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 .
Election/Restrictions
Applicant’s amendment filed 9/22/2025 is acknowledged. New claim 60 is added.
Applicant’s election without traverse of Group II in the reply filed on 3/2/2023. No species election was required in the mailing of 1/3/2023 and claims 6-25 were previously canceled by applicants on 3/5/2021.
The requirement is still deemed proper and is therefore made FINAL.
Claims 26-31, 34-44, 46-49, and 51-60 are under examination on the merits.
Response to Amendment
The declaration under 37 CFR § 1.132 filed 9/22/2025 is insufficient to overcome the rejection of the claims under 35 U.S.C. 103(a) and the teachings of Osorio et al (Expert Review of Vaccines, 2016, Vol. 15, No. 4, pp 497-508; see below) as set forth in the last Office action because: the Declaration under 37 C.F.R. § 1.132 by Dr. Hansi Dean is acknowledged and has been fully considered by the Examiner but is not persuasive for the reasons listed below. There is a reasonable expectation that one of ordinary skill in the art would have arrived at the claimed invention, as discussed below. The prior art is discussed in the rejections below.
The Declaration is not convincing because Dr. Dean and Applicant argue that there is a safety concern, and there is a fundamental problem with Dengvaxia because it is a tetravalent vaccine. However, it is important to consider how similar are the tetravalent vaccines, because we cannot compare apples to oranges. All of the mentioned safety issues that might arise, they are a risk when Dengvaxia is administered. However, the claimed invention, and the vaccine disclosed by Osorio, appear to be structurally distinct from Dengvaxia. One of ordinary skill in the art reading Osorio would not necessarily be concerned with the safety issues related to Dengvaxia, because they are fundamentally different dengue vaccines. The primary similarity between the vaccines is that they utilize a representative prM of each of the four dengue serotypes. On the other hand, the vaccine of Osorio and the claimed invention is a dengue virus backbone, specifically the 16681 backbone. Dengvaxia has a yellow fever backbone, which may be associated with the seronegative reaction.
The examiner reviewed the declaration and appreciate the statements made therein, ultimately the concern is: Applicant is arguing there is a safety concern with administering Dengvaxia; however, the claimed invention and the teaching of Osorio appear to provide a fundamentally different dengue virus vaccine because they are providing a dengue virus backbone rather than yellow fever virus, so those concerns are not particularly persuasive. The scope of the claimed invention does not appear to be different than Osorio, that is why Osorio is relevant prior art, because the composition appears to be the same. Therefore, the argument made in Declaration and Remarks is not persuasive. One of ordinary skill in the art would arrive at the claimed invention based on the teachings of Osorio et al.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 7/10/2025, 7/28/2025, and 9/22/2025 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Response to Arguments
Applicant's arguments filed 9/22/2025 have been fully considered but they are not persuasive towards the rejections previously raised. TAK-003 is another name for TDV or Denvax (Malabadi, et al. Malabadi, et al. Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; p. 13, col. 1, para. 2), which is the vaccine administered in Osorio. See response below.
Applicant has elected to hold the double patenting issues in abeyance pending resolution of the other claim rejections. The previous rejection of based on copending Application No. 17818610 is withdrawn due to abandonment of the application. The remaining double patenting rejections have been determined to be proper by the Examiner and are therefore maintained for reasons of record.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Dengue disease is a disease in which a second infection can lead to severe disease complications in a subset of patients. Antibody-dependent enhancement (ADE) can occur after a primary infection because that primary infection elicits antibodies with varying capacity to neutralize dengue virus serotypes. Antibodies with poor neutralizing activity can bind heterotypic dengue virus at a suboptimal occupancy threshold. Rather than neutralizing the heterotypic virus, these antibodies can cause the virus to have increased ability to infect Fc gamma receptor bearing cells. This can lead to increased viremia, enhanced pathogenesis, and increased disease severity. This complication creates a potential safety issue in dengue vaccine development, and that potential safety issue became reality for Dengvaxia based on events that occurred after it was introduced to the public. At the filing date of the present claimed invention, it is Dr. Dean’s opinion that Dengvaxia could be eliciting an incomplete or imbalanced immune response to dengue virus serotypes and causing ADE of dengue disease in seronegative patients when they were subsequently infected with dengue virus. Because of dengue’s ADE tendency, there were concerns within the scientific community (i.e., those of ordinary skill in the art) at the filing date of the present claimed invention that the safety problems which arose with Dengvaxia could occur with another dengue vaccine in seronegative patients, even with a product distinct in structure from Dengvaxia. The actual detailed cause of the safety issue with Dengvaxia, i.e., what part or combination of parts of the vaccine caused the incomplete or imbalanced immune response in seronegative patients, was not understood. Therefore, it could not be predicted with certainty whether a different dengue vaccine, with a different structure and/or different immunological responses to the 4 different dengue virus strains, would be safe in seronegative patients. Several members of the scientific community voiced the same concerns, note in publications.
