DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the papers filed on 07/23/2026. Claims 26-50 are currently pending as per claims filed on 10/20/2023. Claims 1-25 are cancelled and claims 26-50 are newly added per applicant’s claim amendment filed 10/20/2023. Applicant’s election of Group I, claims 26-47 in the reply filed on 07/23/2026 is acknowledged. Because Applicants did not distinctly and specifically point out supposed errors in the restriction requirement, the election has been treated as an election without traverse. See MPEP § 818.03(a).
Therefore, claims 48-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 26-47 are subject to examination to which the following grounds of rejection are applicable. Claim 26 is an independent claim.
Priority
The instant application is a 371 of PCT/SE2022/050389 filed on 04/21/2022.
The instant application claims benefit of foreign filed application SWEDEN 2150511-0 filed on 04/23/2021
Filing of certified translated copies of the applications SWEDEN 2150511-0 filed on 04/23/2021 is acknowledged.
Thus, the earliest possible priority for the instant application is 04/23/2021.
Claim Interpretation
Claim 1 recites “an adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori ….and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject”. The claims as written do not indicate that the nucleic acid sequences are different or separate sequences. Therefore, the examiner is interpreting that the nucleic acid sequences can be the same sequence and not separate sequences.
Claim Objections
Claim 46 is objected to because abbreviations such as E1B should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 26-47 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 26, and by dependence, claims 27-47 are indefinite in its recitation of “Heliobacter pylori neutrophil-activating protein (NAP)” as it is unclear if the NAP abbreviation corresponds to only being from Heliobacter pylori or NAP can be from a different organism.
Claims 27-33 are vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138.
Claim 26, and by dependence, claims 27-47, recites the term “and/or” in line 2. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only a Helicobacter pylori neutrophil-activating protein, or all of the Helicobacter pylori neutrophil-activating proteins and the immunologically equivalent fragment of NAP, or, “or” would imply that the NAP and immunologically equivalent fragment of NAP are in the alternative. As such the metes and bounds of the claim are indefinite.
Claim 27, by dependence, claims 28-30 and 32, recites the term “and/or” in line 8. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only dendritic cell (DC) maturation or all of a dendritic cell (DC) maturation and T cell activation and NK cell activation, or, “or” would imply that dendritic cell (DC) maturation, T cell activation and NK cell activation are each in the alternative. As such the metes and bounds of the claim are indefinite.
Claim 30, and by dependence claim 31, recites the term “and/or” in line 5. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include CD4+ T cell activation and CD8+ T cell activation, or, “or” would imply that CD4+ T cell activation and CD8+ T cell activation are in the alternative. As such the metes and bounds of the claim are indefinite.
Claim 31 recites the term “and/or” in line 7. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include CD4+ T cells and CD8+ T cells to express cluster of differentiation 69 (CD69) and CD107a., or, “or” would imply that CD4+ T cells and CD8+ T cells to express cluster of differentiation 69 (CD69) and CD107a are in the alternative. As such the metes and bounds of the claim are indefinite.
Claim 40, and by dependence claim 41, recites the term “and/or” in line 12. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only a self-cleaving peptide positioned between the nucleic acid sequence encoding NAP and the immunologically equivalent fragment of NAP, or, “or” would imply that the self-cleaving peptide positioned between the nucleic acid sequence encoding NAP the immunologically equivalent fragment of NAP are in the alternative. As such the metes and bounds of the claim are indefinite.
Claim 46 recites the term “and/or” in line 10. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include the nucleic acid sequence encoding NAP and the nucleic acid sequence encoding the immunologically equivalent fragment of NAP, or, “or” would imply that the nucleic acid sequence encoding NAP and/or the nucleic acid sequence encoding the immunologically equivalent fragment of NAP are in the alternative. As such the metes and bounds of the claim are indefinite.
Claim Rejections - 35 USC § 112 (a)
Written Description
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 are 26-47 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.
