferons, tumor necrosis factors, lymphokines, and monokines, and identifies selected species including IL-2, IL-7, IL-12, IL-15, IL-21, IL-33, and variants thereof (¶[0870]). The specification describes several possible ways in which such cytokines may be encoded or administered, including expression with an antigen from the same arenavirus particle, expression from different arenavirus particles, separate administration, IL-2/antibody complexes, IL-2 fusion proteins, and modified IL-2 molecules (¶[0871-0876). These passages show that the Applicants contemplated infectious disease treatment and contemplated many checkpoint and cytokine agents; they do not, however, reasonably convey possession of the full therapeutic combinations now encompassed by the claims. The disclosure does not describe any particular bacterial, fungal, parasitic, or viral infection treated by one of the claimed checkpoint/cytokine combinations. It does not identify a representative set of pathogen antigens paired with checkpoint pathways or cytokines for treatment of those infections, nor does it provide identifying characteristics from which one skilled in the art could recognize which combinations belong to the claimed genus of methods for treating or preventing infectious disease.
The deficiency is not simply that every claimed species was not tested; rather, the disclosure moves from lists of possible diseases, antigens, checkpoint pathways, and cytokines to the asserted therapeutic genus without describing representative infectious-disease combinations showing possession of that genus. The identification of possible ingredients for later combination does not itself demonstrate possession of methods for treating or preventing the broad range of infectious diseases recited by the claims. This distinction is reinforced by the working disclosure. The specification (¶[0995]) introduces the examples as demonstrating enhancement of the immunogenicity and anti-tumoral efficacy of arenaviral vector treatment by concurrent immune stimulation. Examples 1-15 are directed to oncology models (¶[0995-1057]). For example, the disclosure evaluates arenavirus vectors encoding tumor antigens with 4-1BB or CD40 agonism, vector-encoded 4-1BBL, OX40-related treatment, NKG2A modulation, vector-encoded IL-12, and an IL-2/anti-IL-2 immune complex. The final example reports treatment of the TC-1 tumor model with an artLCMV-E7E6 vector and an IL-2 immune complex (¶[1054-1057]).
These examples reasonably convey possession of certain specific cancer-immunotherapy combinations, but they do not provide representative species of the separately claimed infectious disease genus. No example describes administration of a arenavirus vector encoding a pathogenic antigen (or an antigen from an oncogenic virus) with an immune checkpoint modulator or cytokine to treat or prevent infection. No example describes an arenavirus encoding both a pathogen antigen and an immune checkpoint modulator or cytokine for any infectious disease. Finally, the examples do not describe a first arenavirus encoding a pathogen antigen together with a second arenavirus encoding an immune checkpoint modulator or cytokine for treatment of infection.
Claims 1-4 and 8-10 encompass the infectious disease embodiment in which an antigen-encoding arenavirus particle is administered with an immune checkpoint modulator and/or cytokine. The additional limitations of claims 2-4 and 8-10 do not cure the deficiency because these claims continue to encompass treatment or prevention of infectious disease without identifying a supported pathogen-antigen/immune-modulator treatment combination. Limiting the cytokine to an IL-2-related composition, specifying a particular arenavirus architecture, specifying a route of administration, or further defining an altered arenavirus ORF does not provide written-description support for the therapeutic infectious-disease genus incorporated from claim 1. Claims 5-7 similarly encompass treatment or prevention of infectious disease using an arenavirus particle having a first heterologous ORF encoding an antigen and a second heterologous ORF encoding an immune checkpoint modulator or cytokine. The specification describes the general possibility that these components may be encoded by the same particle (¶[0858][0871]). However, the infectious disease portion of these claims is not limited to a disclosed pathogen antigen, a disclosed infectious disease, or a representative antigen/immunomodulator pairing. The specification does not describe representative infectious-disease species across this claimed therapeutic genus.
Claims 12-17 encompass the further arrangement in which a first arenavirus particle encodes the antigen and a second arenavirus particle encodes the immune checkpoint modulator or cytokine. While the specification expressly states that these components may be expressed on different arenavirus particles (¶[0858][0871), the written-description issue is not the mere recitation of two particles. Rather, the claims use that broadly described delivery arrangement to encompass treatment or prevention of any infectious disease in a general manner without describing any representative pathogen-antigen/immune-modulator combinations that demonstrate actual possession of the claimed therapeutic genus. The additional vector architecture, route, ORF, replication, and LCMV/Pichinde limitations of claims 13-17 do not cure this deficiency.