Therefore, according to Dr. Dean, it was unpredictable to a person of ordinary skill in the art, as of the filing date of the above-referenced application, whether the present claimed invention of administering a tetravalent dengue virus composition could safely be conducted without determining or knowing the subject’s serostatus. Dr. Dean states that the scientific community would have thought that switching out the yellow fever backbone for a dengue backbone would not make the claimed invention predictably successful, i.e., safe and efficacious without knowing serostatus. It was not known what caused the incomplete response in Dengvaxia. Options included other factors than the yellow fever backbone, such as an imbalanced immune response across the 4 different dengue strains. Therefore, at the time of filing, it was not predictable within the scientific community that the vaccine composition taught by Osorio would be safe and efficacious in seronegative patients and could be administered safely without determination of serostatus.
According to Dr. Dean, the results of the Phase 1 and Phase 2 studies in Osorio would not support a conclusion by the scientific community and thereby a person of ordinary skill in the art that the claimed method of dengue vaccination would be predictably successful in terms of safety and efficacy with no determination or knowledge of serostatus, as presently claimed. The phase 1 and phase 2 studies were not designed to make such a determination, and were insufficient to predictably identify less common risks, such as risk identified with Dengvaxia regarding the safety issue seen with subsequent dengue infection in baseline seronegative patients. A sufficiently large Phase 3 study in a dengue endemic region would be necessary to determine whether the present claimed invention method could be practiced successfully with no determination or knowledge of serostatus. The scientific community, at about the time of the filing date of the present invention, voiced similar opinions.
Phase 1 studies discussed in Osorio were conducted in dengue non-endemic regions in the US and in the high elevation town of Rionegro in Columbia, which is free of the dengue-carrying mosquito. Therefore, the patients would not be expected to suffer dengue infection during these Phase I studies and so the safety issue associated with Dengvaxia would not have been expected to be detectable in the Phase I subjects even if such a safety issue had existed. No conclusions about the safety of TDV in seronegative subjects could be made for at least this reason, in addition to other reasons.
The Phase 2 study DEN-203 reported in Osorio was conducted in a dengue endemic area, but the number of seronegative subjects in the study and their seropositive counterpart subjects were both small. Therefore, it is highly improbably that the less common safety event in seronegative subjects seen with Dengvaxia could be detected in DEN-203. Even if a relevant safety event had been detected, no meaningful analysis of the data would have been possible. As can be determined in Table 2 of Osorio, approximately 130 seronegative vaccinated subjects were included in the study and were compared to approximately 50 seronegative placebo subjects. Given the less common occurrence of the Dengvaxia safety issue in seronegative subjects, results from a clinical trial different than that reported by Osorio, namely a sufficiently large Phase 3 trial conducted in a dengue endemic region (as in the present application which included over 20,000 subjects), would need to be evaluated in order to determine with reasonable predictability that the dengue virus composition of the invention did not cause a similar safety issue and could safely be administered without determining or knowing serostatus.
Applicant’s argument was fully considered but determined to not be persuasive:
The Dengvaxia vaccine had problems but it had a yellow fever backbone, which is different from the tetravalent dengue vaccine of Osorio. One of ordinary skill in the art, being aware of the problems associated with Dengvaxia, would be motivated to use something different, like the vaccine composition taught by Osorio. Applicant asserts that the statement by Wilder is indicative of the opinion of one of ordinary skill in the art at the time of the instant application’s filing. Other than the assertions made by Applicant, Applicant’s arguments focus on an opinion by an expert in the field (Wilder), but the expert in the field made assumptions that, because Dengvaxia had significant problems, others vaccine compositions would as well. Applicant’s suggestion that the scientific community, based on that the information presented in Wilder, did not know whether the problems associated with Dengvaxia were attributable to the Dengue components or if they had to do with the difference in the Dengvaxia product, are ultimately opinions. The opinions are valid, but Osorio was published in 2016, two years before applicant's earliest priority date. Furthermore, the TDV vaccine of Osorio appears to be the same as what applicants employ in their claimed methods. Therefore, if applicants are attempting to question the enablement of the teachings of Osorio for vaccinating against dengue virus, the perhaps the same enablement concerns would apply to the instant invention.