M.P.E.P. § 2163 recites, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number
of species by actual reduction to practice (see i)(A), above), reduction to drawings (see
i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or
other physical and/or chemical properties, by functional characteristics coupled with a
known or disclosed correlation between function and structure, or by a combination of
such identifying characteristics, sufficient to show the applicant was in possession of the
claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.”
Further, the written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her
knowledge of the art, would have considered it to expand with only routine
experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed.
Cir. 2010) (en banc); see also id. at 1352 (“[I]t is the specification itself that must
demonstrate possession A description that merely renders the invention obvious does
not satisfy the requirement.").
Claim 26 is directed to an adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori neutrophil-activating protein (NAP) and/or a nucleic acid sequence encoding an immunologically equivalent fragment of NAP, wherein the immunologically equivalent fragment of NAP is a fragment including at least one polypeptide domain of at least 20 amino acid residues of NAP; and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject. Claim 34 further limits claim 26 to the immunomodulator is a TNFSF member. Claim 35-37 further limits claim 34-36 to the TNFSF member is a species selected from a recited group. Applicants broadly claim a genus of: i) immunologically equivalent fragment of NAP is a fragment including at least one polypeptide domain of at least 20 amino acid residues of NAP and 2) a genus of immunomodulators. Applicant is not entitled, nor is the specification enabled for the use of any and all polypeptide domain of at least 20 amino acid residues of NAP variant species of a full-length NAP molecule nor immunomodulators inducing an immune response. There is not structure /function correlation for the claimed nucleic acid sequences, e.g, inducing an immune response in a subject.
The specification discloses 3 constructs which comprise a DNA coding sequence that encodes NAP from Heliobacter pylori (HP). The 3 constructs are termed: “Ad(OB)”, comprising NAP and E1a-Δ24; “Ad(O9B)”, comprising NAP, E1a-Δ24, and SF9; and “Ad(O18B)”, comprising NAP, E1a-Δ24, and SF18 (Figure 1; Example 1, para 0093 of US Application). The immunomodulators are encoded by a DNA sequence of SF9 and SF18, which correspond to TNFSF9 and TNFSF18, respectively (para 0042-0044) and were derived from genes of human and mouse and used in human and mouse cell line models, respectively. The “E1a-Δ24” corresponds to the E1A coding sequence mutated with a 24 bp deletion (para 0093). Additionally, Ad(O9B) and Ad(O18B) comprise a self-cleaving peptide, T2A, in between the respective SF sequence and the NAP sequence (Figure 1). The specification recites that the NAP comprises an amino acid sequence selected from SEQ ID NO: 3-10, and that the immunologically equivalent fragments of NAP consist of the sequences set forth in SEQ ID NO: 11-14 (page 4 of Specification). More specifically, the amino acid sequences of the immunologically equivalent fragments of NAP must be consecutive sequences of NAP as shown by SEQ ID NO: 11-14 (para 0063) which are each between 35 and 36 amino acids in length. In regard to claim 46 which recites specific replacements of nucleic acid sequences encoding 19-kDa and 55-kDa adenovirus E1B protein, the specification only discloses that the 3 constructs comprise the native p19K and p55K of the E1B coding sequence of the wildtype adenovirus 5 being replaced with NAP only, SF9, T2A, and NAP, and SF18, T2A, and NAP, (Example 1, Figure 1).
The specification does not disclose any nucleic acid sequence that encodes at least 20 amino acid residues of NAP which is capable of expressing an immunologically equivalent variant of NAP, nor does it teach that the amino acid residues can be in any order and the replacement of either the 19-kDa and 55-kDa with a nucleic acid sequence encoding NAP and/or immunologically equivalent fragment of NAP. The function of the nucleic acid being able to encode a NAP protein or immunologically equivalent fragment of NAP is not supported by the specification. In other words, the specification fails to recite any nucleic acid which is shown to perform the function of encoding the NAP and an immunologically equivalent variant of NAP. Rather, the specification only recites that the adenovirus has an “coding sequence of NAP” (para 0093) and the amino acid sequences encoded are at least 35 amino acids in length and are consecutive residues sequences from the SEQ ID NOs: 3-10. There are no structural details of the nucleic acid sequences which could encode a NAP protein or immunologically equivalent fragment of NAP.
