DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on October 29, 2025 have been received and entered. Claims 1-50, 52-53, 56-57 and 59 have been canceled, while claim 51 has been amended. Claim 71 is newly added. Claims 51, 54-55, 58, 60-70 and 71 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 51-62 in the reply filed on July 15, 2025 is acknowledged.
Claims 62-70 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 15, 2025.
Priority
This application is a Divisional of US application no 18/134,095 filed on 04/13/2023, which is a continuation of PCT/US21/61205 filed on 11/30/2021, which claims priority from US provisional 63/152,832 filed on 02/23/2021 and 63/120,189 filed on 12/01/2020
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/29/2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 51, 54-55, 58, 60-62 and 71 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 51-52, 54-61 and 62 were rejected under 35 U.S.C. 103 as being unpatentable Vandenberghe (WO/2015/054653, 4/15/2015, IDS), as evidenced by Ambion Catalogue (PBS, Catalog #: AM9624-AM9625, 2006, page 1). Suzuki (Scientific Reports, 2017, 7: 45524, 1-10, IDS), and Simons (WO2019126329, dated 6/27/2019, IDS). In view of Applicants’ amendment of base claim 51, introducing the limitation from the dependent claims 52-53, the previous rejections of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below:
Maintained & New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 51, 54-55, 58, 60-62 are rejected under 35 U.S.C. 103 as being unpatentable Vandenberghe (WO/2015/054653, 4/15/2015, IDS), as evidenced by Ambion Catalogue (PBS, Catalog #: AM9624-AM9625, 2006, page 1), Suzuki (Scientific Reports, 2017, 7: 45524, 1-10, IDS), and Simons (WO2019126329, dated 6/27/2019, IDS) as applied above for claim 51 and further in view of Bennicelli et al (Molecular Therapy, 2008, 16 (3), 458-465, art of record).
Claim interpretation: Th transitional phrase “comprising” which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (se MPEP 2111.03).
Regarding claims 51, 54-56, 58-62, Vandenberghe teaches a composition comprising (i) an Anc80L65 capsid and (ii) a nucleic acid construct comprising a gene of interest (reporter) under the control of CMV promoter (see example 3 and page 29, lines 19-24, example 2-3, 7, page 28, lines 23-24, fig. 10-11). Vandenberghe contemplate gene of interest being VEGF binding agent that is ranibizumab encoded by DNA (see example 10). It is further disclosed that the composition comprising the virus is suspended in a physiologically compatible carrier that include saline (0.9% NaCl~154mM NaCl) , which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline), and water (see page 21, lines 14-17). The PBS is known to comprises 137 mM of NaCl, 2.7mM of KCl, 8 mM of Na2HPO4 and 2 mM of K2HPO4 as evidenced by Ambion Catalogue. Further, given that Vandenberghe reported using the composition comprising a AAVanc80capsid and transgene is intended for treating hearing loss carrier (see page 20, lines line 17 and page 21, lines 11-28). therefore, the composition disclosed in Vandenberghe is a pharmaceutical composition.
The teaching of Vandenberghe is further supported by disclosure of Suzuki who reported use of AAV2/Anc80L65 comprising AAV2 ITR flanked genome encoding CMV driven EGFP is capable of transducing all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal (abstract), wherein AAV2/Anc80L65 (see page 8, para. 3).
With respect to claim 60-61, Vandenberghe teaches that AAV Anc80 capsid is an AAVAnc80L65 capsid comprises the amino acid sequence as set forth in SEQ IDNO: 23 that has 100% sequence identity to the amino acid sequence according to SEQ ID NO: 114 (see claim 11, sequence search result).
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With respect to claim 62, Vandenberghe teaches the amount of AAV in the composition is about 1x101 to I x 1012 genome copies (GCs) in about 0.1 ml to about 10 ml of a solution meeting the limitation of 51-55 (see page 21, lines 29-31).