Notably, Osorio provides peer-reviewed, scientific information. The question is, does Osorio provide enough information, when taken into consideration along with the Dengvaxia issues, to make it sound like, if it were offered to somebody, they would not be worried. One important aspect of Osorio are that there were no side effects. The TDV safety section of Osorio does not present anything that is alarming. One of ordinary skill in the art would, after reading this section of Osorio would not be concerned about the safety and tolerability of using TDV, because of its apparent lack of side effects and its nature as distinct from the Dengvaxia construct. Osorio is very detailed in terms of what they tested and results they got, observing reactions and the severity of reactions. It is not apparent to the examiner what evidence from that would suggest that the TDV would elicit anything close to that of Dengvaxia in patients, whether they be seropositive or seronegative. The examiner is not ignoring Applicant's assertions regarding concerns about Dengvaxia, but to say that any other tetravalent vaccine will have similar problems is not really indicated by the results shown in Osorio. Dengvaxia is fundamentally different than the claimed TDV. The TDV that Osorio used appears to be a species of one of the TDVs of claim 26, but certainly, and most likely, the same TDV of claim 28. The intent of Osorio is to vaccinate, and they're using the same product. Lastly, it would appear that the TDV of Osorio carried out its normal process of inducing immune responses when administered to seropositive and seronegative subjects (see MPEP 2112.02 (I.)) and did not elicit serious side effects in those patients. Therefore, given that the TDV of Osorio and the instant invention appear to be the same, the safety and tolerability of the TDV of Osorio would be inherent.
The examiner acknowledges that the described Dengvaxia® experience, causing more severe disease in seronegative subjects, would lead one of skill in the art to determine the dengue serostatus before vaccinating a subject with Dengvaxia®. However, Dengvaxia® and the both the TDV vaccine of Osorio et al. and the claimed TDV candidate vaccine are distinct vaccines and thus one of skill in the art would not necessarily expect the TDV vaccine of Osorio et al. to have the same side-effects observed with Dengvaxia®. When one of skill in the art further considered that Osorio et al. specifically noted that in Phase 1 and 2 studies, the live attenuated tetravalent vaccine candidate was well tolerated by children and adults aged 1.5-45 years, irrespective of prior dengue exposure (see Abstract), he or she would not expect serostatus testing to ensure no prior dengue infection in the subject to be necessary for safe or effective administration of the vaccine. Ultimately, Dengvaxia® and the claimed vaccine TDV are distinct compositions that one of skill in the art would be motivated to administer TDV in place of Dengvaxia, since it can be administered to a subject regardless of dengue serostatus.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(Previous Rejection Maintained and Claim 60 added) Claims 26-31, 34, 39-44, 46 and 54-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-9 of U.S. Patent No. 11464815 B2, in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”).
Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions claim a method of inoculating a subject against virologically confirmable dengue disease with a tetravalent dengue virus composition including 4 live attenuated dengue virus strains, serotypes 1-4. The method comprises a vaccination consisting of the steps of:
selecting a subject for administration of the unit doses of the tetravalent dengue virus composition in need for protection against dengue infection
administering a first unit dose of the tetravalent dengue virus composition to the subject, and
administering a second unit dose of the tetravalent dengue virus composition to the subject within three months after the first unit dose, wherein the method does not include a step of determination whether there was a previous dengue infection in the subject, wherein determination of the previous dengue infection is characterized by a laboratory confirmed history of dengue or a validated serological test.
The method, which is safe and effective in providing a combined vaccine efficacy of at least 60%, which represents at least 60% reduction in dengue disease occurrence in vaccinated subjects compared to unvaccinated subjects for at least 12 months after a second unit dose administration in subjects aged 4 to 60 years of age against all four serotypes.
The tetravalent dengue virus (TDV) composition includes chimeric dengue serotype 2/1 strain, 2/3 strain and 2/4 strain, and a dengue serotype 2 strain. The dengue serotype 2 strain is derived from wild-type DEN-2 16681 and is characterized by differing in at least a), b), and c) from the wild type as follows: a) 5’-noncoding region (NCR)-57 (nt-57 C-to-T), b) NS1-53 Gly-to-Asp (nt-2579 G-to-A) and c) NS3-250 Glu-to-Val (nt-5270 A-to-T); and the 3 chimeric strains (2/1, 2/3, and 2/4) are derived from the serotype 2 strain by replacing the structural proteins prM and E from serotype 2 strain with the corresponding structural proteins from the other dengue serotypes, resulting in the chimeric dengue strains: a DENV -2/1 chimera, DENV-2/3 chimera, and DENV-2/4 chimera.
The tetravalent dengue virus composition can be in the form of a unit dose comprising:
a dengue serotype 1 in a concentration of at least 3.3 log10 pfu/0.5 ml,
a dengue serotype 2 in a concentration of at least 2.7 log10 pfu/0.5 ml,
a dengue serotype 3 in a concentration of at least 4.0 log10 pfu/0.5 ml, and
a dengue serotype 4 in a concentration of at least 4.5 log10 pfu/0.5 ml.
This TDV composition is in the form of a lyophilized unit dose which is reconstituted with 0.5 ml of a pharmaceutically acceptable diluent.