Claim 18 is particularly broad with respect to the infectious disease subject matter because the claim requires an arenavirus particle encoding an immune checkpoint modulator or cytokine but does not require that the administered particle actually encode an antigen of the infectious agent. The specification describes the general concept of an arenavirus encoding a checkpoint modulator or cytokine (¶[0726][0858][0871]); however, the disclosure does not describe a representative infectious disease treatment in which such an immunomodulator-expressing arenavirus particle, that lacks a pathogen antigen, somehow treats or prevents infection. The disclosure of the desired treatment context together with a list of candidate immunomodulators does not reasonably convey possession of this full therapeutic genus. Claim 20, as amended to depend from claim 1, does not cure the deficiency by identifying 4-1BB, OX40, or NKG2A modulation. The specification describes these checkpoint pathways in substantial detail and demonstrates selected oncology embodiments involving these pathways (¶[0854-0869][0995-1053]). However, the specification does not describe a representative infectious disease embodiment employing 4-1BB, OX40, or NKG2A modulation with a pathogen-antigen arenavirus vector. The claim therefore continues to encompass unsupported infectious disease treatment methods. Claim 24 expressly limits the method to preventing or treating infectious disease and the antigen to an antigen of the causative pathogen or an antigenic fragment thereof. This limitation continues to place the claim within the unsupported disclosure discussed supra. The optional immunologic, efficacy, or survival limitations added to claim 24 do not require those features in every embodiment and therefore do not cure the lack of written-description support for the underlying infectious-disease treatment genus.
The optional limitations added to claims 1, 5, 12, and 18 likewise do not resolve the deficiency. Optionally administering another immune checkpoint modulator does not identify a representative infectious disease treatment combination. The further optional recitation in claims 1 and 5 that the arenavirus may be derived from LCMV or Pichinde virus also does not limit every embodiment to those vector species and does not supply the missing description of a representative pathogen-antigen/immune-modulator therapeutic combination.
The specification therefore provides a detailed description of numerous contemplated components and delivery arrangements, but it does not describe a representative number of infectious disease treatment species or other identifying characteristics sufficient to show possession of the full claimed therapeutic genus. One skilled in the art would have to select a pathogen and corresponding antigen, select a checkpoint pathway or cytokine intervention, choose the claimed delivery arrangement, and then determine whether that previously undescribed combination constitutes a method for treating or preventing the infection. The specification does not reasonably convey that the inventors had possession of that substantially broader collection of therapeutic methods at the time of filing.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventors had possession of the full scope of the subject matter recited in claims 1-10, 12-18, 20, and 24 at the time the application was filed. The dependent claims identified above do not cure the deficiency because they continue to encompass the unsupported infectious-disease scope inherited from claims 1, 5, or 12.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-10, 12-18, 21, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schmidt et. al. (US20180344830A1, Pub. 12/06/2018; hereafter “Schmidt”.)
The Prior Art
Schmidt teaches a method for treating a neoplastic disease in a subject comprising, administering to a subject in need thereof an arenavirus particle and an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising:
(i) a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and
(ii) at least one arenavirus open reading frame (ORF) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (GP), the nucleoprotein (NP), the matrix protein Z (Z protein) or the RNA dependent RNA polymerase L (L protein) of said arenavirus particle (reference claim 1; ¶[0089]; instant claims 1, 5). Schmidt teaches the methods may include delivery of one or more arenavirus particles expressing a heterologous antigen, wherein the heterologous antigens between particles may be different (¶[0349][0370][0372]; instant claims 12, 18). Schmidt teaches wherein the arenavirus particle is tri-segmented and replication-competent and comprises one L segment and two S segments, wherein one of the two S segments is selected from the group consisting of:
a) an S segment, wherein the ORF encoding the NP is under control of an arenavirus genomic 5′ UTR;
b) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 5′ UTR;
c) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 5′ UTR;
d) an S segment, wherein the ORF encoding the GP is under control of an arenavirus genomic 3′ UTR;
e) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus genomic 3′ UTR; and
f) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus genomic 3′ UTR (reference claim 13; Fig. 1; ¶[0251][0349][0370][0372]; instant claims 4, 6, 9, 13, 15). Schmidt teaches that one to four ORFs encoding GP, NP, Z, and L may be replaced with heterologous ORFs (¶[0126]). Figure 1 of Schmidt shows a trisegmented genome wherein green fluorescent protein (GFP) has replaced two ORFs of the arenavirus (Fig. 1-ii; instant claim 7). Schmidt teaches that the arenavirus compositions may be administered via intravenous injections (¶[0382-0383]; instant claims 8, 14). Schmidt teaches the arenavirus comprises at least one functionally inactivated or deleted ORF (reference claims 19-21), and wherein the cells are only able to generate further infectious progeny on complementing cells (reference claim 53; instant claims 10, 16). Schmidt teaches the arenaviruses or segments thereof may be from Pichinde virus or Lymphocytic choriomeningitis virus (LCMV)(¶[0133][0203][0216]; instant claim 17). Schmidt teaches that viral antigens which are from oncogenic viruses may be delivered as the heterologous antigen, such as human papillomavirus (HPV) E6/E7 or antigens from human T-lymphotropic virus (HTLV), Epstein-Barr virus (EBV), or Kaposi’s sarcoma associated herpesvirus (KSHV)(¶[0232-0233]; instant claims 21, 24).
