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 .
Remark
The preliminary amendment filed on May 12, 2023 has been acknowledged and entered. . Claims 4-6, 8-9, 12-17 and 19 have been amended. Claims 1-20 are pending and considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification pages 17 and 22 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 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.
The term “derived” in claims 1, 4-6, 9-10, 12, 16-18, and 19-20 is a relative term which renders the claim indefinite. The term “derived” 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. Please amend the rejected claims to overcome the rejection.
Claim 8 is 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 unit of 20” because it is unclear what the “20 “ measurement is referred to” Are they referred to 20 amino acid residues between the amino acid residue from 52nd to 277th or 20% homology to the position from 52 to 277? . Please clarify.
Claim 9 is confusing for citing” the HA protein from which the antigens are derived includes a hypervariable region and the hypervariable region is deleted from the at least different influenza HA derived antigens” The first confusing is how the HA protein because the proteins, which lacks antecedent bases.
Moreover, it is also confusing how the hypervariable region is deleted from the at least different influenza HA derived antigens? DO Applicants means the sequence encoding the endogenous hypervariable protein region is deleted and it is further replaced with a heterologous hypervariable region? This rejection affects all depended claim 9. Please clarify. However, for the compact prosecution, the following rejections are based on the notions of BRI of the claims that the HA antigen(s) is a chimeric antigenic protein(s) either as monovalent or bivalent wherein the endogenous hypervariable protein region from either 1st or 2nd HA is replaced with a heterologous hypervariable region in either same or different type or serotype or subtypes for any monovalent HA or bivalent or other multivalent HV influenza vaccine development .
Claim 12 is confusing for citing “where the HA proteins from which the first and second influenza HA derived antigens contains a hypervariable region, and the hypervariable region is deleted from the first and second influenza HA derived antigens” It is unclear if none of the cited 1st or 1nd HA mutated antigens contain the hypervariable region or none of them contain the heterologous hypervariable regions.
However, for the compact prosecution, claim 12 is interpretated as either stations in the following rejection.
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.
The claimed subject matter is directed to a vaccine composition comprising at least two different influenza hemagglutinin (HA) derived antigens, wherein an HA protein from which the antigens are derived includes a hypervariable region and the hypervariable region is deleted from the at least different influenza HA derived antigens, and wherein each of the at least two different influenza HA derived antigens has a similarity with HA molecules of more than one influenza serotype in excess of at least 60, as calculated by the emboss explorer cons program.
Examiner’s notes:
1). The structural property of similarity of the HV molecules calculated by the emboss explorer cons program is considered as product by process, Therefore, as long as the sequence similarity of the HA compared with other HA serotype is 60, 70 or 80 % homology, the limitation is met;
2). Serotype: the nomenclature of influenza virus is officially classified as type and subtype base on the CDC 2025 guideline , which describes that influenza virus are divided into four epidemic types categorized as A, B, C and D and further divided as subtype based in both influenza viral surface protein, hemagglutinin (HA) and neuraminidase (NA) e.eg. influenza A H1N1 and A(H3N2) and influenza B-Victoria and B-Yamagata (CDC publication on Spt. 25, 2025).
While the serotype is not considered as officially accepted classification, it is still wildly used with and subtype in the field of influenza virus. The experts in this filed summarize the key difference for the serotype and subtype as follow:
Serotype: Classified based on the antigenic properties of the virus, specifically the immune response they elicit serologically. It is about how the immune system recognizes and differentiates between different viruses;
Subtype: Classified based on genetic and molecular characteristics. It is more about the genetic and structural composition of the virus.
Therefore, bases on the common accepted explanation, the serotype is the common serological response within the same types and/or subtypes as long as they have common serological immune response for a common epitope and/or high antigen amino acid sequence homology which may within the same type and/or same or different subtype as long as the same serological response toward one or more epitopes in HA antigen is inducible apparently or inherently due to the high homology in HA antigenic proteins or polypeptides. This notion is supported by claim 10 and its depended claims. Hence, based on the BRI discussed above, some prior art rejections are made hereinto:
Claims 1-20 are rejected under 35 U.S.C. 102((a) (1) as anticipated by Kramer et al. Krammer et al. Curr Opin Virol. 2013 Aug 24;3(5):521–530) or CA 2849434 to Adolfo et al.
It is noted that Krammer et al. and Adolfo et al. belonged to the same investigation team lead by the Expertise who has been well known in the art. Therefore, the detail disclosure is cited based on the Krammer et al.
Krammer et al. teach an approaches for making seasoning and/or universal influenza vaccines, the products made and a method for using the same as well.
