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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/15/2023 is considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group II, and species DENV-443 (SEQ ID NOS: 25/26,51,52, 89-91 and 128-130) in the reply filed on 9/18/2025 is acknowledged.
Accordingly, claims 1, 26, 36, 47, 76 and 97 are withdrawn from consideration for being directed to non-elected subject matter. Claims 13-25 and 61 are currently under examination.
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 13-25 and 61 are 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.
Claims 13, 14, 15, 16, 17, 18, 19 recite Table 1, Table 2 or Table 3 and Table 4 for antibody heavy and light chain sequences. MPEP 2173.05(s) requires that all claims must be complete by themselves. Since the nucleic acid sequences and amino acid sequences of Table 1-4 can be readily incorporated into the above claims, reference to the specification in these is improper.
Dependent claims 20-25 and 61 are rejected for same reason because they depend on the above claims and fails to remedy the indefiniteness.
Regarding claim 21, it is unclear whether the limitation in parenthesis (line 3 and 5) is part of the claim limitation. The phrase "such as" (line 4 and 6) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 13-25 and 61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
Nature of the invention
Claim 13 is drawn to a method of treating a subject infected with dengue virus or reducing the likelihood of infection of a subject at risk of contracting dengue virus comprising delivering to said subject an antibody or antibody fragment having clone-paired heavy and light chain CDR sequences from Table 3 and 4. Table 3 are heavy chain CDR (CDRH1-3) sequences for DENV-115, 144, 286, 290, 297, 298, 354, 404, 406, 415, 419, 437 and 443, wherein Table 4 are light chain CDR (CDRL1-3) sequences for same antibody. Claims 14-16 recite the antibodies are encoded by clone paired heavy and light chain variable nucleic acid sequences having 70%, 80%, 90%, 95% or 100% identity to SEQ IDs listed in Table 1. Claims 17-19 recite the antibodies are encoded by clone paired heavy and light chain variable amino acid sequences having 70%, 80%, 90%, 95% or 100% identity to SEQ IDs listed in Table 2. Claim 21 recites the antibody is an IgG and comprises FcR mutation. Claim 22 recites the antibody is a chimeric or bispecific antibody. Claims 23 and 25 recite the antibody is administered prior to infection or after infection, and delivers as protein, or RNA or DNA encoding said protein. Claims 24 and 61 recite that the method is for treating female or pregnant female.
The breadth of the claim
The claim scope is rather broad. Claim 13 encompasses preventing and treating a subject, including human of any age and gender, with the antibody or fragment thereof that comprises the CDR listed in Table 3 and 4, for primary or secondary infection of dengue virus, wherein the dengue virus includes all genotypes (I-IV).
The teaching from the specification and the presence of working examples
The specification teaches that DENV3-specific hmAbs were isolated from three children with primary or secondary DENV3 infection (page 77, line 12-17). The specification teaches 15 DENV3-specific neutralizing antibodies neutralizes DENV3 with different level of potencies, and 13 out of the 15 are listed in Tables 1-4. The specification teaches the DENV3-specific hmAbs are grouped into three neutralizing classes, with group 1 antibodies targeting core residues in DENV3 EDI domain, group 2 targeting residues in EDII and a small portion of EDIII of DENV3, and group 3 targeting EDIII and/or a smaller footprint in EDI. The specification teaches that groups 1 and 3 contain a mixture of weak to highly potent neutralizing antibodies, whereas all group 2 antibodies exhibited high neutralizing potency (page 85, 2nd paragraph and page 87, 2nd paragraph). The specification teaches in vitro neutralization potency of anti-flavivirus antibodies does not always correlate with in vivo activity, especially when antibodies target different epitopes or have distinct mechanisms of action (page 89, lines 21-24). The specification teaches group 1a hmAbs DENV-298, 404 and 443 and 1c DENV-144, which recognize EDI showed mixed level of capacity to reduce virus replication in vivo in a mouse model (page 89, lines 31-33), and group 2 hmAbs also has high neutralizing potency in the mouse model, whereas group 3 has less potency to reduce viral load (page 89, lines 6-17). However, the specification does not teach whether any of hmAbs can treat a subject infected with dengue virus in other animal models for human subject. The specification does not teach whether any of the hmAbs can reduce the likelihood of infection of a subject (animal or human) at risk of contracting dengue virus.
