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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 31, 2025. Claims 1-10 and 12-21 are pending and currently examined.
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.
Claims 1-10 and 12-21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection has at least the following grounds.
A. Claim 1 recites “the individuals of the human subject population”, which does not have antecedent basis. Applicant may consider removing the word “the” from the phrase “the individuals”. Additionally, claim 1 and its dependent claims recite “a first, second and third (booster) administration”. It is not clear how to the word “booster” in parenthesis modifies the word “third”. In other words, it is not clear how to correctly interpret the limitation “third (booster) administration”. E.g., it is not clear if there is any difference between a limitation of just “a third administration” and the limitation of “a third (booster) administration”. Applicant must clarify by proper amendment and/or explanation.
B. Claims 2-4, 8-10, 14 and 16 recite the word “about” to modify claimed ranges of a number of parameters. Since the ranges are already proximate, it is not clear what variation to the claimed ranges the word “about” would allow.
Additionally, claims 2-4, 7-10, 14 and 16-17 recite a broad range together with a narrow range in the same claim. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, claim 9 recites “such as 28 days apart”. It is not clear if this limitation is required or not.
C. Claim 5 recites the limitation “wherein the antigen is an inactivated whole Zika virus and the method does not require a third (booster) administration, or wherein the method consists of a first and second administration” which renders the claim indefinite, because it is not clear how to interpret the clause “the method does not require a third (booster) administration” in the context of the claim. E.g., it is not clear if the limitation excludes a third (booster) administration, or just “not required” but not excluded. Applicant must clarify by proper amendment and/or explanation, and explain what difference there is between the limitation of the clause and the limitation of “wherein the method consists of a first and second administration.”
D. Claim 6 recites “wherein the antigen is an inactivated whole Zika virus and the human subject or the individuals of the human subject population are flavivirus primed”. This limitation renders the claim indefinite because the limitation “the human subject or the individuals of the human subject population are flavivirus primed” is not clear.
The Specification defines the term “flavivirus primed human subjects” in [00281] as “Within the meaning of the disclosure, flavivirus primed human subjects are human subjects that provide serum antibodies directed against at least one of the flaviviruses selected from the group consisting of Zika virus, Dengue virus, Yellow fever virus (YFV), Japanese Encephalitis virus (JEV), Usutu-Virus (USUV), St. Louis Encephalitis virus (SLEV) and West Nile virus (WNV) above the threshold of the Luminex assay described above and in Example 6.” However, the specification does not provide a definite value for the “threshold” nor does it provide a clear and specific protocol for measuring “serum antibodies directed against at least one of the flaviviruses” to provide a definite value for one to access if a human subject producing “serum antibodies” against one of the specified flaviviruses can be considered as a “flavivirus primed human subject”.
E. Claim 12 recites “The method according to claim 10, wherein the main peak of the inactivated whole Zika virus when analyzed by size exclusion chromatography is more than 65% or more than 75% or more than 85% of the total area under the curve in the size exclusion chromatography.” This claim is indefinite because it is not clear how to interpret the limitation in the wherein clause. First, it is not clear if a step of analysis by size exclusion chromatography is required for the claimed method. Secondly, the claim does not specify any structural feature for the claimed size exclusion chromatography and vaccine antigen. Since different features (e.g., pore size of the chromatography resin and vaccine antigen components) may produce different results (e.g., peak areas and shapes), it is not clear how the claim-specified values are related to the purity of the vaccine antigen.
F. Claim 14 recites ranges for amount of aluminum adjuvant but fails to specify how these amounts are associated with the vaccine to be administered to a subject. E.g., it is not clear if the specified aluminum amount is contained in one single dose of the vaccine or in a balk volume of vaccine composition containing multiple doses.
