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 .
Election/Restrictions
Applicant’s election without traverse of group I, claims 1-9, 11-12, 14-19 and 22-23 , species of CA04(A/California/04/2009) as the influenza viral genome in the reply filed on 6/16/2026 is acknowledged. Hence, claims 3, 8, 14, 16, and 19 read on the elected species.
Claims 1, 3-5, 7-8, 9, 11-12, 14-19, 22-23 with the elected species are considered.
Specification Objection
The specification on page 11 is objected for incorporation by a hyperfine. 37 CFR 1.57(e) states that an incorporation by reference by hyperlink or other form of browser executable code is not permitted. Examples of a hyperlink or a browser-executable code are a URL placed between these symbols "< >" and http:// followed by a URL address. When a patent application with embedded hyperlinks and/or other forms of browser-executable code issues as... reference to a URL. The attempt to incorporate subject matter into the patent application by reference to a hyperlink and/or other forms of browser-executable code is considered to be an improper incorporation by reference. See 37 CFR 1.57(e) and MPEP § 608.01(p), paragraph I regarding incorporation by reference. Where the hyperlinks and/or other forms of browser-executable codes themselves rather... Forms of Browser-Executable Code 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
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-5, 7-8, 9, 11-12, 14-19, 22-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the reference sequences for each of mutations cited in the rejected claims.
Furthermore, Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite in that it fails to point out what is included or excluded by the claim. This claim is an omnibus type claim. In the instant case, the citation of “ optionally” is indefinite because it is not sure the citation after . Therefore, it is considered the claim is indefinite because there is no any exclusive limitation rather than an optional . This rejection effect all dependent claims 3-5, 7-8, 9, 11-12, 14-19, 22-23.
Examiner’s notes: A broad reasonable interpretation of the scope of claim 1 read on just of “a live attenuated chimeric virus comprising (a) an influenza A virus genome, wherein the influenza A virus genome comprises a deletion of a virulence factor activity” wherein the other limitaiton is only an optional choice rather than exclusive limitations including a first set of one or more mutation(s) that confers replication at 37 °C in the absence of the virulence factor activity; and a second set of one or more mutation(s) that confers replication at a temperature below 35 °C, or an influenza B virus genome, wherein the influenza B virus genome comprises a deletion of a virulence factor activity (DELNS1-B), and optionally, one or more mutations selected from the group consisting of PA(T210C), NA T(1424C), NP(C182T) and M (A281G) (AM/ LAIVB/DelNS1), and (b) an insertion of one or more genes encoding one or more Sars-CoV-2 antigens (CoV2Ag) or one or more genes encoding one or more hemagglutinin (H) or neruaminidase (N) subtypes selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, H10, N1, N2, N6-N9.
Claim 2 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of influenza virus genome is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: However, the influenza A subtype H1N1 or H3N2 is not same as the influenza B (B/HK/8038/2011)(DELNS1-B8038) because the influenza A does not have the NS1 deletion by the influenza virus H1N1 o H2N2. .
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. For instant, if they have all NS1 deletion.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-8, 9, 11-12, 14-16, 19, and 22-23 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case, the rejected claims 8, 9, 11-12, 14-16, 19, and 22 are all ultimately cited as the depended claims for claim 1. However, each of them cites a limitation as only an optional choice rather than an exclusive limitation of the claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. This rejection affects the depend claims 9 and 23.
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 –(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)(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) 1, 4, 17 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by SK 2888544 to Palese et al. .
The ground of this rejection of Claim 1 and some of its depended claims is based on a broad scope of claim 1 and its depended claim(s) is reasonable interpretated as a live attenuated chimeric virus comprising two essential elements, i.e. the element (a) directed to an influenza A virus genome, wherein the influenza A virus genome comprises a deletion of a virulence factor activity, or an influenza virus B, wherein the influenza B virus genome comprises a deletion of a virulence factor activity (DELNS1-B),which optionally, comprises one or more mutations selected from the group consisting of PA(T210C), NA T(1424C), NP(C182T) and M (A281G) (AM/ LAIVB/DelNS1) and element (b) drawn to an insertion of one or more genes encoding one or more Sars-CoV-2 antigens (CoV2Ag) or one or more genes encoding one or more hemagglutinin (H) or neuraminidase (N) subtypes selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, H10, N1, N2, N6-N9.
Palese et al. teach an engineered attenuated chimeric influenza virus, the genome of which (i) comprises a heterologous sequence, which codes for an influenza virus gene segment, and (ii) encodes a truncated NS1 protein consisting of 99 N-terminal amino acids of the NS1 protein of an influenza virus strain, wherein the genetically engineered attenuated chimeric influenza virus has an impaired interferon antagonist phenotype.