The method can be used on subjects under 9 years of age, 4-5 years of age, 6-11 years of age, or 12-16 years of age, and the subject or subject population can be from a dengue endemic or non-endemic region. The method can be applied wherein the subject population is from a region wherein the seroprevalence rate is unknown, and/or wherein the seroprevalence is below 80%, 70%, or 60%.
The method inherently includes use of a pharmaceutically acceptable carrier for the tetravalent dengue vaccine composition because otherwise it would not be safe or effective.
Alternatively, the method’s combined vaccine efficacy against dengue serotype 2 can be measured using a 2-sided 95% confidence interval, wherein the lower bound is more than 70% measured against the placebo against dengue serotype 2 in a subject population of at least 5,000 healthy subjects.
Alternatively, the method’s combined vaccine efficacy against virologically-confirmed dengue disease with hospitalization against all four serotypes can be measured using a 2-sided 95% confidence interval, wherein the lower bound is more than 70% when measured against placebo in a subject population of at least 2,000 healthy subjects being seronegative against all serotypes at baseline.
Additionally, the dengue serotype 2 construct possesses genes that encode dengue virus NS1, NS2 (NS2A and NS2B), NS3, NS4 (NS4A and NS4B), NS5 nonstructural proteins, as well as capsid, pre-membrane (prM) and envelope (E) proteins (Page 9, Figure 1).
While the patented invention does not require that the TDV vaccine is TAK-003, Malabadi discloses that TAK-003 is another for TDV, also known as Denvax (p. 13, col. 1, para. 2). Therefore, one of ordinary skill in that art would be motivated to and have a reasonable expectation of success at adapting the patented invention to include TAK-003.
(Previous Rejection Maintained and Claim 60 added) Claims 26-31 and 34-44, 46-49, & 51-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11590221 B2 in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”). Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions claim a method of inoculating a subject against virologically confirmable dengue disease with a tetravalent dengue virus composition including 4 live attenuated dengue virus strains, serotypes 1-4. The method comprises a vaccination consisting of the steps of:
selecting a subject from the subject population without determining whether the subject had a previous dengue infection,
administering a first unit dose of the tetravalent dengue virus composition to the subject population comprising seropositive subjects, seronegative subjects, or a combination thereof, the tetravalent dengue virus composition comprising four dengue virus strains representing serotype 1, serotype 2, serotype 3 and serotype 4, and
administering a second unit dose of the tetravalent dengue virus composition to the subject population within 3 months of administration of the first unit dose.
The method, which is effective in providing a combined vaccine efficacy of at least 60%, which represents at least 60% reduction in dengue disease occurrence in vaccinated subjects compared to unvaccinated subjects for at least 18 months after a second unit dose administration in subjects against all four serotypes.
The method can be applied wherein the subject population is from a region wherein the seroprevalence rate is unknown, and/or wherein the seroprevalence is below 80%, 70%, or 60%, or wherein the subject population is exposed to a dengue outbreak, which can be due to dengue serotype 2 and/or dengue serotype 1. The associated virologically confirmable dengue disease can be due to dengue serotype 2, and/or dengue serotype 1.
Alternatively, the method provides a combined vaccine efficacy against virologically confirmable dengue disease with hospitalization of at least 65%, which is represented by a reduction of at least 65% dengue disease with hospitalization occurrence in vaccinated subjects compared to unvaccinated subjects, in each of seropositive and seronegative subjects, for at least 18 months after a second unit dose administration. The total concentration of dengue serotypes in this alternative method can be: serotype 2 in pfu/0.5 ml is less than 10%; serotype 4 in pfu/0.5 ml is at least 50%; serotype 1 in pfu/0.5ml is at least 1%; and concentration of serotype 3 in pfu/0.5 ml is at least 8%, or at least 10%, or at least 12%, or at least 14%, or at least 16%, or at least 18% (and where the subject population is 2-17 years of age or 4-16 years of age). Or, the total concentration of dengue serotypes in this alternative method can be: serotype 2 in pfu/0.5 ml is less than 2%, concentration of dengue serotype 4 in pfu/0.5 ml is at least 50%, the concentration of dengue serotype 1 in pfu/0.5 ml is at least 1%, and the concentration of dengue serotype 3 in pfu/0.5 ml is at least 6%, wherein the subject is 18 to 60 years of age.
