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 .
Claims 1, 13-26, 36, 47, 99 and 100 are pending. Claims 1, 26, 36 and 47 are withdrawn. Claims 13-25, 99 and 100 are currently under examination.
This office action is in response to the amendment filed on 4/29/2026.
All previous rejection not reiterated in this office action are withdrawn.
Claim Rejections - 35 USC § 112
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, 99 and 100 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of reducing viral load in a subject for DENV3 infection comprising delivering to said subject an antibody or antibody fragment comprising heaving chain CDR1-3 comprising SEQ ID NO: 89-91 and light chain CDR-3 comprising SEQ ID NO: 128-130, encoded by SEQ ID NO: 25 and 26, or SEQ ID NO: 51 and 52, does not reasonably provide enablement for a method of treating a subject infected with dengue virus comprising delivering to said subject an antibody or antibody fragment that comprises heaving chain CDR1-3 comprising SEQ ID NO: 89-91 and light chain CDR-3 comprising SEQ ID NO: 128-130, encoded by SEQ ID NO: 25 and 26, or SEQ ID NO: 51 and 52, or said antibody encoded by sequences having 70% and above identity with SEQ ID NO: 25 and 26, or 70% and above identity with SEQ ID NO: 51 and 52. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims. This rejection is rewritten to address the amendment.
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 comprising delivering to said subject an antibody or antibody fragment having clone-paired heavy and light chain CDR sequences comprising heaving chain CDR1-3 of SEQ ID NO: 89-91 and light chain CDR1-3 of SEQ ID NO: 128-130. 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 ID 25 and 26. 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 ID NO: 51 and 52. Claim 21, 99 and 100 recites the antibody is an IgG and comprises FcR mutation, or glycan modified to eliminate or enhance FcR or FcRn interaction. 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 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 a method of treating a subject, including human of any age and gender, with the antibody or fragment thereof that comprises the CDR of SEQ ID NO: 89-91 and 128-130, 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. The specification teaches the in vivo potencies of the EDI antibodies were highly variable, and the panel recovered mAbs included both potent and weak inhibitors of virus replication in mice as seen with the group 1a HmAbs DENV-443 and -298. The specifications indicates that future studies are required to evaluate the potency of a subset of these neutralizing human antibodies in a lethal DENV challenge mouse model under prophylactic and therapeutic conditions (page 95, lines 10-12). Based on the teaching from the specification, experimental evidence suggests -443, the antibody comprising CDR1-3 of SEQ ID NO: 89-91 and SEQ ID NO: 128-130, encoded by SEQ ID NO: 25 and 26 or SEQ ID NO: 51 and 52 can reduce viral load in a mouse model challenged with DENV3 infection. There is no experimental evidence said antibody can treat different strain/genotype of dengue virus infection in animal or human subject. It is also unpredictable whether said hmAbs is safe and effective in treating dengue virus infection in pregnant female subject. With regard to other antibody having sequence similarity with SEQ ID NO: 25 and 26 or SEQ ID NO: 51 and 52, or an antibody that only comprises short segments of CDR1-3 of SEQ ID NO: 89-91 and SEQ ID NO: 128-130, the specification does not teach whether such antibodies have same inhibitory effect on viral load.
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 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 provide therapeutic treatment of dengue virus in human or 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 dengue viral infection using neutralizing antibody as claimed of the present application unpredictable. 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. Nor does the specification teaches whether antibody encoded by sequences having 70% or above identity with SEQ ID NO: 25 and 26, or SEQ ID NO: 51 and 52 provides neutralizing activity with hmAbs having 100% sequence identity with SEQ ID NO: 25 and 25, or SEQ ID NO: 51 and 52. Therefore, a skilled artisan would have to engage in undue experimentation to practice the method as claimed to its full scope.