It is well known in the art that the influenza virus HA as the vaccine neutralizing immunogen can be divided into the highly divergent membrane distal globular head domain. i.e. the hypervariable region and membrane proximal stalk domain of the HA is, in contrast to the head domain, conserved among group 1, among group 2 and among influenza B viruses. The influenza virus HA can be divided into the highly divergent membrane distal globular head domain (red) and the conserved membrane proximal stalk domain (green). Cysteines 52 and 277 (H3 numbering) form a disulfide bond that serves as demarcation line between the two subdomains (See Fig. 1Ato E).
Krammer et al. teach as shown in Fig. 1 that a seasoning and/or universal influenza vaccine can be designed by creating a homotrimeric HA molecule. (See Fig. 1).
In more detail Kramer et al. at Fig. 4 teach that the globular head domain located between cysteines 52 and 277 (H3 numbering) was replaced by a glycine linker. Structures shown in B/F and C/G are likely to be mis-folded if expressed on their own. C/G The long alpha helix (LAH) of the HA2 hosts the epitope of broadly neutralizing antibody 12D1 and was successfully used as vaccine construct. It spans amino acid 404 to 458 (H3 numbering) (28). D/H Chimeric HA molecules consist of either an H1 or an H3 stalk domain combined with ‘exotic’ globular head domains. Here, cH6/1 (H6 head on top of an H1 stalk) is shown as an example. The H6 globular head domain (blue) is located between conserved cysteines 52 and 277 (H3 numbering). TMD is transmembrane domain; CT is cytoplasmic tail. Structures are based on PDB 1RU7. In this stalk base influenza vaccine, the endogenous hypervariable region of stalk of the H1 serotype influenza virus is replaced with the either glycine linker as the headless influenza vaccine or the endogenous H1 or H3 is removed and replaced with the ‘exotic’ globular head domains from H6 , which is genetically placed between conserved cysteines 52 and 277 (H3 numbering). Hence, a chimeric HA molecules consist of either an H1 or an H3 stalk domain combined with ‘exotic’ globular head domains. Here, cH6/1 (H6 head on top of an H1 stalk) is shown as an example. To this context, the hypervariable region is deleted and replaced with the linker sequence , i.e. the influenza virus vaccine is made by the chimeric HA without any hypervariable region, wherein the hypervariable region is replaced with a linker. Another recombinant influenzas virus vaccine is made by a chimeric H1 or H2 endogenous headless but replaced with exotic H6 globular head region, both of them are located between conserved cysteines 52 and 277 (H3 numbering) plus the conserved H1 or H2 stalk .
Krammer et al. also teach that they have developed such novel chimeric HA molecules (cHA) that combine H1 (group 1) or H3 (group 2) stalk domains in combination with ‘exotic’ head domains (e.g. H4, H5, H6, H7 or H9, Figure 4D and H) [14]. Sequential vaccination with these constructs, which always have the same stalk but divergent heads to which no cross-reactivity exists (measured by HI), boosts antibodies against conserved epitopes in the stalk domain. This vaccination regimen induces high titers of stalk-reactive antibodies in mice and ferrets (Figure 5A) [51,70]. It is able to protect animals from heterologous (divergent H1/H3 strains) as well as from heterosubtypic challenge (challenge with members for the same HA group). Animals vaccinated with cHAs based on the H1 stalk were protected against lethal H5N1 and H6N1 challenges and developed broadly neutralizing antibodies against other group 1 HA expressing viruses (e.g. H2N2). Animals vaccinated with H3 stalk based constructs showed similar broad protection that included challenge with H7N1 and H7N9 strains. It was demonstrated that the protective mechanism is mainly based on broadly neutralizing antibodies but probably includes ADCC and complement as well. In contrast to HA2 or headless HA constructs, cHAs have a globular head domain (as defined by the amino acids between C52 and C277, H3 numbering) in place which guarantees the correct folding of the stalk domain. Since most adult humans already have pre-existing humoral immunity to conserved epitopes in the stalk domain, it is expected that one or two immunizations would be sufficient to boost these antibody levels to neutralizing titers (Figure 5B). Importantly, cross-neutralization between group 1 and group 2 HAs is therefore likely to become an effective universal influenza virus vaccine for a group 1, a group 2 and an influenza B HA immunogen.
Regarding the similarity between the serotype, Krammer et al. illustrated in Fig. 1 E, Phylogenetic tree of influenza virus HAs. Influenza A virus HAs can be divided into group 1 and group 2 based on their sequence. Influenza A virus subtypes that currently circulate in humans or that have historically demonstrated their potential to do so are marked in red. Subtypes with pandemic potential are marked in green. The tree was built using ClustalW and was visualized in FigTree. The scale bar represents a 7% change in amino acid. After 2009 HiN1 merging , infection with pandemic H1N1 virus which features a very divergent H1 head domain is approx. 30% difference as compared to pre-pandemic seasonal strains (See Fig. 3). Therefore, similarity of the HA fragment used in the headless universal influenza vaccine (Fig . 3) or chimeric influenza HA vaccine shown in Fig. 4 is about 70 to more than 90% homology are met implicitly.