G. Claim 21 recites “The method according to claim 5, wherein instead of the inactivated whole Zika virus, an antigen from the Zika virus selected from a subunit antigen or a live attenuated virus or a chimeric virus, or a nucleic acid construct or a viral vector, which is able to express in a human cell a Zika virus antigen, is administered to the human subject or the individuals of the human subject population.” This claim has multiple issues. First, by reciting “instead of the inactivated whole Zika virus”, the claim appears to exclude “the inactivated whole Zika virus”. This is contradictory to claim 5 which requires administration of an inactivated whole Zika virus antigen. Additionally, the claim uses the phrase “selected from” to specify a selection from a list of different vaccine antigens. However, the antigens in the list are linked with “or” which render the list unclear. Applicant may consider using “and” in place of “or” to link the recited antigen forms.
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.
Claim 21 is 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. As indicated in the 112(b) rejection above, claim 21 appears to exclude the “inactivated whole Zika virus” which is required by base claim 5. Therefore, claim 21 fails to include all the limitations of the claim upon which it depends.
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.
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, 6, 8-10, 13-15 and 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Modjarrad et al. (Lancet 2018; 391: 563–71; submitted in IDS filed on Apr. 1, 2025).
Base claim 1 is directed to a method of preventing Zika virus disease in a human subject or a human subject population in need thereof, the method comprising administering to the human subject or the individuals of the human subject population a vaccine or immunogenic composition comprising an antigen from a Zika virus as a first, second and third (booster) administration, wherein the antigen is an inactivated whole Zika virus.
Base claim 5 is directed to a method of preventing Zika virus disease in a human subject or a human subject population in need thereof, the method comprising administering to the human subject or the individuals of the human subject population a vaccine or immunogenic composition comprising an antigen from a Zika virus as a first and a second administration, wherein the antigen is an inactivated whole Zika virus and the method does not require a third (booster) administration, or wherein the method consists of a first and second administration.
Base claim 6 is directed to a method for preventing Zika virus disease in a human subject or a human subject population in need thereof, the method comprising administering to the human subject or the individuals of the human subject population a vaccine or immunogenic composition comprising an antigen from a Zika virus, wherein the antigen is an inactivated whole Zika virus and the human subject or the individuals of the human subject population are flavivirus primed.
Modjarrad teaches a clinical trial study in human subjects for a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate. The study included three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. Adverse events and Zika virus envelope microneutralisation titres up to day 57 were recorded. The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. See Abstract.
Modjarrad teaches that the ZPIV contains a chromatographic-column-purified, formalin-inactivated Zika virus strain (PRVABC59) that was initially obtained from the Centers for Disease Control and Prevention (Fort Collins, CO, USA) and cultivated and passaged in a qualified Vero cell line. After purification and inactivation, ZPIV was diluted to 20 μg/mL, transferred to vials containing phosphate buffered saline, and adsorbed 1:1 to 2 mg/mL aluminium hydroxide gel (Brentagg Biosector, Frederikssund, Denmark). Each vial provided one 0.5 mL dose of 5 μg protein and 500 μg aluminium hydroxide adjuvant. See para bridging pages 564-565.
Modjarrad teaches that 67 individuals were vaccinated (55 with ZPIV and 12 with placebo) on days 1 and 29 and were followed up to day 57 for this analysis (table 1, figure 1). The mean age of all study participants was 31.5 years (SD 8.9), with a slightly younger age distribution among those enrolled at BIDMC. See page 566, right column, para 4. This teaching and together with Figure 1 indicate that two vaccination injections were administered on day 1 and day 29 each.
Modjarrad further teaches that the phase 1 trials are being modified to investigate whether a second boost (i.e., third vaccination) or higher dose will yield more potent and sustained immunogenicity. See page 570, right column, para 3.
Accordingly, Modjarrad teaches a vaccination method against Zika virus comprising administering to a human subject a vaccine candidate comprising a purified formalin-inactivated whole Zika virus. Modjarrad teaches that the vaccination can be done in a two-dose, prime-boost, schedule or a three-dose, prime-boost-boost, schedule.
Regarding claim 6, as indicated in the 112(b) above, the claim is not clear how to interpret the limitation that the subject is “flavivirus primed”. To expedite examination, this limitation is considered as reading on a subject who produces serum antibodies against a flavivirus caused by a pre-infection or a vaccination. Modjarrad teaches that some subjects included in the study had a positive status of flavivirus infection. Moreover, the prime vaccination injection of the Zika virus vaccine can also be considered as causing the subject receiving the second and third doses to be “flavivirus primed”.