Further, the cited reference teaches genetically engineered attenuated chimeric influenza virus, characterized in that its genome (i) comprises a heterologous sequence that encodes an influenza virus gene segment, and (ii) encodes a truncated NS1 protein consisting of the 99 N-terminal amino acids of the NS1 influenza virus strain protein. , wherein the genetically engineered attenuated chimeric influenza virus has a phenotype with reduced interferon antagonizing ability. The genetically engineered attenuated chimeric influenza virus is a hemagglutinin or neuraminidase gene segment. (See Summery of the invention and claims 1-14).
In particular, the genetically engineered attenuated chimeric influenza virus characterized in that the attenuated influenza virus is influenza A virus or attenuated influenza virus is influenza B. A vaccine composition comprising said genetically engineered attenuated chimeric influenza virus A or B and a physiologically acceptable adjuvant and a method for using the same for treatment and/or prevention of infectious susceptible diseases in a subject (See entire documentation and claims 1-14).
Therefore, the recombinant influenza virus disclosed by Palse et al. meets the limitations of an influenza A virus genome, wherein the influenza A virus genome comprises a deletion of a virulence factor activity, or an influenza virus B, wherein the influenza B virus genome comprises a deletion of a virulence factor activity (DELNS1-B) that further comprises a heterologous influenzas virus antigen although it does not comprises SARS-Cov2 antigen. Hence, the cited reference by Palese et al. anticipates claims 1, 4 and 17.
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.
Claim(s) 1, 3-5, 7-9, 11-12, 14, 16, 19 and 22-23 are rejected under 35 U.S.C. 102( (a) (1) ) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over WO2017184626A1 to Lau et al. and further in view of Yuan et al. (Nat. Commun. 2017, April. 10, Vol. 8; pages 109) for claims 15-16 .
The ground of this rejection of Claim 1 and some of its depended claims is based on a broad scope of claim 1 and its depended claim(s) is reasonable interpretated as a live attenuated chimeric virus comprising two essential elements, i.e. the element (a) directed to an influenza A virus genome, wherein the influenza A virus genome comprises a deletion of a virulence factor activity, or an influenza virus B, wherein the influenza B virus genome comprises a deletion of a virulence factor activity (DELNS1-B),which optionally, comprises one or more mutations selected from the group consisting of PA(T210C), NA T(1424C), NP(C182T) and M (A281G) (AM/ LAIVB/DelNS1) and element (b) drawn to an insertion of one or more genes encoding one or more Sars-CoV-2 antigens (CoV2Ag) or one or more genes encoding one or more hemagglutinin (H) or neuraminidase (N) subtypes selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, H10, N1, N2, N6-N9.
Lau et al. disclose a live, attenuated influenza vaccine suitable for nasal administration. The vaccine composition comprises either the influenza A such a 2009 H1N1 strain, A/Calif ornia/04/09 from which an extended portion or all of the NS 1 encoding intron (e.g. extending beyond the segment encompassed by nucleotides 57 to 528) has been deleted. Utilizing methods of the inventive concept a DelNS 1 strain of such an influenza virus was developed with a G345A mutation within the NP region, which enable efficient replication of the DelNS 1 virus in cell culture and in eggs. Surprisingly, this novel adaptive mutation was different and distinct from the M region mutations of the DelNS 1 A/WSN/33 and the H7N9 viruses, and has not been previously reported as a mutation in DelNS 1 influenza viruses. In example 1, Lau et al. teach that A California(CA)/04/09 strain was used for construction of CA4-DelNS 1 virus through reverse genetic procedures that deleted an intron at 56-529. Rescued virus was passaged until the DelNS l virus was stabilized by replication in MDCK cells at 37° C. After sequence confirmation of mutations, CA (cold adapted) 4-DelNS l virus was further adapted to replicate at lower temperatures by passage at 30°C in chicken embryonated eggs until the virus titer was stabilized. A schematic depiction of the process is shown in FIG. 1.
Moreover, Paragraph [0063] also teaches that Sequence analysis was performed on CA4-DelNS l following passage in MDCK cells. One adaptive substitution of G to A in the NP segment at position G346A (D101N in protein sequence) was confirmed. This substitution was found to support CA4-DelNS l virus replication in MDCK cells and in eggs. Results of sequence analysis of non-mutated (PI) and mutated strains of the CA4-DelNS l virus are shown in FIG. 2.