Furthermore, the specification does not disclose any nucleic acid sequence encoding an immunomodulator is capable of inducing an immune response when comprised in the adenovirus, rather it only describes SF9 and SF18 “coding sequence as indicated in the Example 1” (para 0093). The specification does not disclose any details pertaining to the structure of what the nucleic acid sequence could be such that it encodes an immunomodulator, and furthermore, does not provide any details to the structure of the immunomodulator such that it is capable of inducing an immune response in a subject.
Structural features that could distinguish the adenovirus of the claimed genus from others not encompassed by the genus of adenoviruses are missing from the disclosure. No common structural attributes identify the members of the genus, other than the adenovirus comprising the E1a-Δ24, and there is no indication of the relationship of the structure required for its claimed function. The broad and generic scope of the adenoviruses that can encode NAP and/or immunologically equivalent fragment of NAP and encode an immunomodulator capable of inducing an immune response in a subject is rendered as being unpredictable. An adequate description of the materials, which provide the means for practicing the invention, i.e. encoding NAP and/or NAP and/or immunologically equivalent fragment of NAP and encoding an immunomodulator capable of inducing an immune response.
Applicant were referred to the guidelines for Written Description Requirement
published January 5, 2001 in the Federal Register, Vol.66, No.4, pp.1099-1110 (see
http://www.uspto.gov). The disclosure of a single species is rarely, if ever, sufficient to
describe a broad genus, particularly when the specification fails to describe the features
of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue
Pharma L. P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000). The possession may
be shown by actual reduction to practice, clear depiction of the invention in a detailed
drawing, or by describing the invention with sufficient relevant identifying characteristics
(as it relates to the claimed invention as a whole) such that a person skilled in the art
would recognize that the inventor had possession of the claimed invention. See, e.g.,
Pfaff v. WellsElectronics, Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,
1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai
Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The “written description” requirement may be satisfied by using such descriptive
means as words, structures, figures, diagrams, formulas, etc., that fully set forth the
claimed invention. See Noelle v. Lederman, 355 F.3d 1343, 1349, 69 USPQ2d 1508,
1514 (Fed. Cir. 2004) and Lockwood v. American Airlines, Inc., 107 F.3d at 1572, 41
U.S.P.Q.2d at 1966. A definition by function alone “does not suffice” to sufficiently describe a coding sequence “because it is only an indication of what the gene does,
rather than what it is.” Regents of the University of California v. Eli Lilly & Co., 119 F.3 at
1568, 43 USPQ2d at 1406 (Fed. Cir. 1997) (discussing Amgen Inc. v. Chugai
Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016 (Fed. Cir. 1991)). In Fiers v.
Ravel, 984 F.2d at 1169-71, 25 U.S.P.Q.2d at 1605-06 (1993), the CAFC found that “a
mere wish or plan for obtaining the claimed chemical invention” is not sufficient to
describe a chemical invention (discussed in Eli Lilly at 1404).
In view of the large breadth of adenoviruses claimed by their function of encoding NAP and/or an immunologically equivalent fragment of NAP and encoding an immunomodulator capable of inducing an immune response in any subject and the lack of adequate description of the structure-function relationship of the claimed genus, one of ordinary skill in the art would not have recognized Applicant as being in possession of the claimed genus. The limited disclosure in the specification is not deemed sufficient to reasonably convey to one skilled in the art that the applicants were in possessions of the genera adenoviruses as recited in the claims at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genera.
Claim Interpretation
In light of the “and/or” clause recited, claim 26 is interpretated as “an adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori neutrophil-activating protein (NAP) and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject (i.e. no inclusion of a nucleic acid sequence encoding an immunologically equivalent fragment of NAP), thus the following 102 rejection below applies.