For at least these reasons, Schmidt teaches the limitations of instant claims 1, 4-10, 12-18, 21, and 24, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Schmidt as applied to claims 1, 4-10, 12-18, 21, and 24 above, and further in view of Mostbock et. al. (Mostböck S, et. al. J Immunol. 2008 Apr 1;180(7):5118-29.; hereafter “Mostbock”.)
The Prior Art
The teachings of Schmidt have been set forth supra. Schmidt teaches the altered arenavirus as a viral antigen vaccine and is expressly concerned with augmenting antigen specific antitumor immunity. While Schmidt teaches that the arenavirus may be engineered to additionally encode an immune checkpoint modulator, Schmidt fails to specifically teach that a cytokine may be administered by the virus, or an antibody which specifically binds to said cytokine, especially wherein said cytokine is IL-2. However, the addition of IL-2, anti-IL-2 antibodies, or IL-2/IL-2 antibody complexes to viral vaccines was suggested in the art, as taught by Mostbock.
Mostbock teaches IL-2 is well described as a cytokine with two markedly distinct functionalities: as a necessary signal during CD4 and CD8 T cell activation/expansion and as an essential cytokine for the maintenance of CD4 CD25 FoxP3 T cells (regulatory T (TREG ) cells) during homeostasis (entire document; see abstract.) Mostbock teaches adding IL-2/anti-IL-2 complexes to a viral vaccine enhances the vaccine effectiveness and expands antigen specific effector/memory CD8+ T cells (entire document; see abstract.) Mostbock teaches that the treatment with IL-2 or anti-IL-2 alone led to some effects on the immune system, but they were much weaker than combining IL-2 with anti-IL-2 and, when either was used alone, there was an unwanted increase of Treg cell percentages in the spleen (“Discussion”, p. 5128.)
Given the teachings of Schmidt, one of skill in the art would be motivated to deliver anti-cancer agents or tumor-associated antigens using an arenavirus. Given the teachings of Mostbock, one of skill in the art would be aware that co-delivery of IL-2 along with an anti-IL-2 antibody would enhance an immune response to virally-delivered immunogens. Therefore, given the teachings of Schmidt and Mostbock, a skilled artisan would find it obvious to arrive at the limitations of instant claim 2.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Schmidt in order to deliver IL-2 and anti-IL-2 along with the modified arenavirus vector, thereby enhancing the immune response to the antigens delivered by said viral vector. One would have been motivated to do so, given the suggestion by Mostbock that the IL-2/anti-IL-2 complex elicited a stronger and more appropriate immune response to the viral vector-delivered antigen than either element alone. There would have been a reasonable expectation of success, given the knowledge that arenavirus-based vectors could deliver tumor-specific antigens and generate an immune response against tumors in a host, as taught by Schmidt. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Schmidt as applied to claims 1, 4-10, 12-18, 21, and 24 above, and further in view of Letvin et. al. (WO1999016466A2.; Pub. 04/08/1999; hereafter “Letvin”).
The Prior Art
The teachings of Schmidt have been set forth supra. While Schmidt teaches that the arenavirus vector may encode an immune checkpoint modulator, or an immune checkpoint modulator may be co-delivered with the vector, Schmidt fails to teach that a cytokine may be co-delivered with the vector or may be encoded by the vector, such as an IL-2 related cytokine or IL-2/Ig fusion protein. However, co-delivery of a IL-2-related cytokine, namely an IL-2/Ig fusion protein, with a viral vector was taught in the art, as evidenced by the teachings of Letvin.
