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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Feb 12, 2026 has been entered.
Claim Amendments
3. The amendment filed August 25, 2025 have been entered. Claim 69 has been amended. Claims 2-3, 6-7, 9-14, 16-21, 23-24, 27-29, 34, 36-49, 51-52, 54-68, and 71-89 are canceled. Claims 1, 4-5, 8, 15, 22, 25-26, 30-33, 35, 50, and 53 are withdrawn from further consideration. Claims 90-102 were newly added. Claims 69-70 and 90-102 are under consideration in this Office Action.
Priority
4. 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 97-102. There is disclosure of VIS513 in Application No. IN 201621044139 filed 2016-12-23; therefore priority is granted for claims 67-70 and 90-96.
Withdrawn Grounds of Rejection
5. The rejection of claim 69-70 under 35 U.S.C. 103 as being unpatentable over
Hay et al; Babuka et al., and Erb et al., in view of Robinson et al., (2015, Cell 162, 1-12. July 30, 2015) is withdrawn in view of applicants amendment of claim 69.
New 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.
6. Claims 69-70 and claims 90-96 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) 1-100 mg/ml of at least one antigen binding protein; wherein the antigen binding protein is an anti-Dengue monoclonal antibody VIS513; 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; 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 20 mg/mL to about 40 mg/mL, about 30 mg/mL to about 50 mg/mL, about 40 mg/mL to about 60 mg/mL, about 50 mg/mL to about 70 mg/mL, about 60 mg/mL to about 80 mg/mL, about 70 mg/mL to about 90 mg/mL [para 9]. Thus teaching the claimed antigen binding protein ranges recited by claims 69-70 and 90. 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 69-70 and 91. 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 55 mM to about 95 mM, e.g., about 75 mM. Thus teaching the claimed arginine range limitations of claims 69-70 and 92.
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, e.g., 100 mg/mL or greater, e.g., 100 mg/mL to 500 mg/mL, 100 mg/mL to 250 mg/mL, or 100 mg/mL to 150 mg/mL. Such high concentrations can be achieved, for example, by reconstituting a lyophilized formulation in an appropriate volume of diluent [para 374]. Thus teaching the claimed arginine ranges recited by claims 69-70.
The tonicity agent comprises sodium chloride. In an embodiment, the tonicity agent comprises sodium chloride and is used at a concentration of about 80 mM to about 120 mM, e.g., about 100 mM [Summary]. Thus teaching the claimed sodium chloride range limitations of claims 69-70 and 94. 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 69-70. The formulation has a pH of about 6 to about 6.5, e.g., about 5.5, about 6, about 6.5, or about 7. Thus teaching the pH limitations of claims 69-70. The formulation further comprises a surfactant, e.g., a nonionic surfactant. The surfactant is present at a concentration of about 0.005% to about 0.1% (w/v). The surfactant is polysorbate 80 (TWEEN® 80). Polysorbate 80 is present at concentration of about 0.01% and about 0.05%, e.g., about 0.01% to about 0.03%, e.g., about 0.02% [Summary]. Thus teaching the claimed polysorbate 80 range limitations of claims 69-70 and 93. 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 69-70.
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, e.g., a human subject, e.g., in vivo, to neutralize dengue virus. Accordingly, in some aspects, 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].
While Hay 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) 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, and between about 25 mg/ml and about 150 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, of the invention comprises histidine as a buffering agent. In one embodiment the histidine is present in the formulation of the invention at a concentration between about 20 mM and about 40 mM, or between about 20 mM and about 30 mM histidine [para 290]. The surfactant may be polysorbate 80 [para 286].The formulations may comprise a polysorbate which is at a concentration ranging from between about 0.001% to about 0.1%, including 0.002%, or 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 4.0 and 8.5. In a further embodiment, 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, but not limited to, 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, but are not limited to, dengue virus, or any related virus thereof [para 7]. The composition can include sucrose and/or trehalose, 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), 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].