In addition, to the extent that claim 26 is interpretated as “An adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori neutrophil-activating protein (NAP) and a nucleic acid sequence encoding an immunologically equivalent fragment of NAP, wherein the immunologically equivalent fragment of NAP is a fragment including at least one polypeptide domain of at least 20 amino acid residues of NAP; and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject.”, thus the following 103 rejection below applies.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 26-33, 42-45, and 47 and are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al (US 20130302313 A1; as cited in IDS), as evidenced by Ramachandran et al (The Journal of Immunology, 2014, pages 2287-2298; as cited in IDS) and Ullrich et al (EXCLI Journal, 2020, pages 1563-1589).
The applied Yu and Ramachandran reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Yu and Ramachandran is 14 November 2013 and 1 September 2014, respectively. The earliest effective filing date of the instant application is 23 April 2021.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(c) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 26, 42, and 47, Yu teaches an oncolytic adenovirus (termed “Ad5PTDf35(D24-sNAP)” which Ad5 refers to human adenovirus serotype 5) comprising a HP-NAP coding sequence (i.e. a nucleic acid sequence for NAP) inserted downstream of a E1aΔ24 gene (para 0090, Example 9). Yu teaches that the adenovirus comprises one or more therapeutic genes (i.e. can comprise more than one nucleic acid sequence) (claim 15 of Yu), the therapeutic gene can be CD40L (para 0070) and CD40L leads to activation of dendritic cells, which leads to further activation/expansion of tumor-reactive T cells (para 0066), thus anticipating an adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori neutrophil-activating protein (NAP) and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject (claim 26), the adenovirus is an oncolytic adenovirus (claim 42), and the adenovirus is a human adenovirus type 5 (claim 47).
Regarding claims 27-33, the teachings of Yu anticipate claim 26.
While Yu does not explicitly state that the immunomodulator (i.e. NAP) is capable of:
inducing DC maturation, T cell activation, and NK cell activation (claims 27 and 28)
inducing dendritic cells to express cluster of differentiation 80 (CD80), CD40, CD86 and C-C chemokine receptor type 7 (CCR7) (claim 29)
inducing CD4+ T cell activation and/or CD8+ T cell activation (claim 30)
inducing CD4+ T cells and/or CD8+ T cells to express cluster of differentiation 69 (CD69) and CD107a. (claim 31)
inducing CD56+ NK cell activation (claim 32)
inducing CD56+ NK cells to express cluster of differentiation 69 (CD69) and CD107a (claim 33);
it is noted that the claim is directed to an inherent result based on the structure of the of the adenoviral particles. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Furthermore, Ramachandran provides evidence that oncolytic adenoviruses encoding HP-NAP promote maturation of DCs (with expression of maturation markers CD83, CD80, CD86, HLA-DR, CD40, and CCR7) and subsequently activate Ag-specific T cells in addition to provoking innate immunity (abstract, page 2287). Oncolytic adenoviruses encoding HP-NAP cause DCs to secrete high levels of IL-12 (page 2290, right col, para 2), and IL-12 causes activation of proliferation and cytotoxicity of NK cells and CD4+ and CD8+ T cells, as evidenced by Ullrich (page 1571, right col, Cancer).
Regarding claim 34-36, the teachings of Yu anticipate claim 26. Moreover, Yu teaches that the therapeutic gene can be CD40L (para 0070), which is also known as the tumor necrosis factor superfamily member, TNFSF5. Yu teaches expression of CD40L in a tumor area leads to activation of dendritic cells, which leads to further activation/expansion of tumor-reactive T cells (para 0066). Hence, Yu anticipates wherein the immunomodulator is a tumor necrosis factor superfamily (TNFSF) member (claim 34) and wherein the TNFSF member is TNFSF5 (35 and 36).