Response to Arguments
Applicant argues that mouse model provided in the specification is an art accepted model. Applicant argues that the antibodies were obtained from human subjects that had survived a highly viral infection and that the antibodies were shown to exhibit neutralizing in vitro prior to animal testing is strong evidence in favor of operability. Applicant argues that antibody DENV-443 was shown to reduce viral burden in a mouse model, reduced viral titers by greater than 3 log with IC50 values in the 4-7 ng/ml range and was considered a potent inhibitor of virus replication. Applicant argues that the rejection against a non-existent claim because the office action states that there is no evidence supporting effective treatment of all strains of DENV. Applicant argues that the alleged need for vaccines to have long term protective antibody titers are not required by the claim and cannot be required to enable the mere treatment of a subject. Applicant argues that natural variation/resistance is always a problem with immunological vaccines, and just because viruses can mutate and evade vaccines do not render vaccines “non-enabled.” Applicant argues that hundreds of SARS-CoV-2 patents have issued despite this concern, and problems, challenges, hurdles and difficulties do not equate to non-enablement because all that is required of the claim is that the antibody DENV-433 be able to neutralize dengue, to reduce viral dengue load, or to impair viral replication to some extent. Applicant argues that potential to cause ADE can be eliminated by engineering point mutations in the Fc region. Applicant argues there is no well-established in vivo model that fully recapitulate the process of dengue virus induced pathogenesis in humans or the concern of potential antibody-enhanced disease in humans, and regulators of candidate vaccine, drug and antibody trials have allowed testing even licensure of medical countermeasures for which the principal in vivo preclinical data were obtained in the mouse model used in the specification. Applicant argues that clinical trials of dengue vaccines have shown that there is in fact a correlation between protection in animal against virus replication and antibody levels in the serum.
The above argument has been fully considered. In view of the claim amendment filed on 4/29/2026, limiting the antibody to comprise heavy chain CDR1-3 of SEQ ID NO: 89-91 and light chain CDR1-3 of SEQ ID NO: 128-130, the rejection is modified to indicate the enabled scope as discussed above. However, the arguments are not persuasive for the entire scope for reasons discussed in previous rejection and above. Applicant is reminded that the 112(a) statues requires the specification to provide 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. Applicant erroneously interpreted the rejection, which is not based on a single problem, challenge and/or hurdle discussed in the art, but based on a thorough analysis of a combination of Wands factor, including (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)). In the present case, the nature of the invention is a treatment method for subjects infected with dengue virus. According to commonly used term therapeutic treatment refers to any intervention or method aimed at healing, alleviating symptoms, or curing of a disease. In the present case, as discussed in the specification, symptoms of a dengue viral infection encompasses mild fever, severe Dengue Hemorrhagic Fever and Dengue Shock syndrome (page 1, last paragraph). Since claim 13 broadly claim a method of treating dengue virus infection, the enablement scope encompasses provide treatment an infected subject and evaluate whether any of the symptoms are alleviated, cured or at least improved in said subject. The claim scope also broadly covers the infection by different subtypes and strain of DENV. The fact that claim does not recite a specific subtype and/or strain does not mean the claim is non-existent, but an indication that the claim broadly covers all types of infection and a wide range of symptoms being treated. Lastly, the experimental evidence provided in the specification for antibody -443 has been considered and the enabled scope is indicated as above for this antibody in reducing viral replication and viral load. However, as indicated in the breadth of the claim, the claim is not limited this specific antibody -443, but any antibody that comprises a short segments that comprises SEQ ID NO: 89-91 and SEQ ID NO: 128-130, or having sequence identity 70%-95% to SEQ ID NO: 25 and 26, or SEQ ID NO: 51 and 52. In view of lack of teaching from the specification for this broadly claimed genus of antibody, and art recognized unpredictability, a skilled artisan would have been engage in undue experimentation to make such antibody, and testing them to determine whether they would function as -443. Therefore, for reason discussed in previous rejection and set forth above, the claimed invention is enabled to the scope as indicated above.
The declaration under 37 CFR 1.132 filed 4/29 is partially persuasive so that the rejection of claims 13-25, 99 and 100 based upon 112 (a), has been modified to the scope of enablement rejection as set forth above.
The declaration states the there is no well-established in vivo model that fully recapitulates the process of dengue virus induced pathogenesis in human or concern of potential antibody-enhanced disease in humans, but regulators of candidate vaccine, drug and antibody trials have allowed testing and licensure of medical countermeasures for which the principal in vivo preclinical data were obtained in exactly the animal models used in the specification. The declaration states that the general principle for evaluation is to examine the antiviral effects (reduction of viral load) in animals receiving antibody, and clinical trail of dengue vaccines have shown there is a correlation between protection in animals against virus replication and antibody levels in serum. The declaration states that the preclinical studies presented in the application as filed established the potential for these antibodies in clinical use and would be readily accepted by those of skill in the art.
As discussed in the above response, in view of the claim amendment filed on 4/29/2026, and considering the mouse model in evaluating the viral load, the rejection has been modified to indicate the enabled scope.
Conclusion
THIS ACTION IS MADE FINAL. 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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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