Letvin teaches a vaccine composition comprising: a) a vaccine, and b) a timed-release formulation of a cytokine or cytokine/Ig fusion protein or plasmid wherein the formulation or device releases the cytokine protein or plasmid at one or more temporal points subsequent to vaccine administration (reference claim 1). Letvin teaches that the cytokine/Ig fusion protein may be IL-2/Ig fusion protein (reference claims 7, 9), and the vaccine is a viral vector vaccine (reference claim 8). Letvin teaches the vaccines may be used to treat cancer (p. 3, ¶1-¶3), and the immunological enhancement observed with these fusion protein compositions includes an increased antibody response, an increased cellular proliferative response, and/or an enhancement in CTL levels (p. 3, ¶1).
Given the teachings of Schmidt, one of skill in the art would be motivated to deliver anti-cancer agents or tumor-associated antigens using an arenavirus. Given the teachings of Letvin, one of skill in the art would be aware that co-delivery of IL-2/Ig fusion proteins along with a vectored vaccine would enhance an immune response to virally-delivered immunogens, and would be useful in the treatment of cancer. Therefore, given the teachings of Schmidt and Letvin, a skilled artisan would find it obvious to arrive at the limitations of instant claim 3.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Schmidt in order to deliver IL-2/Ig fusion proteins along with the modified arenavirus vector, thereby enhancing the immune response to the antigens delivered by said viral vector. One would have been motivated to do so, given the suggestion by Letvin that the IL-2/Ig fusion proteins elicited a stronger and more appropriate immune response to the viral vector-delivered antigen than IL-2 alone. There would have been a reasonable expectation of success, given the knowledge that arenavirus-based vectors could deliver tumor-specific antigens and generate an immune response against tumors in a host, as taught by Schmidt. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Schmidt as applied to claims 1, 4-10, 12-18, 21, and 24 above, and further in view of Mulder et. al. (US20180140670A1, Pub. 05/24/2018; hereafter “Mulder”.)
The Prior Art
The teachings of Schmidt have been set forth supra. While Schmidt teaches that viral cancer related antigens, such as E6/E7, may be delivered in the arenavirus vectors, and teaches that said vectors may be co-delivered with immune checkpoint modulators, Schmidt is silent of the codelivery of an immune checkpoint modulator being an agonist of 4-1bb costimulatory pathway, an agonist of OX40 costimulatory pathway, an antagonist of NKG2A coinhibitory pathway, or a combination thereof. However, the codelivery of such a modulator would be obvious to a skilled artisan, given the teachings of Mulder.
Mulder teaches vaccine compositions comprising peptides derived from HPV E6 and E7, including HPV16 E6 and E7 peptides (reference claim 1, ¶[0174-0182]). Mulder further teaches administering 4-1BB (CD137) and/or CD40 ligands, agonistic antibodies, OX40 ligands, or compounds having similar agonistic activity separately or in combination with the vaccine peptides in order to further stimulate the mounting of an optimal immune response (¶[0023][0056][0105][0158][0233][0431]; reference claim 1).
Given the teachings of Schmidt, one of skill in the art would be motivated to deliver anti-cancer agents or tumor-associated antigens using an arenavirus. Given the teachings of Mulder, one of skill in the art would be aware that co-delivery of CD137 agonists or OX40 agonists along with a vectored vaccine would enhance an immune response to virally-delivered immunogens, such as E6/E7, and would be useful in the treatment of cancer. Therefore, given the teachings of Schmidt and Mulder, a skilled artisan would find it obvious to arrive at the limitations of instant claim 20.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Schmidt in order to deliver a 4-1BB agonist or OX40 agonist as taught by Mulder along with the modified arenavirus vector, thereby enhancing the immune response to the antigens delivered by said viral vector. One would have been motivated to do so, given the suggestion by Mulder that identified the HPV E6/E7 derived antigens as vaccine antigens for which costimulatory agents may be used, and would have been directly related to the embodiments of Schmidt which taught delivery of HPV E6/E7 antigens. There would have been a reasonable expectation that augmenting 4-1BB or OX40 costimulatory signaling would enhance the T cell response against the arenavirus-delivered antigen. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4-10, 12-18, 21, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,266,727 in view of Schmidt et. al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming methods for treating a neoplastic disease in a subject comprising, administering to a subject in need thereof an arenavirus particle and an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising: a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and (ii) at least one arenavirus open reading frame (“ORF”) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (“GP”), the nucleoprotein (“NP”), the matrix protein Z (“Z protein”) or the RNA dependent RNA polymerase L (“L protein”) of said arenavirus particle. While the instant claims do not specify that the tumor antigen is HPV E6 and/or E7, such a modification would be obvious given the teachings of Schmidt (detailed supra). Both claim the arenavirus particle and said immune checkpoint inhibitor can be co-administered, with the administration intervals being routine to optimize, as taught by Schmidt (¶[0369]), rendering the simultaneous/prior/after limitations of the ‘727 claims obvious over the instant claims. Both claim the same arrangement of arenavirus segments, proteins, and 3’/5’ UTRs. Both claim the arenavirus is derived from LCMV, such as the MP strain, WE strain, Armstrong strain, or Armstrong Clone 13 strain taught by Schmidt (Schmidt claim 40). Both claim the use of immune checkpoint modulators, and the use of inhibitors of PD-1 or PD-L1 would be obvious given the teachings of Schmidt (¶[0061] of Schmidt, teaching PD-1 and PD-L1 inhibitors co-administered with the arenavirus). Given the similarities between the claims and the differences being obvious variants, as shown by the teachings of Schmidt, the instant claims and the ‘727 claims are not patentably distinct.