Regarding claim 43-45, the teachings of Yu anticipate claim 26 and 42. Moreover, Yu teaches the adenovirus comprises a mutated version of E1a mutated version with a 24 base pair deletion which confers selectivity to replication in pRb pathway-deficient cancer cells (example 3 and 8, para 0080). Indeed, Yu references the deletion is taught by Fueyo which further teaches deletion of bases 919 to 943 (i.e 24 bases deleted) of adenovirus type 5 which corresponds to lacking amino acids 121-128 (see Figure 1 of Fueyo). Therefore, Yu anticipates wherein the oncolytic adenovirus comprises a mutated adenovirus early region lA (EIA) gene encoding a mutated ElA protein having a lower Rb protein binding capability as compared to a wild-type ElA protein (claim 43), wherein the mutated EIA gene comprises a 24 bp deletion of nucleotides 919 to 943 of wild-type EIA gene (claim 44), and wherein the mutated ElA protein lacks amino acids 121 to 128 of wild-type ElA protein (claim 45).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as 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.
Claim(s) 26 and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al (US 20130302313 A1; as cited in IDS), as evidenced by Ramachandran et al (The Journal of Immunology, 2014, pages 2287-2298; as cited by IDS) and Ullrich et al (EXCLI Journal, 2020, pages 1563-1589), and further in view of Wang et al (Cancer Immunol Immunother, 2012, pages 489–495).
Regarding claim 26 and 34-37, Yu teaches an oncolytic adenovirus (termed (termed “Ad5PTDf35(D24-sNAP)” which Ad5 refers to human adenovirus serotype 5) comprising a HP-NAP coding sequence (i.e. a nucleic acid sequence for NAP) inserted downstream of a E1aΔ24 gene (para 0090, Example 9). Yu teaches that HP-NAP is a chemo-attractant that can recruit neutrophils to the site of infection and it is also a potent immunomodulator, capable of inducing secretion of proinflammatory cytokines and promotes T helper 1 (Th1) type immune polarization (para 0070). Yu teaches that the adenovirus comprises one or more therapeutic genes (i.e. can comprise more than one nucleic acid sequence) (claim 15 of Yu). Yu teaches that the therapeutic gene can be CD40L (para 0070), which is also known as the tumor necrosis factor superfamily member, TNFSF5. Yu teaches expression of CD40L in a tumor area leads to activation of dendritic cells, which leads to further activation/expansion of tumor-reactive T cells (para 0066), thus teaching an adenovirus comprising: a nucleic acid sequence encoding a Helicobacter pylori neutrophil-activating protein (NAP) and a nucleic acid sequence encoding an immunomodulator capable of inducing an immune response in a subject (claim 26)
Hence, Yu renders obvious wherein the immunomodulator is a tumor necrosis factor superfamily (TNFSF) member (claim 34) and wherein the TNFSF member is TNFSF5 (35 and 36).
Yu does not teach wherein the immunomodulator (i.e. nucleic acid sequence) is a tumor necrosis factor superfamily (TNFSF) member selected from the group TNFSF9, TNFSF18, and a combination thereof (claim 37).
However, one of ordinary skill in the art would have considered the teachings of
Wang as this reference is analogous prior art pertaining to inclusion of CD137L (also known as TNFSF9) in immunotherapies for enhancing immune response.
Wang teaches that CD137L, when bound to its receptor CD137, can enhance cellular immunity and lead to expansion of tumor-reactive T cells and suppression of tumor growth, and in some cases regression of established tumors (Introduction, page 489). Wang teaches combinations of anti-CD137 antibody (i.e. behaves like a CD137L ligand) with multiple experimental or approved cancer treatments in rodent cancer models have resulted in marked synergistic effects (Introduction, page 489).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the adenovirus comprising two therapeutic genes, one of which is HP-NAP, as taught by Yu, and the second therapeutic gene comprise CD137L (i.e. TNFSF9) since Wang teaches that CD137L can enhance cellular immunity and expand T cells and suppress of tumor growth and have a synergistic effect when combined with other treatments (i.e. in combination with HP-NAP). One would be motivated to do so to generate a more effective adenovirus as a cancer therapy and since use of HP-NAP and CD137L in adenoviruses for cancer therapy has been shown in the art, one would have a reasonable expectation of success.