Regarding claim 17, Modjarrad teaches that ZPIV contains a chromatographic-column-purified, formalin-inactivated Zika virus strain (PRVABC59). See page 564, right column, last para. The zika virus strain PRVABC59 contains a polypeptide sequence that is at least 99% identical to the claimed SEQ ID NO: 6. See GenBank: AYI50275.1. (polyprotein [Zika virus]. Dated Oct. 29, 2018) as evidence, which discloses the polyprotein sequence of the zika virus strain PRVABC59.
Therefore, Modjarrad teaches each and every aspect of claims 1, 5, 6, 8-10, 13-15 and 17-18.
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 of this title, 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.
Claims 2-4, 7, 12, 16, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Modjarrad et al. (Lancet 2018; 391: 563–71), Lecouturier et al. (NPJ Vaccines. 2020 Mar 12;5(1):19), Shi et al. (US 2020/0197505, published on Jun. 25, 2020) and Kardani et al. (Vaccine 34 (2016) 413–423).
Relevance of Modjarrad is set forth in the 102 rejection above.
Lecouturier teaches that study on optimization of the vaccination process for purified inactivated Zika virus vaccine in cynomolgus macaques. It teaches that among the vaccine candidates, a first-generation ZIKV purified inactivated vaccine (ZPIV), adjuvanted with aluminum hydroxide, developed by the Walter Reed Army Institute of Research (WRAIR), has elicited high seroconversion rates in participants in three phase-I clinical trials. In collaboration with the WRAIR, Sanofi Pasteur (SP) optimized the production scale, culture and purification conditions, and increased the regulatory compliance, both of which are critical for clinical development and licensure of this vaccine. Using a clinical batch of the first generation ZPIV as a benchmark, the authors report that different doses of the optimized vaccine (ZPIV-SP) elicited sustained neutralizing antibodies, specific T- and memory B-cells, and provided complete protection against a ZIKV challenge in cynomolgus macaques. These data provide evidence that the ZPIV-SP vaccine performs at least as well as the ZPIV vaccine, and provide support for continued development in the event of future ZIKV outbreaks. See Abstract.
Fig. 1 of Lecouturier shows a three-dose vaccination schedule with a first, second, and third dose administered respectively on day 1 (D1), day 2 (D2) and day 176 (D176). Fig. 2 shows host immune responses to the ZPIV vaccines caused by the vaccination measured up to day 180. See below:
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Accordingly, Lecouturier teaches a vaccination schedule for inactivated zika virus vaccine containing three doses administered on day 1, day 28 and day 176, as well as serum conversion status until about day 180.
Shi teaches that both inactivated and live-attenuated vaccines have been developed for flaviviruses, including YFV, JEV, TBEV, and DENV (Reference 3). Rapid and promising progress has been made toward ZIKV vaccine development (References 4 and 5). Inactivated ZIKV and subunit vaccines (expressing viral prM/E proteins) have shown efficacy in mice and nonhuman primates (References 6-8). A successful vaccine requires a fine balance between immunogenicity and safety. Live-attenuated vaccines generally offer fast and durable immunity, but sometimes with the trade-off of reduced safety; whereas inactivated and subunit vaccines provide enhanced safety at the cost of reduced immunogenicity, and often require multiple doses and periodic boosters. See [0007].
Accordingly, teachings of Shi indicate that various forms of Zika virus vaccines exist besides inactivated while zika virus vaccines, and that they may be used in prime-boost vaccinations.