Claims 1, 4-10, 12-18, 21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 6, 12, 24, 28, 35, and 43-44 of copending Application No. 17/928,098 in view of Schmidt et. al. (US20180344830A1, Pub. 12/06/2018;hereafter “Schmidt”).
Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming methods for treating a neoplastic disease in a subject comprising, administering to a subject in need thereof an arenavirus particle and an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising: a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof. While the instant claims do not specify that the tumor antigen is HPV E6 and/or E7, and the ‘098 claims do not provide the specific constructs of the arenavirus segments, such modifications would be obvious optimizations, especially given the teachings of Schmidt (detailed supra). Both claim the arenavirus particle and said immune checkpoint inhibitor can be co-administered, with the administration intervals being routine to optimize, as taught by Schmidt (¶[0369]), rendering the simultaneous/prior/after limitations of the ‘098 claims obvious over the instant claims. Both claim the arenavirus is derived from LCMV, such as the MP strain, WE strain, Armstrong strain, or Armstrong Clone 13 strain taught by Schmidt (Schmidt claim 40). Both claim the use of immune checkpoint modulators, and the use of inhibitors of PD-1 or PD-L1 would be obvious given the teachings of Schmidt (¶[0061] of Schmidt, teaching PD-1 and PD-L1 inhibitors co-administered with the arenavirus). Given the similarities between the claims and the differences being obvious variants, as shown by the teachings of Schmidt, the instant claims and the ‘098 claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-10, 12-18, 21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 15, 21-22, 26, 33, 38-42, 54, 58, 61, and 73 of copending Application No. 18/558,885 in view of Schmidt et. al. (US20180344830A1, Pub. 12/06/2018;hereafter “Schmidt”).
Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming methods for treating a neoplastic disease in a subject comprising, administering to a subject in need thereof an arenavirus particle and an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising: a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and (ii) at least one arenavirus open reading frame (“ORF”) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (“GP”), the nucleoprotein (“NP”), the matrix protein Z (“Z protein”) or the RNA dependent RNA polymerase L (“L protein”) of said arenavirus particle. While the instant claims do not specify that the tumor antigen is HPV E6 and/or E7, such a modification would be obvious given the teachings of Schmidt (detailed supra). Both claim the arenavirus particle and said immune checkpoint inhibitor can be co-administered, with the administration intervals being routine to optimize, as taught by Schmidt (¶[0369]), rendering the simultaneous/prior/after limitations of the ‘885 claims obvious over the instant claims. Both claim the same arrangement of arenavirus segments, proteins, and 3’/5’ UTRs. Both claim the arenavirus is derived from Pichinde virus or LCMV, such as the MP strain, WE strain, Armstrong strain, or Armstrong Clone 13 strain taught by Schmidt (Schmidt claim 40). Both claim the use of immune checkpoint modulators, and the use of inhibitors of PD-1 or PD-L1 would be obvious given the teachings of Schmidt (¶[0061] of Schmidt, teaching PD-1 and PD-L1 inhibitors co-administered with the arenavirus). Given the similarities between the claims and the noted differences being obvious variants, as shown by the teachings of Schmidt, the instant claims and the ‘885 claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-10, 12-18, 21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 72-73, 85-91 of copending Application No. 19/230,758 in view of Schmidt et. al. (US20180344830A1, Pub. 12/06/2018;hereafter “Schmidt”). Both sets of claims are drawn to arenavirus vectors, such as Pichinde virus vectors, comprising similar genomic segments and encoding heterologous antigens. Both claim that said antigens may be tumor associated antigens, and as the instant claims also provide that said vectors may be used to treat infections, this includes oncolytic viruses, such as HPV antigens. Both claim the vector may be delivered in methods to treat infection and/or cancer, and can be delivered via intravenous injection. The main differences are in how the specific viruses are made, such as the use of bi-directional promoters and expressing the viral segments in host cells, but such method would be obvious to the arenavirus art, given the teachings of Schmidt (see e.g. ¶[0117-0122]). Therefore, the differences between the instant claims and the ‘758 copending claims are not patentably distinct, especially in light of the teachings of Schmidt.