Vandenberghe differs from claimed invention by not disclosing that the (i) construct comprising coding sequence includes a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent, wherein (a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 16, (b) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or both (a) and (b) (limitation of claim 51) and (ii) composition comprising 8.1 mM of Na2HPO4, 1.8 mM of K2HPO4, 172mM NaCl and 0.001% PF-68 (poloxamer-188)..
Simons cure the deficiency by teaching a nucleic acid construct comprising a coding sequence encoding an antibody Fab directed against VEGF such as ranibizumab (see page 30). It is further disclosed that the construct includes a promoter that is operably linked to the sequence encoding the antibody or the antigen-binding antibody fragment (see page 58, lines 28-34, page 59, line 1-3, line 32-34 to page 60, line 1), wherein said construct is packaged in any AAV capsid to target cochlear hair cells (see page 43, line 16). Simons teaches SEQ ID NO: 54 that has 100% sequence identity to VEGF binding agent comprising the amino sequence of SEQ ID NO: 16 (example 1, also see sequence search report) (limitation of claims 51). Simons teaches a composition comprising the AAV as discussed above for claim 1 (see page 20, lines 1-2). Simons teach a composition comprising the AAV r and a pharmaceutical carrier (see page 63, lines 1-20) and could be formulated in neutral-buffered saline, phosphate-buffered saline (see page 63, line 5) or perilymph solution includes 20-200 mM, NaCl; 1-5 mM KCl, 0.1-10 mM CaC12; 1-10 mM glucose; 2-50 mM HEPES, having a pH of between about 6 and about 9 (page 64, lines 19-21, limitation of claim 57).
. The combination of references teaches a pharmaceutical composition comprising claimed AAV particle in phosphate buffered saline comprises 137 mM of NaCl, 2.7mM of KCl, 8 mM of Na2HPO4 and 2 mM of K2HPO4 but differs from claimed invention by not disclosing composition comprises 8.1 mM of Na2HPO4, 1.8 mM of K2HPO4, 172mM NaCl and 0.001% PF-68 (poloxamer-188). .
Bennicelli cure the deficiency by disclosing AAV particle formulated in PBS180 (180mM sodium chloride) + PF68 (0.001%) enable quantitative recovery of vector genome titer and functional activity of dilute AAV solutions following handling manipulations, incubation at room temperature (see page 459, col. 2, para. 3, fig. S1).
Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to produce an AAV particle suitable for gene therapy for ocular or inner ear disorder would combine the teaching of prior art to modify the pharmaceutical composition comprising AAV particle in a modified PBS as disclosed in Vandenberghe and Simons by further incorporating (poloxamer-188) as suggested by Bennicelli, to formulate a more stable formation containing AAV particle , with reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. It would have been customary for an artisan of ordinary skill to determine the optimal concentration of imiquimod to achieve the desired results of treating inner ear disorder. Regarding limitation of claims 62 pertaining to the concentration of AAV particle in claimed volume is explicitly taught in prior art which falls within the claimed concentration and volume. It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). Thus, absent some demonstration of unexpected results from the claimed parameter, the optimization of concentration of Na2HPO4 , K2HPO4 , NaCl within PBS would have been obvious to optimize the concentration of each at the time of applicant's invention. "Where 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). See MPEP 2144.05 One of ordinary skill in the art would be motivated to do so as prior art recognized without surfactant (PF-68) most of the AAV is lost to inert surfaces thereby reducing the dose that is delivered for therapy (see Bennicelli, page 463, col. 2, last para). One who would have practiced the invention would have had reasonable expectation of success because prior art successfully reported adding PF68 to the formulation containing PBS improved the stability of the AAV particle. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 51 and 71 are rejected under 35 U.S.C. 103 as being unpatentable Vandenberghe (WO/2015/054653, 4/15/2015, IDS), as evidenced by Ambion Catalogue (PBS, Catalog #: AM9624-AM9625, 2006, page 1). Suzuki (Scientific Reports, 2017, 7: 45524, 1-10, IDS), and Simons (WO2019126329, dated 6/27/2019, IDS), Bennicelli et al (Molecular Therapy, 2008, 16 (3), 458-465) and further in view of Natsoulis et al (WO9709442, dated 3/13/1997).