Kardani teaches that among different vaccine modalities, prime-boost vaccine strategies could enhance cellular and also humoral immunity in several animal models. These strategies have been applied for the development of vaccines against important infectious diseases such as HIV, SIV, HCV, HSV, and HBV indicating promising results even in clinical trials. Several factors including selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, the order of vector injection, and the intervals between different vaccinations influence the outcome of prime-boost immunization approaches. The reported data suggest that the prime-boost strategy as a combination of vaccines (i.e., heterologous prime-boost) may be better than a single vaccine for protection against infectious diseases. Indeed, in many cases, heterologous prime-boost can be more immunogenic than homologous prime-boost strategy. This review discusses the recent advances in prime-boost immunization strategies as well as their benefits and mechanisms of action. See Abstract.
Accordingly, even though Kardani is silent on Zika virus vaccines, its teachings suggest that heterologous prime-boost immunization regimens exist for vaccination that combine vaccines of different forms in one immunization regimen in the vaccine development to enhance host immune response to vaccine antigens.
Regarding claims 2-4, Modjarrad is silent on when the third administration takes place relative to the second administration. On the other hand, Modjarrad teaches that the first and second vaccine administration were on day 1 and day 28, and that the study on three-dose vaccination is underway.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Modjarrad and Lecouturier to arrive at the invention as claimed, i.e., to arrive at the number of days in the interval between the second and third administrations as claimed based on the teachings of Modjarrad and Lecouturier and through routine experimental optimization.
Regarding claim 7, Modjarrad is silent on the percentage of subjects in the population receiving the vaccine having serum conversion 182 after the second administration. However, claim 7 does not specify additional information about the vaccine to be administered except that the vaccine antigen is inactivated whole zika virus and that the vaccination comprises two administrations. Therefore, the claimed effect is considered as intended results. Based on the teachings of Lecouturier about serum conversion status on various days after the second administration, one of skill in the art would have found it obvious to arrive at the claimed serum conversion status by routinely modify the vaccination, such as antigen dosage, administration routes, adjuvants, intervals between doses, etc., to optimize the vaccination efficiency.
Regarding claim 12, as indicated in the 112(b) rejection, the claim does not specify any structural characteristics of size exclusive chromatography that is used to measure the purification of the inactivated whole zika virus vaccine as claimed. On the other hand, Modjarrad teaches that the ZPIV contains a chromatographic-column-purified, formalin-inactivated Zika virus strain (PRVABC59). See page 564, right column, last para. Based on the above reasoning, one of skill in in art would have found it obvious to produce an inactivated zika virus antigen composition that is pure enough to produce a superb vaccination effect. And, one of skill in the art would expect that the a superb purity would produce a measurement result as claimed.
Regarding claim 16, Modjarrad teaches that after purification and inactivation, ZPIV was diluted to 20 μg/mL, transferred to vials containing phosphate buffered saline, and adsorbed 1:1 to 2 mg/mL aluminium hydroxide gel (Brentagg Biosector, Frederikssund, Denmark). See page 565, left column, para 1. Modjarrad is silent on how much of the antigens is adsorbed to the adjuvant. However, it the percentages of absorbance as claimed are desired that lead to good vaccination effect, one of skill in the art would have found it obvious to do so in the study of Modjarrad.
Regarding claims 19 and 20, Modjarrad is silent on the amount of residue formaldehyde content or residual replicating zika virus. However, if the claimed values represent the amount that are desired in the development of zika virus vaccines, one of skill in the art would have found it obvious to modify the vaccine production process to arrive at the claimed values through routine experimentation.
Regarding claim 21, as indicated in the 112(b) rejection above, the claim is indefinite. To expediate examination, claim 21 is interpreted as if it were directed to a method that comprises the method according to claim 5, further comprising administering to the subject zika virus antigen that is a subunit antigen, a live attenuated virus or a chimeric virus, or a nucleic acid construct or viral vector which is able to express in a human cell a zika virus antigen. This interpretation reads on a heterologous prime-boost immunization regimen.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Modjarrad, Lecouturier, Shi and Kardani to arrive at the invention as claimed. One would have been motivated to do so to develop a heterologous prime-boost vaccination regimen based on the teachings of Kardani using the Zika virus vaccine antigens of Modjarrad, Lecouturier and Shi. There is a reasonable expectation of success that such a vaccination regimen can be designed and tested for efficacies.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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