The specification taches dengue vaccine induced immunity relies on the development and maintenance of long term protective antibody titers, and B and T cell memory responses, and recent studies with people exposed to natural DENV infections or live attenuated vaccines indicate the specificity rather than total quantity of neutralizing antibodies correlates best with long term protection (page 91, lines 1-5). The specification teaches all 15 hmAbs efficiently neutralized DENV3 strain encoding a G-III E glycoprotein, but natural variation altered the neutralization potency of a subset of antibodies target EDI, EDII and EDIIII (page 94, lines 19-22). The specification teaches the complexity of the DENV3 neutralizing antigenic landscape suggests that the diversity of neutralizing epitopes in other DENV strains also remains largely undiscovered. Based on the teaching from the specification, whether the hmAbs listed in Tables 1-4 can treat and/or prevent different strain/genotype of dengue virus infection in animal or human subject is unpredictable. It is also unpredictable whether said hmAbs is safe and effective in treating and/or prevent dengue virus infection in pregnant female subject.
The teaching from prior art and the level of predictability in the art
The prior art is silent on the hmAbs listed in Tables 1-4 of the specification. In a review article written by Malik in 2023, 3 years post filing (Vaccine 2023, Vol. 11, 1328), it states “to date, no specific antiviral drugs have been approved for dengue virus treatment.” (page 7, 3rd paragraph, 1st line). Malik teaches genomic mutations in the viral genome and drug resistance are the major obstacles in the process of vaccine development (page 7, 4th paragraph, lines 4-5). Malik teaches antibody-dependent enhancement (ADE) is a phenomenon in which certain antibodies, instead of neutralizing them, actually enhance the entry of a virus into target cells and facilitate its replication. Since dengue virus have four different serotypes, a primary infection with one of these serotypes usually leads to long-lasting protective immunity against that particular serotype, but subsequence infections with a different serotype can lead to more severe disease due to ADE (page 12, lines 1-6). Malik teaches ADE poses a major obstacle to the development of a dengue vaccine and vaccine candidate must ensure that the induced antibodies are highly neutralizing and do not enhance viral entry, as well as elicit a balanced immune response to multiple dengue serotypes to reduce the risk of ADE during subsequent infections (page 12, 2nd-3rd paragraph).
With regard to Dengue treatment and/or prevention in pregnant woman, Giraldo-Garcia (Current Tropical Medicine Reports, 2019, Vol.6, pages 231-238) teach there are multiple obstacles that have delayed the progress in obtaining a DENV vaccine for use during pregnancy, including the co-circulation of multiple DENV serotypes as well as other flaviviruses, imperfect knowledge of viral pathogenesis, lack of understanding of the immunological mechanisms of the cross reactive specific cellular and humoral immune responses of DENV antigens with other flaviviruses, lack of a reliable animal model, the complexity of the host immune mechanisms, deficiency of clinical studies involving pregnant women and their infants, and knowledge gaps of the immune mechanisms of DENV infection during pregnancy and in the fetus since pregnancy can alter immune response and the fetal immune response can change throughout pregnancy (bridging paragraph of page 234-235). Giraldo-Garcia concludes “despite the risk of obstetric complications in pregnant women due to infection with dengue virus infection, there is currently no specific treatment or licensed vaccine for use during pregnancy.” (abstract, and page 236, 2nd col., 2nd paragraph, lines 1-4).
As such, at the time of filing of the present application, whether neutralizing antibodies isolated from 3 patients may treat and/or prevent dengue virus in human or other animal is unpredictable.
The amount of experimentation required to practice the invention
Based on the state of art at the time of filing and post filing, there are considerable obstacles for the development of dengue virus vaccine and/or treatment, especially in pregnant women, rendering treating and/or preventing dengue viral infection using neutralizing antibody as disclosed in Table 1-4 of the present application. A skilled artisan would have to rely solely on the teaching from the specification to practice the method as claimed. However, the specification only provide limited information for these hmAbs with varying level of potency toward DENV3 in vitro and in one mouse model. The specification does not teach how to overcome the art recognized obstacle, especially ADE, in human subject or animal model. The specification does not provide any evidence that said hmAbs can treat pregnant women. Therefore, a skilled artisan would have to engage in undue experimentation to practice the method as claimed in claims 13-25 and 61.
Note: the elected species DENV-443, having paired sequences of SEQ ID NO: 25/26, 51/52, 89-91 and 128-130 is free from prior art.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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, Jennifer Dunston can be reached at 571-272-2916. 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.
/CELINE X QIAN/Primary Examiner, Art Unit 1637