In summary of invention at [0016], it describes that One embodiment of the inventive concept is a mutated influenza virus for vaccine production. The virus includes a H1N1 influenza virus genome that includes a deletion of a virulence factor activity, a first set of one or more mutation(s) that confers replication at 37° C in the absence of the virulence factor activity, and a second set of one or more mutation(s) that confers replication at a temperature below 35° C. The deletion of virulence factor activity can include a deletion of at least part of a virulence factor gene. Such a deletion can be a deletion of at least part of an NS 1 gene extending beyond nucleotides 57 to 528 of an NS 1 segment of the mutated virus. The first set of one or more point mutation(s) that confer replicative competence, which can lie outside of an M region of the mutated H1N1 influenza virus (for example, a G346A mutation in the H1N1 influenza virus genome). The second set of one or more mutation(s) can include one or more point mutation(s), such as a T261G or a A310G mutation in the H1N1 influenza virus genome. Paragraph [0017] also described that such a mutated influenza virus can also include a third set of one or more mutation(s) that confers replication at a temperature below 35° C. These can include one or more point mutation(s) that are distinct from the second set of mutation(s), such as a T261G or an A310G mutation in the H1N1 influenza virus genome. The mutated influenza virus can show reduced replicative ability, relative to a temperature of 35° C or lower, at a temperature of 37° or higher. At paragraph [0018], it describes that In some embodiments the mutated influenza virus includes an insertion of a gene encoding for an exogenous antigen. Such an exogenous antigen can be derived from a human pathogen, for example a virus (e.g. an influenza virus, a SARS virus, a MERS virus et al.
Therefore, the limitation of claims 1, 3-5, 7-8, 9, 11-12,17-19 and 22-23 are met.
However, Lau et al. do not teach using the antigen of receptor binding domain of SARS-Cov2 as an heterologous SARS-Cov2 antigen inserted into the influenza viral vector. But they teach using the MERS-RBD.
Regarding expressing the heterologous sequence of Sars-Cov2 . For instance, it teaches at paragraph [0018] that In some embodiments the mutated influenza virus includes an insertion of a gene encoding for an exogenous antigen. Such an exogenous antigen can be derived from a human pathogen that includes a SARS virus, a MERS virus coronavirus. In particular, the cited reference have found that insertion of a MERS RBD domain into such a modified influenza virus backbone can be used in a nasally administered vaccine that confers protection from MERS infection to DPP4-transduced mice. Such DPP4-transduced mice are commonly utilized as murine models for MERS vaccine development. Inventors have also successfully incorporated a Zika virus RBD domain into such a modified influenza virus backbone. (See paragraph l0055]. Therefore, the substitution of the RBD of MERS with the RBD of SARS-Cov2 is expected based on whether the structural and functional similarity between the MERS and DARS-Cov2.
Yuan et al. present structural analyses of trimeric MERS-CoV and SARS-CoV S proteins in pre-fusion conformation, and reveal the two RBD antigenic proteins contains many conserved structures and functional domains, For instant , they did conservation analysis of full-length sequences of the S protein from six human-infecting CoV2 (MERS-CoV, SARS-CoV, HKU1, NL63, OC43 and 229E) revealed that the glycosylation variable regions are mainly located on the S1 subunit, including the NTD and RBD regions, whereas the S2 subunits are relatively conserved (Fig. 4e,f). It is worth to note that the fusion peptide (FP) and HR1 region are exposed at the surface of stem region of the S trimer, and provide a patch of conserved region for epitope-focused vaccine immunogen design aimed at raising broadly neutralizing antibodies against human-infecting CoV2 (Fig. 4e,f). In addition, the flexible RBD regions allow the top of S1 in an open state, and enable the central stem region of the S trimer, including the top region of the upstream helix, HR1 and central helix, to become accessible to antiviral protein inhibitors (Fig. 4e,f). Hence, they concluded that the common receptor binding domain (RBD) suggest new avenues for the generation of neutralizing antibodies in the same common regions .
As described above, MERS-CoV S protein and SARS-CoV S proteins have extremely similar structures including their receptor domain (RBD) , it would have been obvious for a person with an ordinarily killed in the art to be motivated by the cited references to combine the science and technologies taught by Lau Yuan et al. and further in view of Yuan et al. to arrive the current claims, particularly for claims 15-16 with a reasonable expectation of success.
As there are no unexpected results have been provided, hence the claimed invention as a whole is prima facie obvious absence unexpected results.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
SK/BAO Q LI/Primary Examiner, Art Unit 1671
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