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 response and amendment filed on June 4 have been acknowledged and entered. Claims 1, 8, 10, h12, 18 and 20 have been amended. Claim 17 has been canceled. Claims 1-16 and 18-20 are pending and considered.
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.
(Maintained) Claims 1-6 and 8-20 are still rejected for using a relative word “derived” in the independent claims 1 and 10 as well as some of depend claims. Appropriate amendment to remove these related words are required.
(Withdrawn) The rejection of Claim 8 with other issue under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph has been removed.
(Withdrawn) The rejection of Claim 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph with other issue has been removed.
(New Ground). Claim 1 is indefinite for using an undefined terminology of an empirical relationship based on the specification and also claim. It is unclear what percent of a molecular similarity is considered to be an empirical relationship?
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.
Claims 1-5 and 8-9 are still rejected under 35 U.S.C. 102((a) (1) as anticipated by Krammer et al. (Curr Opin Virol. 2013 Aug 24;3(5):521–530) or CA 2849434 to Adolfo et al. which is potentiated by Lu et al. (PLoSONE, 2018, 2018 Sep 27;13(9):e0204776. doi: 10.1371/journal.pone.0204776).
In the response, Applicants traverse the rejection and asserted that the claims do not merely recite influenza hemagglutinin stalk antigens, chimeric hemagglutinin constructs, or broadly neutralizing influenza vaccines. Rather, the claims require specific influenza HA-derived antigens having a defined similarity relationship with HA molecules of more than one influenza serotype, wherein the similarity is expressly defined as a measure of an empirical relationship between protein sequences. The Office Action does not establish that the cited references disclose this claimed similarity relationship. With respect to Krammer, the Office Action acknowledges that Krammer generally describes stalk-based influenza vaccines, headless hemagglutinin constructs, and chimeric hemagglutinin constructs. See, Office Action, pp. 5-8; Krammer, p. 1. The Office Action further relies upon Krammer's discussion of phylogenetic relationships among influenza hemagglutinins and a statement that the pandemic H1N1 head domain is approximately 30% different from pre-pandemic strains. See, Office Action, p. 7; Krammer, p. 4. Based on these disclosures, the Office Action concludes that the claimed similarity limitations are "about 70 to more than 90% homology" and are therefore allegedly met implicitly.
Applicants’ argument has been respectfully considered; however, it is not found persuasive with the following reasons;
While the rejected claims do not cite using the influenza hemagglutinin stalk antigens of the influenza viruses for preparing the influenza vaccine, the influenza vaccine construct made by Krammer et al. meets the limitations of the rejected claims.
The influenza vaccine made by the Krammer et al. comprises a chimeric stalk domains of the HA antigenic proteins of H1 and H3 influenza viruses, wherein the hypervariable head regions of the Has for both influenza viruses are deleted and replaced by a glycine peptide linker that connects the tow stalk domains.
Regarding the similarity of the two stalk regions of the HA and H3 viruses, the common stalk domains shared by the two groups of the influenza virus that are free of the variable head regions (headless). The similarity between the serotype, Krammer et al. illustrated in Fig. 1 E, Phylogenetic tree of influenza virus Has are analyzed and built using Clustal W was actually the same program used by the current Application, while the claim 18 cites that the determination of the antigen selected are based on an Emboss explorer cons program. The sequence structures represented by a scale bar shows only 7% change in amino acids. 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).
Moreover, Krammer teach that the hypervariable region is located between conserved cysteines at positions 52 and 277 using the amino acid numbering of an influenza HA of the serotype H3 (See Fig. 4 and page 2).
The high similarity of stalk domains among different influenza viruses , particular between the H1 in group I and H3 in group 2 serotypes are used by the Krammer et The Cross-Subtype Conservation of the Stalk homology between subtypes within the same group is typically from about 40\% to about 80%. When subtypes from different groups are compared (e.g., H1 vs. H3), the sequence homology drops significantly, but the core 3D structure and the long \(\alpha \)-helix features remain well conserved to facilitate membrane fusion. In particular, a High Sequence Identity: Within the same genotype or serotype (e.g., A/H1N1 or A/H3N2 strains circulating in the same few years), the amino acid sequence identity in the stalk region is typically from 95% to 100%.
Because the stalk is highly conserved within subtypes and across broader groups, it is the primary target for universal influenza vaccines and broadly neutralizing antibodies. Researchers utilize this homology to develop chimeric HA constructs and Universal influenza vaccines that redirect the immune system to recognize the conserved stalk rather than the rapidly mutating head.
Moreover, It is worth to note that any process for making or obtaining the claimed product is considered as product by process rather than a structural limitation. Therefore, such process is not considered to have any patentable weight for the product. Therefore, the claimed product is read on a composition comprising a vaccine composition comprising least two different influenza hemagglutinin (HA) wherein the hypervariable regions are deleted, the remaining antigens are the antigens with high similarity is at least 60% , preferably 70% or more preferably 80% between the at least two different influenzas viruses, the deleted hypervariable regions are replaced with a peptide linker in the at least two different influenza A antigens.
As described above, the cited reference still anticipates claims 1-5, 8-9. The rejection for these claims are maintained
Claims 1-5 and 8-9 are still under 35 U.S.C. 102((a) (1) as anticipated by Hai et al. J Virol, 2012 May;86(10):5774–5781)
In the response, Applicants traverse the rejection and submit arguments as cited in paragraph 20,. Moreover, Applicants further asserted that Hai's disclosure that certain head regions exhibit approximately 70% similarity, certain stalk regions exhibit approximately 90% similarity, and certain full-length hemagglutinins exhibit approximately 82% similarity. See, Office Action, pp. 8-9; Hai, p. 5776. However, the cited portions of Hai merely describe sequence relationships among particular chimeric hemagglutinin constructs. The Office Action does not demonstrate that the disclosed values correspond to the specific similarity relationships recited in the claims.
Applicants argument has been respectfully considered, however, it is not persuasive to overcome all claims rejection for the same reasons presented in the last prior art rejection.
In the instant case, Hai et al. teach a 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 are replaced with the stalk region of A/PR/8/34/H1 to make the chimeric HA named cH1/1HA1 and cH5/H1 respectively, wherein the replacements and basis depended on the different influenza HA sequence similarity /homology analysis are presented in Fig. 1. 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 as the whole procedure in Fig. 1 and legend for method).
Moreover, Hai et al. also teach constructing a DNA expressing plasmid vector to express said chimeric influenza HA antigen as a recombinant subunit vaccine as well as a recombinant pseudo virus like particle comprising the DNA construct and RNA transcript molecules inherently.
While 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, 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).
As described above, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAO Q LI whose telephone number is (571)272-0904. The examiner can normally be reached M-F 8 am to 8 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/Primary Examiner, Art Unit 1671
Prosecution Insights