The tetravalent dengue virus (TDV) composition includes chimeric dengue serotype 2/1 strain, 2/3 strain and 2/4 strain, and a dengue serotype 2 strain. The dengue serotype 2 strain is derived from wild-type DEN-2 16681 and being characterized by differing in at least a), b) and c) from the wild type as follows: a) 5’-noncoding region (NCR)-57 (nt-57 C-to-T), b) NS1-53 Gly-to-Asp (nt-2579 G-to-A) and c) NS3-250 Glu-to-Val (nt-5270 A-to-T); and the dengue serotype 1, serotype 3, and serotype 4 strains being derived from the serotype 2 strain by replacing the structural proteins prM and E from serotype 2 strain with the corresponding structural proteins from the other dengue serotypes, resulting in the chimeric dengue strains: a DENV -2/1 chimera, DENV-2/3 chimera, and DENV-2/4 chimera.
The tetravalent dengue virus composition can be in the form of a unit dose comprising:
a dengue serotype 1 in a concentration of at least 3.3 log10 pfu/0.5 ml,
a dengue serotype 2 in a concentration of at least 2.7 log10 pfu/0.5 ml,
a dengue serotype 3 in a concentration of at least 4.0 log10 pfu/0.5 ml, and
a dengue serotype 4 in a concentration of at least 4.5 log10 pfu/0.5 ml.
This TDV composition is in the form of a lyophilized unit dose which is reconstituted with 0.5 ml of a pharmaceutically acceptable diluent.
The method is safe, can be used on subjects under 9 years of age, 4-5 years of age, 6-11 years of age, or 12-16 years of age, and the subject or subject population can be from a dengue endemic or non-endemic region.
The method inherently includes use of a pharmaceutically acceptable carrier for the tetravalent dengue vaccine composition because otherwise it would not be safe or effective.
Additionally, the dengue serotype 2 construct possesses genes that encode dengue virus NS1, NS2 (NS2A and NS2B), NS3, NS4 (NS4A and NS4B), NS5 nonstructural proteins, as well as capsid, pre-membrane (prM) and envelope (E) proteins (Page 8, Figure 1).
While the patented invention does not require that the TDV vaccine is TAK-003, Malabadi discloses that TAK-003 is another for TDV, also known as Denvax (p. 13, col. 1, para. 2). Therefore, one of ordinary skill in that art would be motivated to and have a reasonable expectation of success at adapting the patented invention to include TAK-003.
(Previous Rejection Maintained and Claim 60 added) Claims 26-28, 36, 37, 39, 52, 56-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7-8, 10, 15, 17-19, 21, 22, 31, and 44-45 of copending Application No. 18149742 (reference application) . Although the claims at issue are not identical, they are not patentably distinct from each other because the 18/149742 application claims would anticipate the present claims. Both sets of claims are drawn to vaccinating a subject against dengue disease utilizing a tetravalent dengue virus composition with four live attenuated dengue virus strains, with overlapping limitations including age of the subject, and specific mutations relative to DEN-2 16681. The composition of each method includes a chimeric dengue serotype 2/1 strain, a dengue serotype 2 strain, a chimeric dengue serotype 2/3 strain, and a chimeric dengue serotype 2/4 strain. The applications also both involve at least two unit doses of the tetravalent dengue composition. Each method involves the composition further comprising at least dengue non-structural proteins NS1, NS2, and NS4, and specifically NS1, NS2 (NS2A and NS2B), NS3, NS4 (NS4A and NS4B), NS5 nonstructural proteins, as well as capsid, pre-membrane (prM) and envelope (E) proteins (Figure 1). Both methods also have embodiments wherein the subject is exposed to a dengue outbreak, and the outbreak may be due to a dengue serotype 2 and/or serotype 1.
The Applications differ in that the copending method requires a vaccine efficacy of at least 60% against dengue serotype 2 which is represented by at least 60% reduction in dengue disease occurrence attributed to dengue serotype 2 in vaccinated subjects compared to unvaccinated subjects, whereas some embodiments of the instant method require vaccine efficacy against all four serotypes in preventing dengue disease of above 30%. Although embodiments of each method require a second dose of the virus composition to be administered to the subject, where the instant application requires the second dose to be administered within 3 months of administration of the first dose, the copending application requires at least 4 weeks between administration. The applications differ in that the copending method requires at least 4 weeks between administration of the first unit dose and second unit dose. Where the copending method subject is 2 months or older, the instant application describes subjects as under 9 years of age, up to 60 years old, or in alternative embodiments 2-17, 4-16, or 18-60 years of age, or older. The copending method also requires particular sequences for the dengue serotypes, whereas the instant application largely does not.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Previous Rejection Maintained and Claim 60 added) Claims 26-31, 34-36, 39, 40-43, and 55-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8-10, 12, 21, 23-24, 26, 34, 36, and 39 of US Patent No. 12201683 in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”). Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent No. 12201683 claims would anticipate the instant claims. Both sets of claims are drawn to vaccinating a subject against dengue disease utilizing a tetravalent dengue virus composition with four live attenuated dengue virus strains, with overlapping limitations including dosing and proportioning of the dengue viruses, specific mutations relative to DEN-2 16681, and embodiments involving the subject or subject population being seronegative to previous dengue infection. The composition of each method includes a chimeric dengue serotype 2/1 strain, a dengue serotype 2 strain, a chimeric dengue serotype 2/3 strain, and a chimeric dengue serotype 2/4 strain. Each set of claims also both involve at least two unit doses of the tetravalent dengue composition. Additionally, US Patent No. 12201683’s method involves a dengue serotype 2 construct that possesses genes that encode dengue virus NS1, NS2 (NS2A and NS2B), NS3, NS4 (NS4A and NS4B), NS5 nonstructural proteins, as well as capsid, pre-membrane (prM) and envelope (E) proteins (Figure 1).