The Similar disclosures can be found in the results and descriptions by the CA 2949434, because they are the same investigation teams (Please see the Figs, 1-56 and claims 1-85.).
To this contact, the limitations of claims 1-20 are all met by the disclosures of the reference by Krammer et al. or Aldofo et al. explicitly as well as implicitly.
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.
Claims 1-20 are rejected under 35 U.S.C. 102((a) (1) as anticipated by Hai et al. J Virol, 2012 May;86(10):5774–5781. doi: 10.1128/JVI.00137-12 for claims 1-11 and 13-19 or, in the alternative, under 35 U.S.C. 103 as obvious over Kramer et al. Curr Opin Virol. 2013 Aug 24;3(5):521–530) for claims 12 and 20.
Hai et al. teach a method for making a recombinant influenza virus or a virus like particle, wherein the method comprises at least two chimeric influenza virus hemagglutinin DNA constructs by swapping the globular head domain of A/PR/34/8 (H1), which is considered as hypervariable region located between the conserved Cys52 and Cys277 with the head region of A/Ca/04/09H1 or A/VN/1203/04 H5 and both replace it endogenous stalk region with the stalk region of A/PR/8/34/H1 to make the chimeric HA named cH1/1HA1 and cH5/H1 respectively. Hai et al, teach that the similarity of the head regions between of the PR/8/34 (H1) and A/Cal/4/09 H1 is 70%, the Stalk regions is 90% and overall of the full length of HA is 82% (Please see description on page 5775 and results and Fig. 1 on pages 5775-5776). (See Fig. 1 ).
Moreover, Hai et al. also teach constructing a DNA expressing plasmid vector to express said chimeric influenza HA antigen capable of using it as an proteaceous subunit vaccine but also constructing it as a recombinant pseudo virus like particle (Pseud particle) by co-transfecting 293T cells with four plasmids encoding (i) a provirus containing the desired reporter (V1-Gaussia luciferase) (6), (ii) HIV Gag-Pol (6), (iii) chimeric hemagglutinin protein, and (iv) B/Yamagata/16/88 virus neuraminidase (NA). Supernatants were collected and were subsequently filtered (pore size, 0.45 μm). The presence of pseudo type virus-like particles (VLPs) was evaluated through hemagglutination assays successfully . Different VLP preparations were adjusted to the same 4 hemagglutination units prior to inoculation of MDCK cells. To this context, the purified supernatant comprising the chimeric hemagglutination units as a recombinant pseudo RNA virus like particle too.
Hai et al. also teach that the recombinant influenza A viruses comprising different chimeric HA antigens were rescued by transfecting a suitable influenza host cell line with different plasmid DNA molecule isolated alone or in combination. The influenza virus neutralizing assay was performed with the isolated pseudo type influenza virus like particle using the recombinant cHA construct comprising either a VN/04 (H5) or a Cal/09 (H1) head and a PR8 (H1) stalk with the influenza B/Yamagata/16/88 virus NA.
Hai et al. have demonstrated that the antibodies produced by the chimeric HA antigen, such as MAb KB2 can neutralize all cHA-expressing viruses both cH1/1 and cH5/1 chimeric viruses with 100% efficiency (Please see Fig. 5A and B).
Therefore, the cited reference teach the rejected claims 1-11 and 13-19.
Hai et al. do not teach explicitly using the chimeric HA that both 1st and 2nd influenza HA with removed hypervariable region cited in claim 12 as well as an in vivo vaccination test of claim 20 although Hai et al. finally concluded that most antibodies elicited by the HA are strain specific and are directed against the globular head domain, several groups have reported various broadly neutralizing antibodies that bind to epitopes on the influenza virus HA stalk domain. These cHAs could be used as reagents for the study and quantitation of the binding activities of such stalk-specific antibodies. In addition, chimeric HA constructs may be useful in inducing stalk-specific (or head-specific) immune responses (See section of Discussion).
Kramer et al. teach using a headless influenza vaccine as it was discussed in the previous rejection (See Fig. 3) and using the complete headless and same chimeric and endogenous headless cHA as an influenza vaccine candidates (Fig. 1 & 4) and test them in animals models (Fig. 3 & 5).
Kramer et al. concluded that broadly reactive antibodies directed against the stalk domain of the HA are able to neutralize divergent influenza virus strains. Vaccine constructs based on the conserved hemagglutinin stalk domain are able to protect mice from heterosubtypic challenge. Stalk-based vaccines could be further developed into human universal influenza virus vaccines
Therefore, alternatively in view of the Hai et al. teaching and suggestion, it would have been obviously for a person with an ordinarily skilled in the art to be motivated using said chimeric influenza HA fusion protein as a subunit protein vaccine or pseudo influenza virus VLP or pseudo influenza RNA virus to do an animal model challenging assay with an 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 result for claims 12 and 20.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/