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
7. Applicant's arguments filed March 19, 2025 have been fully considered
and are persuasive. Therefore, the rejection over Hay et al., Babuka et al., and Erb et al., in view of Robinson et al., has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Rich et al.
Applicants point to the claim amendments to overcome the rejection of record because the prior art do not recite the 0.5% sucrose. Hay et al., teach low sucrose at less than 2.5% w/v. Rich et al., teach 0.5% sucrose for pharmaceutical formulations for reduced aggregate formation to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
Furthermore, Erb et al., describes sucrose as other sugars. Applicants is reminded that the disclosure of equivalent sugars does not teach away from each reference teaching the inclusion of 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, Babuka et al. and Erb et al., and Hay et al., all specifically and explicitly recite sucrose. The recitation of alternative sugars was recognized in the prior art, because the references refer to the additional sugars as alternatives.
When a claim covers several structures or compositions, either generically or as alternatives, the claim is deemed obvious if any of the structures or compositions within the scope of the claim is known in the prior art. Furthermore, MPEP 2131 states: when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
In this case, Erb et al., teach sucrose and/or trehalose or a combination at a concentration ranging from 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.
Finally, Applicants argue that Erb et al., teach the inclusion of additional ingredients. In response to applicant's argument that Erb et al., recites a list of additional and/or alternative agents, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Erb et al., teach immunogenic compositions and vaccine formulations disclosed herein can include 1.0 to 30.0 mM of Histidine Buffer, sucrose from about 0.5% to about 10.0% (w/v), arginine from about 1.0 mM to about 50.0 mM wherein the combination appeared to have additional stability when NaCl was included. Rich et al., teach formulations with the instantly claimed amounts/concentrations of histidine, Polysorbate 80, NaCl, sucrose, pH and stability The disclosure of additional ingredients and/or alternatives does not change the fact the instantly recited combination was known in the art.
Moreover, Applicants’ are reminded that the claim language recites “comprising.” The transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997) (“Comprising” is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); In re Baxter, 656 F.2d 679, 686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) (“comprising” leaves “the claim open for the inclusion of unspecified ingredients even in major amounts”). Therefore applicants’ argument that are not obvious because it discloses additional components is not persuasive because the additional ingredients are not excluded.
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.
Declaration
8. The declaration of Sambhaji Shankar Pisal under 37 CFR 1.132 filed Feb 9, 2026 is insufficient to overcome the rejection of the claims 1based upon insufficiency of disclosure under 35 USC 112, first paragraph as set forth in the Office action.
The Declaration asserts that the formulation exhibits a non-linear improvement in stability across different temperature profiles. Applicants is reminded that the instant claims are drawn to products. Applicants attention is directed to MPEP 2112.
“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning,
does not render the old composition patentably new to the discoverer.”
Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943,
1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or
unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254,
195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258,
73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that
was not previously sequenced was anticipated by the prior art plasmid
which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties
of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.” Id. See also MPEP § 2112.01 with regard to inherency
and product-by-process claims and MPEP § 2141.02 with regard to
inherency and rejections under 35 U.S.C. 103.”
In the Declaration, applicants argue that the references do not state that the sucrose amount is critical to stability. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) (“[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999) In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. “The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.”). Therefore, the argument is not found persuasive.
In response to applicant's argument that the references do not recite the intended use of sucrose, 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. In this case, all the references describe the need for low amounts of sucrose. Furthermore, Rich et al., specifically states the use of 0.5% sucrose within a pharmaceutical formulation. A reference does not need to state the how critical sucrose is to stability; instead the references needs to state the instantly recited amount of sucrose. Here Rich et al., teach 0.5%, therefore the argument is not found persuasive.
Applicants point out that the new claims recite 25 mM of Histidine and 75 nM of Arginine. However, Hay et al., identifies with specificity and particularity those exact amounts of histidine and arginine. Therefore, the prior art already taught formulations with those amounts.
Claim Rejections - 35 USC § 103
9. Claims 97-102 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
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) 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 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% 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. 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 or 7.0 to about 7.5 [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.
Pertinent Art
10. 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
11. No claims allowed.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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