The Applications differ in that US Patent No. 12201683 is drawn to a method for vaccinating against both dengue and hepatitis A, whereas the instant application focuses on dengue virus. Additionally, whereas the instant application teaches administration of the second dose within three months of the first, the copending method administers the second dose about three months after the first. Where the copending method has embodiments wherein the subject is from a dengue endemic region or non-endemic region, the instant method is drawn to wherein the subject is from a region where the seroprevalence rate is unknown and/or wherein the seroprevalence is below 80%, 70%, or 60%, or alternatively the subject is exposed to a dengue outbreak. Where the copending method subject is 2 to 60 years of age, the instant application describes subjects as under 9 years of age, up to 60 years old, or in alternative embodiments 2-17, 4-16, or 18-60 years of age, or older. Although embodiments of the instant application requires determination of previous dengue infection by laboratory confirmed history of dengue or a validated serological test, the copending application does require the subject to be seronegative to all dengue serotypes.
While the patented invention does not require that the TDV vaccine is TAK-003, Malabadi discloses that TAK-003 is another for TDV, also known as Denvax (p. 13, col. 1, para. 2). Therefore, one of ordinary skill in that art would be motivated to and have a reasonable expectation of success at adapting the patented invention to include TAK-003.
(Previous Rejection Maintained and Claim 60 Added) Claims 26-28, 39, 56-57, and 60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33-39 of copending Application No. 18/821,030 (reference application) in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”). Although the claims at issue are not identical, they are not patentably distinct from each other because the 18/821,030 application claims would anticipate the present claims. Both sets of claims are drawn to vaccinating a subject (instant) or inducing an immune response (copending) against dengue utilizing a tetravalent dengue virus composition with four live attenuated dengue virus strains, with overlapping limitations including age of the subject, and specific mutations relative to DEN-2 16681. The composition of each method includes a chimeric dengue serotype 2/1 strain, a dengue serotype 2 strain, a chimeric dengue serotype 2/3 strain, and a chimeric dengue serotype 2/4 strain. The applications differ in that the copending method is limited to human subjects less than 18 years of age, and limitations regarding chimeric virus supply seeds involving genetic analysis.
While the patented invention does not require that the TDV vaccine is TAK-003, Malabadi discloses that TAK-003 is another for TDV, also known as Denvax (p. 13, col. 1, para. 2). Therefore, one of ordinary skill in that art would be motivated to and have a reasonable expectation of success at adapting the patented invention to include TAK-003.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Previous Rejection Maintained and Claim 60 Added) Claims 26-30, 56-57, and 60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/980,441 (reference application) in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”). Although the claims at issue are not identical, they are not patentably distinct from each other because the 18/980,441 application claim would anticipate the present claims. Both sets of claims are drawn to vaccinating a subject against dengue disease utilizing a tetravalent dengue virus composition with four live attenuated dengue virus strains, with overlapping limitations including age of the subject, and specific mutations relative to DEN-2 16681. The composition of each method includes a chimeric dengue serotype 2/1 strain, a dengue serotype 2 strain, a chimeric dengue serotype 2/3 strain, and a chimeric dengue serotype 2/4 strain.
The applications differ in that the copending method encompasses vaccination against hepatitis A and dengue disease, whereas the instant application is drawn to a method of vaccinating against dengue disease. The applications differ in that the copending method requires particular sequences for the dengue strains, whereas the instant application largely does not.
While the patented invention does not require that the TDV vaccine is TAK-003, Malabadi discloses that TAK-003 is another for TDV, also known as Denvax (p. 13, col. 1, para. 2). Therefore, one of ordinary skill in that art would be motivated to and have a reasonable expectation of success at adapting the patented invention to include TAK-003.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
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.
(Previous Rejection Maintained and Claim 60 Added) Claims 26-31 and 34-44, 46-49, and 51-60 are rejected under 35 U.S.C. 103 as being unpatentable over Osorio et al (Expert Review of Vaccines, 2016, Vol. 15, No. 4, pp 497-508) in view of Malabadi et al. (Dengue Virus Disease: Recent Updates on Vaccine Development. IJRSI. Volume IV, Issue VII, July 2017. ISSN 2321-2705; hereinafter referred to as “Malabadi”).
The claimed invention is drawn to a method of vaccinating a subject against virologically confirmable dengue disease, said method comprising administering to the subject a tetravalent dengue virus composition including 4 live attenuated dengue virus strains representing serotypes 1-4, wherein the method does not include a step of determination whether there was a previous dengue virus infection in the subject, wherein determination of the previous dengue infection is characterized by a laboratory confirmed history of dengue or a validated serological test, and wherein each of the four live attenuated dengue virus strains is selected from a dengue virus comprising all components from the same dengue serotype or a chimeric dengue virus having parts from two dengue serotypes. The tetravalent dengue virus (TDV) composition includes chimeric dengue serotype 2/1 strain, 2/3 strain and 2/4 strain and a non-chimeric dengue serotype 2 strain. The dengue serotype 2 strain is derived from wild-type strain DEN-2 16681 and being characterized by differing in at least a), b) and c) from the wild type as follows: a) 5’-noncoding region (NCR)-57, b) dengue non-structural protein NS1-53 Gly-to-Asp and c) dengue non-structural NS3-250 Glu-to-Val; and the dengue serotype 1, serotype 3, and serotype 4 strains being chimeric strains are derived from the serotype 2 strain by replacing the structural proteins pre-membrane (prM) and envelope (E) from serotype 2 strain with the corresponding structural proteins from the other dengue serotypes resulting in the chimeric dengue strains: a DENV-2/1 chimera; DENV-2/3 chimera and DENV- 2/4 chimera.
The tetravalent dengue virus composition is in the form of a unit dose comprising:
(i) a dengue serotype 1 in a concentration of at least 3.3 log10 pfu/0.5 ml,
(ii) a dengue serotype 2, in a concentration of at least 2.7 log10 pfu/0.5 ml,
(iii) a dengue serotype 3, in a concentration of at least 4.0 log10 pfu/0.5 ml, and
(iv) a dengue serotype 4, in a concentration of at least 4.5 log10 pfu/0.5ml.
This TDV composition is in the form of a lyophilized unit dose which is reconstitution with 0.5mL of a pharmaceutically acceptable diluent.
The method can comprise a primary vaccination with only two administrations of the unit dose comprising the steps of:
administering a first unit dose of the tetravalent dengue virus composition to the subject, and
administering a second unit dose of the tetravalent dengue virus composition to the subject within 3 months of administration of the first unit dose.
The method does not include a step of determination whether there was a previous dengue infection in the subject prior to administration of the unit dose, or where the serostatus of the subject is unknown before administration of the unit dose. Alternatively, the method does not include a step of determination whether there was a previous dengue infection in the subject at any time before, during or after the steps of administration of the unit dose, or wherein the serostatus of the subject is unknown before, during, or after administration of the unit dose.
The method may also comprise a primary vaccination consisting of the steps of:
(A) selecting a subject for administration of the unit doses of the tetravalent dengue virus composition in need for protection against dengue infection
(B) administering a first unit dose of the tetravalent dengue virus composition to the subject, and
(C) administering a second unit dose of the tetravalent dengue virus composition to the subject within 3 months of administration of the first unit dose, wherein the method does not include a step of determination whether there was a previous dengue infection in the subject, wherein determination of the previous dengue infection is characterized by a laboratory confirmed history of dengue or a validated serological test.
The subject is from a region wherein the seroprevalence is unknown and/or wherein the seroprevalence is below 80%, or below 70% or below 60%; the subject is exposed to a dengue outbreak and the dengue outbreak is due to a serotype 2 and/or a serotype 1 dengue virus. The subject is under 9 years of age, 4 to 5 years of age, 6 to 11 years of age or 12 to 16 years, or 6 to 16 years of age, or 4 to 16 years of age, or 2 to 17 years of age, or 9 years of age, or over 9 years of age, or 9 to 19 years of age, or 18 to 60 years of age, or 18 to 45 years of age, or 46 to 60 years of age, or over 60 years of age.
The method provides a combined vaccine efficacy against virologically confirmable dengue disease with hospitalization of at least 65%, which is represented by a reduction of at least 65% dengue disease with hospitalization occurrence in vaccinated subjects compared to unvaccinated subjects, in each of seropositive and seronegative subjects, from first administration until 12 to 18 months after second administration. The determination of the previous dengue infection is characterized by a laboratory confirmed history of dengue or a validated serological test.
The method provides a combined vaccine efficacy against all 4 serotypes in preventing virologically confirmed dengue disease in both seropositive and seronegative subjects of 60% or more when determined in an age group of 14 to 16 year old subjects from first administration until 18 months after the second administration.
The method provides a vaccine efficacy against virologically-confirmed dengue with hospitalization against all four serotypes at least 65% when measured against placebo in 4 to 16 year old subjects irrespective of serostatus from first administration until 12 to 18 months after the last administration.
The total concentration of dengue serotypes of an alternative method can be: serotype 2 in pfu/0.5 ml is less than 10%; serotype 4 in pfu/0.5 ml is at least 50%; serotype 1 in pfu/0.5ml is at least 1%; and concentration of serotype 3 in pfu/0.5 ml is at least 8%, or at least 10%, or at least 12%, or at least 14%, or at least 16%, or at least 18% (and where the subject population is 2-17 years of age or 4-16 years of age). Or, the total concentration of dengue serotypes in this alternative method can be: serotype 2 in pfu/0.5 ml is less than 2%, concentration of dengue serotype 4 in pfu/0.5 ml is at least 50%, the concentration of dengue serotype 1 in pfu/0.5 ml is at least 1%, and the concentration of dengue serotype 3 in pfu/0.5 ml is at least 6%, wherein the subject is 18 to 60 years of age.
The method provides a combined vaccine efficacy against all four serotypes in preventing dengue disease of above 30%.
The claimed invention also requires that a method of vaccinating a subject against virologically confirmable dengue disease with a tetravalent dengue virus composition including four live attenuated dengue virus strains representing serotype 1, serotype 2, serotype 3 and serotype 4, wherein, wherein the serostatus of the subject is unknown, and wherein each of the four live attenuated dengue virus strains representing serotype 1, serotype 2, serotype 3, and serotype 4 is selected from (i) a dengue virus comprising all components from the same dengue serotype; and (ii) a chimeric dengue virus having parts from two dengue serotypes).
The claimed method also encompasses an embodiment wherein the composition further comprises at least the dengue non-structural proteins NS1, NS2, and NS5. In another embodiment, the tetravalent dengue virus composition further comprises dengue structural proteins capsid protein (C), pre-membrane protein (prM), and envelope protein (E), and the dengue non-structural proteins NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.
In one embodiment of the claimed invention, the tetravalent dengue virus composition is TAK-003.
The Prior Art
Osorio et al. teach the development of a tetravalent dengue virus (TDV) immunogenic composition. This composition comprises the recombinant dengue virus serotype 2 identified as PDK-53, which was is derived from wild-type strain DEN-2 16681 and differs in at least three nucleotides from the wild type as follows: a) 5’-noncoding region (NCR)-57 (nt-57 C-to-T), b) NS1-53 Gly-to-Asp (nt-2579 G-to-A) and c) NS3-250 Glu-to-Val (nt-5270 A-to-T). Osorio et al. also teach the use of PDK-53 to express the prM and E proteins of dengue virus serotypes 1, 3 and 4, thereby generating chimeric 2/1, 2/3 and 2/4, as presently claimed. [see “TDV design and development” section and Figure 1] This TDV contained at least 2X104 pfu of 2/1 chimera, 5X104 pfu of PDK-53, 1X105 pfu of chimera 2/3, and 3X105 pfu of chimera 2/4. [see footnotes for Tables 1-4] Notably, TDV chimeric viruses each contain dengue structural proteins capsid protein (C), pre-membrane protein (prM), and envelope protein (E), and the dengue non-structural proteins NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 (Page 498, Figure 1). Osorio et al. also teach the administration of this TDV to human subjects ranging from 1.5 years up to 45 years old, in a prime-boost administration protocol separated by 90 days. Blood samples were collected 30 days after each administration to determine seroconversion percentages. Subjects received the TDV composition either subcutaneously or intradermally. [see section “human immune responses elicited by TDV”’] Osorio et al. reported in Table 4 that following the booster administration, the 5 different age groups reported a seroconversion of between 73%-96%, which included age groups of 1.5-5 years old, 6-11 years old and 12-20 years old.
Furthermore, since Osorio et al. teach the administration of a TDV that appears to be structurally identical to that claimed and the administration of this TDV in the same active steps and in the same time period as claimed, the limitations of combined vaccine efficacy would be inherent properties of the method conducted by Osorio et al. This therefore anticipates the limitations of combined vaccine efficacy of claims 46-49 and 51- 54.
In addition, Osorio et al. determined the serostatus of each of the human subjects before the prime- boost study was conducted. However, the instant invention does not require this determination for every aspect of its method (in one embodiment, the primary vaccination consists of steps selecting a subject without determining whether there was a dengue infection before, during or after the inoculation and the serostatus is also not determined before, during or after the inoculation). Since Osorio et al. teach that “TDV induces neutralizing antibody responses to all four DENV in adults and children as young as 1.5 years, even after a single dose, irrespective of prior dengue exposure” [see left column of page 501], one of