***
Claim 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al (US 20130302313 A1; as cited in IDS), as evidenced by Ramachandran et al (The Journal of Immunology, 2014, pages 2287-2298; as cited by IDS) and Ullrich et al (EXCLI Journal, 2020, pages 1563-1589), as applied to claim 26 above, and further in view of NCBI HP-NAP (NCBI, first published August 23 2011)
Regarding claim 38 and 39, the teachings of Yu render obvious claim 26.
Yu does not teach wherein the immunologically equivalent fragment of NAP is a fragment including at least one polypeptide domain of at least 30 amino acid residues of NAP (claim 38) and wherein the immunologically equivalent fragment of NAP is selected from the group consisting of SEQ ID NO: 11 to 14 (claim 39).
However, NCBI HP-NAP teaches a nucleic acid sequence for Helicobacter pylori napA gene for neutrophil-activating protein which, when translated from nucleic acid to amino acid, is 36 amino acids in length and has 100% identity to the amino acid sequence set forth in SEQ ID: 11 of the instant application, see alignment below:
PNG
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349
639
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Greyscale
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the adenovirus comprising a HP-NAP coding sequence as taught by Yu to specifically be the sequence taught by NCBI HP-NAP since it was known that HP-NAP is a chemo-attractant that can recruit neutrophils to the site of infection and one would be motivated to use the sequence taught by NCBI HP-NAP to be comprised within the adenovirus which comprises NAP from Yu and one would have a reasonable expectation of success.
***
Claim 40 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al (US 20130302313 A1; as cited in IDS), as evidenced by Ramachandran et al (The Journal of Immunology, 2014, pages 2287-2298; as cited in IDS) and Ullrich et al (EXCLI Journal, 2020, pages 1563-1589), as applied to claim 26 above, and further in view of Larson et al (US 20210015878 A1) and NCBI P2A (NCBI, first published June 23, 2020).
Regarding claim 40, the teachings of Yu render obvious claim 26.
Yu does not teach an adenovirus according to claim 26, further comprising a nucleic acid sequence encoding a self-cleaving peptide positioned between the nucleic acid sequence encoding NAP, and/or the immunologically equivalent fragment of NAP, and the nucleic acid sequence encoding the immunomodulator.
However, one of ordinary skill in the art would have considered the teachings of
Larson as this reference is analogous prior art pertaining to oncolytic adenovirus comprising self-cleaving peptide sequences.
Larson teaches oncolytic adenoviruses comprising two transgenes, wherein one transgene can be a nucleic acid sequence which encodes CD137: (also known as TNFSF9) and the two transgenes can be linked by a self-cleaving 2A peptide sequence (para 0146, para 0058) to produce two polypeptide chains.
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the adenovirus comprising two therapeutic genes, one of which is HP-NAP, as taught by Yu, to have the second therapeutic gene comprise CD137L (i.e. TNFSF9) such that the HP-NAP sequence and CD137L sequence are linked by a self-cleaving peptide sequence to produce two different polypeptides from one construct. One would be motivated to do so to more efficiently express the two nucleic acid sequences of interest at the same time in the same vector, but the polypeptides resulting are independent polypeptides from each nucleic acid sequence and one would have a reasonable expectation of success.
Regarding claim 41, the teachings of Yu and Larson render obvious claim 26 and 40.
The teachings of Yu and Larson do not teach wherein the self-cleaving peptide is selected from the group consisting of SEQ ID NO: 16-23.
However, NCBI P2A teaches a nucleic acid sequence for P2A gene which translates to match 100% identity to the amino acid sequence set forth in SEQ ID: 18 of the instant application, see alignment below:
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It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the adenovirus comprising a HP-NAP coding sequence, an immunomodulator sequence which can be linked by a self-cleaving 2A peptide sequence as taught by Yu and Larson to specifically be the sequence taught by NCBI P2A since it was known that P2A is a self-cleaving peptide and one would be motivated to use the sequence taught by NCBI P2A to separate and thus make two polypeptides of HP-NAP and the immunomodulator, separately, and one would have a reasonable expectation of success.
Conclusion
All claims are rejected.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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