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-10, 12-18, 21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 20-28, 30-34, 39-51, 56-75, 82-102, 132-180, 190-198, 213-227, and 237-273 of copending Application No. 19/368,913 in view of Schmidt et. al. (US20180344830A1, Pub. 12/06/2018;hereafter “Schmidt”). Both sets of claims are drawn to an arenavirus vector, wherein said vector comprises an arenavirus protein in a non-native position, and a heterologous tumor antigen. While the instant claims do not require the antigen to be an oncogenic viral antigen, such a distinction would be obvious, given that the instant claims provide for methods of treating infectious disease, and given that Schmidt teaches the delivery of oncogenic viral antigens, such as MCV, HTLV, KSHV, HPV, or EBV antigens via arenavirus vectors.
Both sets of claims are drawn to multiple antigens being encoded by the viral vector, both sets of claims are drawn to the same arenavirus segment constructs. Both sets of claims are drawn to methods comprising delivery of two arenavirus particles. Both claim similar immune checkpoint modulators, and while the modulators claimed are different, both those claimed in the instant claims and the reference claims are taught by Schmidt and would be obvious variants of one another. Both sets of claims provide that the vector cannot grow in non-complementing cells. Both claim the arenavirus is derived from such viruses as LCMV.
While the instant claims do not provide specifics on the oncogenic viral antigens or the use of self-cleaving 2A peptides, such differences would be obvious to a skilled artisan, especially in light of the teachings of Schmidt (¶[0243-0244], see 102 rejection supra). The main differences, such as the types of cancers being treated, the administration schedules, or the specific antigens, or the different potential arenaviruses that can be used, are rendered further obvious by the teachings of Schmidt (detailed supra). Given the similarities between the claimed inventions, the differences would be seen as obvious optimizations to a skilled artisan, especially given the teachings of Schmidt, and as such the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-10, 12-18, 21, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-129 of copending Application No. 19/465.861 in view of Schmidt (supra). Both sets of claims are drawn to methods of treating a neoplastic disease in a host, comprising the administration of an arenavirus vector, wherein said vector comprises an arenavirus protein in a non-native position, and a heterologous tumor antigen. As the instant claims are drawn to treatment of both neoplastic and infectious disease, the delivery of oncogenic viral antigens would be an obvious variant, as claimed by the ‘861 application. Both sets of claims are drawn to multiple antigens being encoded by the viral vector, both sets of claims are drawn to the same arenavirus segment constructs. Both sets of claims are drawn to methods comprising delivery of two arenavirus particles. Both claim similar immune checkpoint modulators, such as CD137 or OX40 or agonists thereof. Both sets of claims provide that the vector cannot grow in non-complementing cells. Both claim the arenavirus is derived from such viruses as LCMV. The main differences, such as the types of cancers being treated, the administration schedules, or the specific antigens, or the different potential arenaviruses that can be used, are rendered further obvious by the teachings of Schmidt (detailed supra). Given the similarities between the claimed inventions, the differences would be seen as obvious optimizations to a skilled artisan, especially given the teachings of Schmidt, and as such the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
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.
Ring S, et. al. Methods Mol Biol. 2016;1404:351-364. Teaches how to engineer LCMV to deliver heterologous cargo. Not utilized as would be redundant to rejections set forth supra.
Lieschke GJ, et. al. Nat Biotechnol. 1997;15(1):35–40. Provides motivation to deliver IL-12 for treatment of tumors. Not utilized as rejection would be redundant to those set forth supra.
Nguyen KG, et. al. Front Immunol. 2020 Oct 15;11:575597. Teaches viral vectors engineered to deliver IL-12. Not utilized as rejection would be redundant to those set forth supra.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights