DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendments
3. The amendment filed August 3, 2026 have been entered. Claims 69, 90-91, 97-98 have been amended. Claims 2-3, 6-7, 9-14, 16-21, 23-24, 27-29, 34, 36-49, 51-52, 54-68, 70-89 and 99-102 are canceled. Claims 1, 4-5, 8, 15, 22, 25-26, 30-33, 35, 50, and 53 are withdrawn from further consideration.
4. The amendment to claims 91-96 is unclear because the amendment recites “91.-96 (Cancelled)…. But goes on to recite a dependent claim limitation. Therefore clarification is requested regarding the status of claims 91-96.
5. For purposes of this action, claims 91-96 are presumed to be cancelled because Claim 1 was amended to incorporate the 25mM of histidine limitation which was previously recited by claim 91. Therefore, claims 69, 90 and 97-98 are under consideration in this Office Action.
Priority
6. The Office acknowledges priority to Application No. IN 201621044139 filed 2016-12-23, which provides adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. There is no disclosure of SEQ ID NO:1 or 2 in Application No. IN 201621044139 filed 2016-12-23. At best, the sequences do not appear until National Phase Application filed under 35 USC 371 as a national stage of PCT/IB2017/058194, filed Dec. 20, 2017 for claims 97. There is disclosure of VIS513 in Application No. IN 201621044139 filed 2016-12-23; therefore priority is granted for claims 69, 90 and 98.
Withdrawal of Rejections
7. The withdrawal of the rejection of claims 70 and 91-96 under 35 U.S.C. 103 as being unpatentable over Hay et al; Rich et al., and Erb et al., in view of Robinson et al., is withdrawn in view of Applicants amendments to the claims.
8. The withdrawal of the rejection of claims 70 and 91-96 under 35 U.S.C. 103 as being unpatentable over Hay et al; Rich et al., and Erb et al., in view of Ong et al., is withdrawn in view of Applicants amendments to the claims.
Maintained Grounds of Rejection Necessitated By Applicants Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
9. Claims 69 and 90 are rejected under 35 U.S.C. 103 as being unpatentable over Hay et al., (WO 2017165736 published Sept. 2017; priority to March 24, 2016); Rich et al., (US 20150299249 published 2015-10-22; priority to Oct. 18,2013) and Erb et al., (WO 2018027075 published Feb 2018; priority to Aug. 3, 2016) in view of Robinson et al., (2015, Cell 162, 1-12. July 30, 2015).
The claims are drawn to a pharmaceutical formulation consisting of: a) 2-80 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody VIS513; b) 25 mM of Histidine; c) 75 mM of Arginine; d) 0.02% of Polysorbate 80 (w/v); e) 101 mM NaCl; and f) 0.5% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; wherein the Osmolality of the formulation is 300 — 450 mOsmol/kg and viscosity is 1.1-1.2 mPa-S and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days.
Hay et al., teach formulations of peptide agents, e.g., antibodies and antigen-binding fragments thereof, that bind dengue viruses, and methods of their use [abstract]. The antibody molecule is present at a concentration of about 10 mg/mL to about 100 mg/mL [Summary]. Hay et al., teach Human monoclonal antibodies as the anti-dengue antibody. The antibody molecule is present at a concentration of about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL [para 9]. Thus teaching the claimed antigen binding protein being between 2-80 and 25 mg/mL as recited by claims 69,90 and 97-98.
The buffering agent is a histidine buffer, comprising histidine at a concentration of about 20 mM to about 40 mM, e.g., about 25 mM [Summary]. Thus teaching the claimed histidine range limitations of claims 69 and 97. In one embodiment, the stabilizer is an amino acid. Arginine is used at a concentration of about 50 mM to about 100 mM [Additions to formulations]. The stabilizing agent comprises arginine and is used at a concentration of about 75 mM. Thus teaching the claimed arginine limitation of claims 69 and 97.
The formulation includes antibody molecules that bind to dengue virus epitopes, with high affinity and specificity. The formulations disclosed herein have superior properties compared to other antibody formulations, including increased stability, decreased degradation, decreased aggregation, and increased shelf life [para 283]. Less than about 1% of the antibody molecules in the pharmaceutical composition are present as aggregates [para 450]. Polysorbate 80 is able to protect proteins from surface and stress-induced aggregation [para 514]. Accordingly, the concentration of anti-dengue antibody molecule in a formulation is sufficient to provide such dosages in a volume of the formulation that is tolerated by a subject being treated and is appropriate for the method of administration. To supply a high dosage subcutaneously, the concentration of antibody is generally at least 25 mg/mL or greater. Such high concentrations can be achieved, for example, by reconstituting a lyophilized formulation in an appropriate volume of diluent [para 374].
The tonicity agent comprises sodium chloride. In an embodiment, the tonicity agent comprises sodium chloride and is used at a concentration of about 100 mM [Summary]. Thus teaching the claimed sodium chloride range limitations of claims 69 and 97. In an embodiment, the tonicity agent provides a tonicity of about 150 mOsm/L to about 400 mOsm/L, about 160 mOsm/L to about 390 mOsm/L [Summary]. Thus teaching the claimed osmolality range limitations of claims 69 and 97. The formulation has a pH of about 6 to about 6.5, or about 7. Thus teaching the pH limitations of claims 69 and 97. The formulation further comprises a surfactant, e.g., a nonionic surfactant. The surfactant is polysorbate 80 (TWEEN® 80). Polysorbate 80 is present at concentration of about 0.02% [Summary]. Thus teaching the claimed polysorbate 80 range limitations of claims 69 and 97. In some embodiments, sucrose is used [Summary]. The viscosity of a formulation is generally one that is compatible with the route of administration of the formulation. In some embodiments, the viscosity of the formulation is between 1 cP and 2 cP, or similar to water (about 1 cP) [Summary]. 1 cP equals 1mPa-S. Thus teaching the claimed viscosity limitations of claims 69 and 97.
The formulations comprising the antibody molecules disclosed herein have in vitro and in vivo pharmaceutical utilities (e.g., therapeutic and prophylactic, and/or diagnostic utilities). The antibody molecules neutralize dengue virus. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to a subject, a human subject, e.g., in vivo, to neutralize dengue virus. Accordingly, the disclosure provides a method of treating a dengue virus infection in a subject, comprising administering to the subject a formulation as described herein of an antibody molecule described herein, such that the dengue virus infection is treated [Uses of Formulations of Anti-Dengue Antibody Molecules].
Therefore, Hay et al., teach a pharmaceutical formulation comprising a) 2-80 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody; b) 25 mM of Histidine; c) 75 mM of Arginine; d) 0.02% of Polysorbate 80 (w/v); e) about 100 (101) mM NaCl; and f) not more than 2.5% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and wherein the Osmolality of the formulation is 300-450 mOsmol/kg and viscosity is less than 2.5 mPa-S and said formulation is stable at 2-8°C for at least 9 months, at 25°C for at least 1 month, at 40°C for at least 40 days, and at 50°C for at least 2 days; Hay et al., do not recite sucrose at 0.5% w/v.
Rich et al., teach a pharmaceutical composition including the preparation produced by any of the foregoing methods [para 37]. The protein of interest is an antibody, or an antigen binding portion thereof. The term “antibody” includes an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds [para 69]. In a specific embodiment, a formulation of the low impurity compositions, for example, low aggregate compositions [para 281]. The concentration of protein of interest (e.g., antibody), which is included in the formulation of the invention, is between about 1 mg/ml and about 25 mg/ml [para 282]. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as histidine [para 285]. The formulation of the low impurity compositions, for example, low aggregate compositions, comprises histidine as a buffering agent. In one embodiment the histidine is present in the formulation at a concentration of between about 20 mM and about 30 mM histidine [para 290]. The surfactant may be polysorbate 80 [para 286]. The polysorbate is at a concentration includes 0.02% [para 297]. In one embodiment, concentration of NaCl is between about 75 mM and about 150 mM [para 305]. A non-limiting example of a suitable formulation including 0.5% sucrose [para 219]. The pH of any of the buffers is between about 5.0 and 7.0 [para 166]. Carbohydrate excipients can act, e.g., as viscosity enhancing agents, stabilizers, bulking agents, solubilizing agents, and/or the like. In these aqueous formulations, the protein of interest is stable without the need for additional agents. This aqueous formulation has a number of advantages over conventional formulations in the art, including stability of the protein of interest in water without the requirement for additional excipients, increased concentrations of protein of interest without the need for additional excipients to maintain solubility of the protein of interest, and low osmolality. These also have advantageous storage properties, as the proteins of interest in the formulation remain stable during storage, e.g., stored as a liquid form for more than 3 months at 7°C or freeze/thaw conditions, even at high protein of interest concentrations and repeated freeze/thaw processing steps. In one embodiment, formulations described herein include high concentrations of proteins of interest such that the aqueous formulation does not show significant opalescence, aggregation, or precipitation [para 329]. In one embodiment, the formulation has improved stability, such as, stability in a liquid form for an extended time (e.g., at least about 3 months or at least about 12 months) or stability through at least one freeze/thaw cycle (if not more freeze/thaw cycles).
Erb et al., teach compositions and methods for stabilizing flaviviruses [para .2]. Flaviviruses can include dengue virus, or any related virus thereof [para 7]. The composition can include sucrose and arginine. For sucrose can have a concentration ranging from about 0.5% to about 10.0% (w/v), arginine can have a concentration ranging from about 1.0 mM to about 50.0 mM [para 23]. Immunogenic compositions and vaccine formulations disclosed herein can include buffers having concentrations of about 1.0 to 30.0 mM of Histidine Buffer, sucrose having a concentration ranging from about 0.5% to about 10.0% (w/v). Erb et al., found flavivirus (e.g. dengue serotype-3) appeared to have additional stability when NaCl was included (data not shown) [para 125]. The buffer can include a salt of sodium chloride having a concentration of about 10 mM to about 150 mM. The buffering media with pH greater than 6.0, or 6.8 to about 8.0 [para 94]. Figure 2 shows after lyophilization and storage at 25°C. These formulations can stabilize and prevent degradation. Formulations disclosed herein are capable of stabilizing dengue virus [para 25]. Upon freezing, freeze drying, at refrigeration temperatures, at room temperature and at about 25°C, as compared to a composition not containing one or more of these agents; these agents in combination provide a stabilize effect [para 69]. However none of the references teach the anti-dengue monoclonal antibody is VIS513.
Robinson et al., teach structure guided design of an anti-dengue antibody directed to a non-immunodominant epitope. The structure-based approach allows for the development of a monoclonal antibody that targets a nonimmunodominant epitope to effectively neutralize all four serotypes of the dengue virus. This antibody treats several symptoms of severe infection in animal models and may provide strategies for treatment in humans [In Brief]. Robinson et al., generated a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes multiple genotypes within all four serotypes [Summary]. Ab513 was able to bind all EDIII proteins and demonstrated affinity improvement relative to 4E5A by as much as 40-fold against DENV-3 and DENV-4 strains while marginally increasing the affinity against DENV-1 and DENV-2 strains (Table 2). Consistent with its strong binding, Ab513 demonstrated strong in vitro neutralization of DENV-1 to -4, with observed EC50 values of <200 ng/ml for all four serotypes (Table 2), which provided substantial enhancement (Figure S3) [Ab513 Neutralizes a wide range of DENVs]. Ab513 was able to fully neutralize all tested challenge viruses [Ab513 Neutralizes a wide range of DENVs]. Robinson et al., demonstrated that Ab513 can neutralize all DENV serotypes in the presence of phagocytosis [Ab513 Neutralizes DENV Despite Fc Receptor-Mediated Phagocytosis]. Ab513 Demonstrates Activity in Multiple Mouse Models Capturing Key Clinical Features of Disease. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue [Summary]. Taken together, these data demonstrate that an immunotherapy has the potential to effectively control viremia and disease in humans [Discussion].
It is noted that Ab513: The initial laboratory designation for the engineered antibody created by scientists, which showed broad, high-affinity binding and neutralization of dengue virus serotypes 1 through 4. VIS513: The name adopted for the monoclonal antibody once Visterra began its clinical development.
Therefore, it would have been prima facie obvious at the time of applicants invention to incorporate the Ab513 (VIS513) anti-dengue monoclonal antibody as the antigen binding protein into the pharmaceutical formulation of Hay et al., and Rich et al., comprising an anti-dengue antibody; Histidine; Arginine; Polysorbate 80; NaCl; and Sucrose w/v wherein pH of the formulation is 6.5 + 0.5; and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days; because the antibody incorporation provides effective neutralization of all four serotypes of dengue virus and treats several symptoms of severe infection. One of ordinary skill in the art would have had a reasonable expectation of success by exchanging the anti-dengue monoclonal of Hay et al., for the Ab513 (VIS513) anti-dengue antibody of Robinson et al., because the Ab513 mitigates thrombocytopenia, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a incorporate anti-dengue monoclonal antibodies in a composition known to comprise anti-dengue antibodies which the art teaches is a well-known to treat dengue where there is no change in the respective function of components; thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
10. Applicant's arguments filed Aug 3, 2026 have been fully considered
and are not found persuasive. The rejection of claims 69 and 90 under 35 U.S.C. 103 as being unpatentable over Hay et al; Rich et al., and Erb et al., in view of Robinson et al., is maintained for reasons of record.
Applicants argue the combination of Hay, Rich, Erb and Robinson fail to teach a pharmaceutical composition consisting of constituents in specific claimed amounts as defined in amended claim 69. In particular, none of the cited art discloses a pharmaceutical composition including 0.5% w/v Sucrose in combination with amounts of the at least one antigen binding protein, Histidine, Arginine, Polysorbate 80 (w/v) and NaCl. Contrary to Applicants assertion, Hay et al., teach a pharmaceutical formulation comprising a) 2-80 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody; b) 25 mM of Histidine; c) 75 mM of Arginine; d) 0.02% of Polysorbate 80 (w/v); e) about 100 (101) mM NaCl; and f) not more than 2.5% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and wherein the Osmolality of the formulation is 300-450 mOsmol/kg and viscosity is less than 2.5 mPa-S and said formulation is stable at 2-8°C for at least 9 months, at 25°C for at least 1 month, at 40°C for at least 40 days, and at 50°C for at least 2 days; Hay et al., do not recite sucrose at 0.5% w/v.
Rich et al., teach a pharmaceutical composition antibody is between about 1 mg/ml and about 25 mg/ml; histidine from between about 20 mM and about 30 mM; surfactant may be polysorbate 80 at 0.02%; NaCl is between about 75 mM and about 150 mM ; sucrose at 0.5% sucrose with the pH of any of the buffers is between about 5.0 and 7 while Erb et al., teach sucrose can have a concentration from about 0.5%, arginine from about 1.0 mM to about 50.0 mM; histidine from about 1.0 to 30.0 mM; NaCl provided additional stability having a concentration of about 10 mM to about 150 mM. with a pH greater than 6.0, or 6.8 to about 8.0. Therefore, both Rich and Erb teach formulations having sucrose 0.5% in combination with the exact same ingredients as instantly claimed. And Robinson teach the inclusion of the VIS513 antibody.
It is noted, that Hay et al., recites sucrose at less than 2.5%, yet Erb and Rich specifically teach 0.5% sucrose and provide the motivation for 0.5% of sucrose. Therefore, Applicants attention is directed to MPEP 2144.05 states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)." Therefore, the prior art references clearly and specifically teach the inclusion of 0.5% sucrose in combination with anti-dengue antibody, histidine, arginine, polysorbate 80 and NaCl.
Next Applicants argue that Rich does not suggest employing a bulking agent for any extended storage and stability purposes. First Applicant is reminded that a different intend purpose of the ingredients is not the criteria upon which the obviousness rejection is based upon. In this case, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure, is capable of performing the intended use, then it meets the claim. Therefore, the argument is not persuasive.
In response to applicant's argument that that Rich and Hay sucrose for a different purpose, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Therefore, the argument is not persuasive.
Next, Applicants urge that Hay and the secondary cited art fail to disclose a specific formulation having VIS513 specific sequences, Histidine, Arginine, Sucrose, Polysorbate 80, NaCl present at the same time in the claimed amounts defined in claim 69. For example, Hay specifies an actual concentration of about 100mM NaCl in combination with sucrose, 25 mM Histidine, 75mM Arginine, and 0.02% Polysorbate 80. Both Erb and Rich teach the inclusion of those same components and overlapping amounts/concentrations. See MPEP 2144.05 teaching: Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents. Therefore, the argument that Hay does not teach 101 mM NaCl; but Hay specifically teaches about 100 mN NaCl ; thus MPEP teach a prima facie case of obviousness clearly exists.
Applicants urge that Hay teaches away from the inclusion of sucrose and provides example formulations that suggest histidine and arginine are interchangeable. . However, it is the examiner’s position that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have “relatively acceptable dimensional stability” and “some degree of flexibility,” but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since “Gurley asserted no discovery beyond what was known in the art.” 27 F.3d at 554, 31 USPQ2d at 1132. Therefore contrary to applicants’ argument, the prior art does not teach away from the instant claims because Hay already taught the inclusion of sucrose while Rich and Erb clearly and specifically state the benefit of including 0.5% sucrose.
In response to applicant's arguments against the prior art references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Hay et al., clearly and specifically already teach the inclusion of sucrose. In this case Rich, Erb and Hay et al., all specifically and explicitly recite the inclusion of sucrose.
In this case, Erb et al., teach sucrose at concentration starting at 0.5% to 15.0% (w/v). Rick et al., teach the use of 0.5% sucrose. Thus, no more than routine skill is required when Hay et al., already teach the inclusion of sucrose. Finally, Applicants is reminded that the rejected claims do not exclude additional ingredients.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). One of ordinary skill in the art would have had a reasonable expectation of success by exchanging the anti-dengue monoclonal of Hay et al., for the Ab513 (VIS513) anti-dengue antibody of Robinson et al., because the Ab513 mitigates thrombocytopenia, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement.
Finally, it would have been prima facie obvious at the time of applicants invention to incorporate the Ab513 (VIS513) anti-dengue monoclonal antibody of Robinson into the pharmaceutical formulation of Hay et al., Rich et al., and Erb et al., comprising the anti-rabies antigen binding protein; Histidine; Arginine; Polysorbate 80; NaCl; and Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days in order to provide a composition including Ab513 (VIS513) which will reduce the public health burden from dengue by neutralizing all serotypes of Dengue.
Accordingly, the rejection is maintained for reasons stated above.
Claim Rejections - 35 USC § 103
11. Claims 97-98 are rejected under 35 U.S.C. 103 as being unpatentable over Hay et al., (WO 2017165736 published Sept. 2017; priority to March 24, 2016); Rich et al., (US 20150299249 published 2015-10-22; priority to Oct. 18,2013) and Erb et al., (WO 2018027075 published Feb 2018; priority to Aug. 3, 2016) in view of Ong et al.
Hay et al., has been discussed above as teaching a pharmaceutical formulation comprising a) 1-100 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody; b) 25 mM of Histidine; c) 75 mM of Arginine; d) 0.02% of Polysorbate 80 (w/v); e) 101 mM NaCl; and f) less than 2% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and wherein the Osmolality of the formulation is 300 — 450 mOsmol/kg and viscosity is less than 1.1- 1.2 mPa-S and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days.
Rich et al., has been discussed above as teaching a pharmaceutical formulation comprising a) 1-100 mg/ml of at least one antigen binding protein; wherein the antigen is monoclonal antibody; b) 20-40 mM of Histidine; c) 50-100 mM of Arginine; d) 0.002 — 0.02% of Polysorbate 80 (w/v); e) 50-—150mM NaCl; and f) 0.5% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days.
Erb et al., teach immunogenic compositions and vaccine formulations disclosed herein can include buffers having concentrations of about 1.0 to 30.0 mM of Histidine Buffer, sucrose having a concentration ranging from about 0.5% (w/v), arginine having a concentration ranging from about 1.0 mM to about 50.0 mM. Erb et al., found flavivirus (e.g. dengue serotype-3) appeared to have additional stability when NaCl was included. The buffer can include a salt of sodium chloride having a concentration of about 10 mM to about 150 mM. The buffering media with pH greater 6.8 to about 8.0 [para 94].
However neither Hay et al., Rich et al., nor Erb et al., teach the anti-dengue monoclonal antibody has any sequence identity to SEQ ID NO: 1 and SEQ ID NO:2.
Ong et al., teach VIS513, a pan-serotype anti-DENV IgG1 antibody, in non-human primates (NHPs) [abstract]. Ong et al., engineered a humanized IgG1 antibody, VIS513, which binds E protein domain III (EDIII), and neutralizes all four serotypes of DENV. While VIS513 neutralized infectious DENV in circulation, we observed slower or delayed clearance of viral RNA possibly due to differential affinity of human Fc to macaque Fc-gamma receptors (FcγRs). Ong et al., teach the administration of VIS513. Ong et al., findings suggest useful antiviral utility of VIS513 [page 44]. Ong et al., indicates a therapeutic potential for VIS513 against dengue and suggest that a significant reduction in RNAemia can be observed 24 h post-infusion compared to placebo. It also suggests that clinical trials on neutralizing antibodies incorporate virus isolation as a laboratory endpoint that, although qualitative, could inform on therapeutic effects of treatment [page 47]. It is noted that applicants concede that VIS513 have sequence identity to SEQ ID NO: 1 or SEQ ID NO 2, thus, VIS153 inherently has sequence identity to SEQ ID NO: 1 or 2.
Therefore, it would have been prima facie obvious at the time of applicants invention to incorporate the anti-dengue monoclonal antibody as the antigen binding protein into the pharmaceutical formulation of Hay et al., Rich et al., and Erb et al., comprising the anti-rabies antigen binding protein; Histidine; Arginine; Polysorbate 80; NaCl; and 0.5% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and said formulation is stable at 2-8 °C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50 °C for at least 2 days; in order to provide a pan-serotype anti-DENV IgG1 antibody. One of ordinary skill in the art would have had a reasonable expectation of success by exchanging the anti-dengue monoclonal of Hay et al., for the monoclonal anti-dengue antibody of Ong et al., in order to neutralizes all four serotypes of Dengue.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a incorporate anti-dengue monoclonal antibodies in a composition known to comprise monoclonal anti-dengue antibodies which the art teaches is a well-known to treat or diagnosis dengue where there is no change in the respective function of components; thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
12. Applicant's arguments filed Aug 3, 2026 have been fully considered
and are not found persuasive. The rejection of claims 69 and 90 under 35 U.S.C. 103 as being unpatentable over Hay et al; Rich et al., and Erb et al., in view of Ong et al., is maintained for reasons of record.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have had a reasonable expectation of success by exchanging the anti-dengue monoclonal of Hay et al., for the monoclonal anti-dengue antibody of Ong et al., in order to neutralizes all four serotypes of Dengue.
Accordingly, the rejection is maintained for reasons stated above.
Pertinent Art
13. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Ab513: The initial laboratory designation for the engineered antibody created by scientists, which showed broad, high-affinity binding and neutralization of dengue virus serotypes 1 through 4.
VIS513: The name adopted for the monoclonal antibody once Visterra began its clinical development.
Visterra, Inc. And Serum Institute of India, Ltd. Announce Collaboration To Advance VIS513, A Monoclonal Antibody In Development For The Treatment Of Dengue, In The Indian Subcontinent
September 9, 2015
https://www.flagshippioneering.com/news/press-release/visterra-inc-and-serum-institute-india-ltd-announce-collaboration-advance-vis513-monoclon
VIS513 is Visterra’s humanized monoclonal antibody that was designed to bind and potently neutralize all four serotypes of dengue virus and was engineered using Visterra’s innovative and proprietary HierotopeTM technology. Preclinical studies of VIS513 have demonstrated a rapid reduction in viral titers after a single systemic administration, which supports its continued development as a single administration for the treatment of dengue virus infection.
Under the terms of the agreement, Serum Institute receives an exclusive license to VIS513 for the Indian subcontinent, including India, Pakistan, Bangladesh, Nepal, Bhutan, Maldives, and Sri Lanka. Serum Institute will pay Visterra a US$ 5 million upfront payment, plus up to US$ 34 million based on the achievement of certain development and commercial milestones. Additionally, once VIS513 is commercialized, Visterra will be eligible to receive tiered, double-digit royalties based on net sales in the licensed territories. Serum Institute will fund and be responsible for the clinical development of VIS513 in the licensed territories, including the filing of regulatory applications.
Asia's biggest vaccine maker to seek fast-track nod for dengue drug in India
By Zeba Siddiqui
September 22, 201510:32 AM EDT Updated September 22, 2015
September 18, 2015. REUTERS/Anindito Mukherjee Purchase Licensing Rights
https://www.reuters.com/article/business/healthcare-pharmaceuticals/asias-biggest-vaccine-maker-to-seek-fast-track-nod-for-dengue-drug-in-india-idUSKCN0RM1R3/
Dengue is common in India and cases generally peak in October, after the monsoon rains. It is one of the biggest causes of hospitalization and death among children in India.
Serum bought exclusive rights from U.S. biotech Visterra to sell its innovative monoclonal antibody, VIS513, as a treatment for dengue in the Indian subcontinent in a deal worth up to $39 million, both companies said earlier this month.
Visterra has tested the antibody on animals so far.
"Once you inject this into a patient who has dengue, they should show a result within three or four days, or even sooner," he said. "It won't be a normal vaccine trial that needs to go into thousands of thousands of patients to prove its safety and efficacy."
Visterra, Inc. To Present Data At ICAAC On VIS513, Its Humanized Monoclonal Antibody That Targets A Conserved Site On The Dengue Virus E Protein
https://www.biospace.com/visterra-inc-to-present-data-at-b-icaac-b-on-vis513-its-humanized-monoclonal-antibody-that-targets-a-conserved-site-on-the-dengue-virus-e-protei600954
September 3, 2014
Visterra, Inc., a biotechnology company that uses its proprietary technology platform to identify unique disease targets and design novel therapeutics, today announced that new preclinical data for VIS513 will be presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, D.C.“VIS513 was developed using Visterra’s innovative and proprietary technology and we are very encouraged by these new data which show the potential of VIS513 to broadly neutralize all four dengue virus serotypes,” said Brian J. G. Pereira, M.D., President and Chief Executive Officer of Visterra. “Currently there is no specific treatment for dengue and prevention depends solely on limiting or eradicating mosquitoes that transmit the virus. VIS513 has demonstrated a rapid reduction in viral titers after a single systemic administration, which supports its potential use as a treatment for dengue virus infection. Based on these data, we plan to advance its development and enter the clinic in 2015.”
(US 20110059079 published 2011-03-10) Babuka et al., teach a pharmaceutical formulation comprising a) 1-100 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody; b) 20-40 mM of Histidine; c) 50-100 mM of Arginine; d) 0.002 — 0.02% of Polysorbate 80 (w/v); e) 50-—150mM NaCl; and f) less than 1% Sucrose w/v; wherein pH of the formulation is 6.5 + 0.5; and said formulation is stable at 2-8°C for at least 9 months, at 25 °C for at least 1 month, at 40 °C for at least 40 days, and at 50°C for at least 2 days. A protein “retains its physical stability” in a pharmaceutical formulation if it shows no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography (SEC) or differential scanning calorimetry (DSC) [para 126]. Further purification can be used to remove high aggregate [para 211]. One of the plurality of antibodies is present in a substantially higher concentration than other antibodies. In some embodiments, at least one of the plurality of antibodies is a monoclonal antibody [para 15]. The relative concentrations of the antibodies can be determined based on the strength and specificity of the antibody, and types and concentration of the antigens [para 168]. The presence of polysorbate 80 was able to reduce the protein loss to approximately 25%, a marked improvement. It appeared that the effective polysorbate 80 concentration was about 0.005%.
Chen et al., (WO 2017066554) teach stable pharmaceutical compositions comprising monoclonal antibodies, about 0.5% sucrose, sodium chloride, or about 5.8 to about 8.0, such as the range buffered by phosphate, histidine at about 10 mM to about 20 mM, polysorbate 80 about 0.002%; and arginine is used as a stabilizer and a viscosity reducer stable for at least 60 days at physiological temperature. The stabilizer can also act as a tonicifier that adjusts the osmolality of the biphasic formulation to match the osmolality of the physiological environment into which the biphasic formulation is deposited. For example, sodium chloride and sucrose each function as a tonicifier.
Patel et al., (WO 2017095848) teach improved pharmaceutical compositions that contain high concentrations of one or more protein biomolecule at 50 mg/ml. In particular, the invention relates to pharmaceutical compositions that include an optimized ratio of protein biomolecule to an amorphous stabilizing compound or compounds, especially a sugar, such as sucrose at 0.5%, or one or more amino acid molecules such as arginine, histidine at 25 to 50 mM being particularly preferred, polysorbate-80 (PS-80) is present at a concentration of 0.02% (w/v), sodium chloride at about 50 mM being particularly preferred. The inclusion of such amorphous stabilizing compound(s), at such optimized ratio, provides acceptable long-term stability of the protein biomolecule, and facilitates shorter lyophilization time, more specifically shorter drying time, even more specifically shorter primary drying time.
Bhatt et al., (Nature. Vol 496, 25 April 2013, pages 504-507) teach Dengue is an acute systemic viral disease that has established itself globally in both endemic and epidemic transmission cycles. Dengue virus infection in humans is often inapparent1,6 but can lead to a wide range of clinical manifestations, from mild fever to potentially fatal dengue shock syndrome.
Crunkhorn (Nature Reviews Drug Discovery. 14, 601 (2015). Published August 15, 2015) teach novel antibodies defeat dengue virus. DENV may be caused by any of four DENV serotypes, DENV-1–DENV-4. Antibodies generated against one serotype do not protect against other serotypes, but rather enhance subsequent infection. This phenomenon — known as antibody-dependent enhancement (ADE) of infection — occurs owing to viral particles binding to existing antibodies, enabling interaction with monocytic Fc receptors, which increases virus infection. A safe DENV vaccine must therefore potently neutralize all four serotypes. Although a tetravalent vaccine candidate is currently in clinical development, it has so far demonstrated only limited efficacy, especially against DENV-2. The ability of Ab513 to prevent antibody-dependent enhancement of infection, in conjunction with the molecular understanding of their epitopes, provides new directions for the development of novel DENV vaccines and therapeutics.
Erb et al., (WO 2018027075 published Feb 2018; priority to Aug. 3, 2016). Erb et al., teach compositions and methods for stabilizing flaviviruses [para .2]. Flaviviruses can include, but are not limited to, dengue virus, or any related virus thereof [para 7]. Immunogenic compositions and vaccine formulations disclosed herein can include buffers having concentrations of about 1.0 to 30.0 mM of Histidine Buffer, sucrose having a concentration ranging from about 0.5% to about 10.0% (w/v), arginine having a concentration ranging from about 1.0 mM to about 50.0 mM. Erb et al., found flavivirus (e.g. dengue serotype-3,) appeared to have additional stability when NaCl was included (data not shown) [para 125]. The buffer can include a salt of sodium chloride having a concentration of about 10 mM to about 150 mM. The buffering media with pH greater than 6.0 to about pH 10, 6.8 to about 8.0 or 7.0 to about 7.5 is contemplated [para 94]. Figure 2 shows after lyophilization and storage at 25°C for about 5. These formulations can stabilize and prevent degradation. Formulations disclosed herein are capable of stabilizing dengue virus [para 25]. Upon freezing, freeze drying, at refrigeration temperatures, at room temperature and at about 25°C, as compared to a composition not containing one or more of these agents; these agents in combination provide a stabilize effect [para 69].
Frei et al., (Virology. Volume 485, Nov2015, pages 371-382) teach the binding of Dengue virus envelope glycoprotein domain III (DIII) by two broadly neutralizing antibodies (bNAbs), 4E11 and 4E5A. There are four serotypes of Dengue virus (DENV-1 to -4), whose DIII sequences vary by up to 49%. Frei et al., used combinatorial alanine scanning mutagenesis, a phage display approach, to map functional epitopes (those residues that contribute most significantly to the energetics of antibody–antigen interaction) on these four serotypes. Additional computational optimization of 4E5A yielded Ab513, which exhibited further enhanced potency against DENV-4, was neutralizing across broad genotypes within the four serotypes, and was protective against clinical features of Dengue-related infections in humanized mice (Robinson et al., 2015). Thus, there is considerable interest in 4E11 and related mAbs as potential immunotherapeutic agents.
Conclusion
14. No claims allowed.
15. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645