The teaching of Vandenberghe, Ambion, Suzuki, Simons and Bennicelli have been described above and relied in same manner here. While Vandenberghe teaches producing viral particle by co-transfecting HEK293 cells with (a) the plasmid encoding the protein of interest flanked by AAV2 ITRs, (b) the AAV packaging plasmid encoding AAV2 rep and the synthesized capsid proteins (see example 1 that includes ancestral AA V sequences Anc80L65),) (c) AAV2-AAP expressing capsid, and (d) adenoviral helper genes needed for AAV packaging and assembly (see example 3). The teaching of Vandenberghe is further supported by disclosure of Suzuki who reported use of AAV2/Anc80L65 comprising AAV2 ITR flanked genome encoding CMV driven EGFP is capable of transducing all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal (abstract), wherein AAV2/Anc80L65 is produced by co-transfection of three constructs (dF6 adenoviral helper, pAAV2/Anc80L65 encoding AAV2 rep and Anc80L65 cap genes, and the ITR flanked transgene plasmid) in HEK293 cells (see page 8, para. 3). Simons teaches AAV sequences typically comprise the cis-acting 5' and 3' ITR sequences that are about 145 nucleotides in length. Simons discloses ability to modify these ITR sequences is within the skill of the art. Further, Simons note that the coding sequences is flanked by 5' and 3' AAV ITR sequences in the AAV vectors, wherein the AAV ITR sequences may be obtained from any known AAV (see page 43, line18-29). Simons teaches the AAV may further comprising two AAV inverted terminal repeats (ITRs), wherein the two AAV ITRs flank the coding sequence and promoter (see fig 1A-D). The combination of references differs from claimed invention by not disclosing wherein the coding sequence is flanked by a 5’ ITR comprising the nucleic acid sequence of SEQ ID NO: 45, and a 3’ ITR comprising the nucleic acid sequence of SEQ ID NO: 46.
Natsoulis provides evidence that nucleotide sequence of AAV2 ITRs are well known in prior art. Natsoulis teaches AAV2 ITR comprise a 5' ITR comprising a nucleic acid sequence as set forth in SEQ ID NO: 1(claim 3, fig. 1) that has 100% sequence identity to SEQ ID NO: 45, and a 3' ITR comprising a nucleic acid sequence as set forth in SEQ ID NO: 1 that has 100% sequence identity to SEQ ID NO: 46 (see sequence search report and below).
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Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to produce an AAV particle suitable for gene therapy for ocular or inner ear disorder would combine the teaching of prior art to modify the composition comprising AAV2/Anc80 formulated in modified PBS as disclosed in Vandenberghe in view of Bennicelli by substituting the reporter gene with the nucleic acid encoding an antibody Fab directed against VEGF such as ranibizumab as disclosed in Simons, for successful delivery and transduction of virus particle in inner ear cells, with reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. A person of ordinary skill in the art seeking to express the coding sequence in hair cells of inner ear would be motivated to modify the AAV particle by using Anc80L65 that is flanked by AAV2 ITRs as disclosed in Simons using the known sequence of AAV ITR as in Natsoulis, with reasonable expectation of success. One of ordinary skill in the art would be motivated to do so as prior art recognized usefulness to deliver ranibizumab encoded by DNA using AAV2/Anc80L65 that is known to transduces hair cells with high efficiency and overcomes the low transduction rates that have limited development of cochlear gene therapy using conventional AAV serotypes (see above Vandenberghe and Suzuki, page 7, para. 3). One who would have practiced the invention would have had reasonable expectation of success because it would have only required routine experimentation to substitute the reporter gene/construct of Vandenberghe /Suzuki with the nucleic acid encoding antibody Fab such as ranibizumab that is flanked by AAV2 ITR as disclosed in Simons and suggested by Vandenberghe, as required by instant invention. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicants disagree with the rejection arguing Office has not provided a reference or pointed to a section of Vandenberghe, Ambion, or Simons that teach or suggest a pharmaceutical composition comprising the recited AAV particle and also includes 8.1 mM sodium phosphate dibasic, 1.5 mM monopotassium phosphate, 2.7 mM potassium chloride, 172 mM sodium chloride, and 0.001 % Poloxamer 188.Applicant continue to argues that Bennicelli relates to reversal of blindness in animal models and discloses a specific vector formulation for subretinal delivery designed for treating Leber congenital amaurosis (LCA). Specifically, Bennicelli describes a vector formulation for subretinal delivery of AAV2.RPE65. Accordingly, the disclosure of Bennicelli is irrelevant to the presently claimed pharmaceutical composition. Applicant notes that the Office itself asserts that the cited references teach different formulations, therefore, how would a POSITA have clarity on which formulation to utilize between the cited references, let alone modify the cited references to arrive at the specific presently claimed pharmaceutical formulation. The Office fails to explain a sufficient rationale for such a modification, while selectively disregarding Bennicelli’. Applicant continue to argues that additional teachings fail to bridge the logical gap between a formulation intended for ocular delivery and those designed for delivery to ear. As such, it would not be obvious for a POSITA to take Bennicelli’s vector formulation for subretinal delivery and modify said formulation by including components from the generic list of formulations disclosed in any of Vandenberghe, Ambion, Simons, or Suzuki. Accordingly, Bennicelli’s disclosure cannot cure the deficiencies of Vandenberghe. Applicants’ arguments have been fully considered, but are not found persuasive.
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). Applicants have further engaged in selective reading of the teachings of Vandenberghe et al. to formulate the grounds for not teaching the invention. It should be noted that the ultimate goal of formulating AAV particle into a buffer solution that provides stability to the AAV viral particle and protect the tissue following the delivery at tissue site (ocular or inner ear). In this context, Vandenberghe teaches the composition comprising the virus is suspended in a physiologically compatible carrier, which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline), and (see page 21, lines 14-17). The PBS is known to comprises 137 mM of NaCl, 2.7mM of KCl, 8 mM of Na2HPO4 and 2 mM of K2HPO4 as evidenced by Ambion Catalogue. It is in this context, Simons teaches an alternative buffer perilymph solution that includes 20-200 mM, NaCl; 1-5 mM KCl, or PBS (page 64, lines 19-21, page 63, line 11, limitation of claim 57) for delivering AAV particle for intra-cochlear administration. Thus, Simons contemplated hypertonic solution with higher salt in the perilymph buffer solution.
In response to applicant's argument that Bennicelli’s vector formulation is intended for subretinal delivery , 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). It is emphasized that a variety of stabilizing agent for providing stability to AAV particles in a solution at room temperature and during freeze thaw cycle are well-known in the art, including PF-68 (see Bennicelli page 459, col. 2, para. 3, fig. S1). This is further evident from the several prior art publications that have shown that the use of 0.001% Pluronic-F68 (PF68), a US Food and Drug Administration (FDA)-approved non-ionic surfactant, prevents rAAV vector losses due to adsorption to the surfaces of the materials used in preparation of the dilution, the loading syringe, and the surgical delivery equipment (see Patrício et al Molecular Therapy: Vol. 17 June 2020, 99-106, and references therein cited as evidence without relying on the rejection). Thus, Bennicelli cure the deficiency in Vandenberghe and Simons by suggesting to incorporate PF-68 in the buffer to provide stability to the AAV particle at room temperature irrespective of mode of delivery or intended target tissue. To the extent that Bennicelli describe incorporation of PF-68 in the buffer to provide stability and handling of AAV particle at room temperature, the rejection is applicable to the instant case. Applicants' selective reading of Vandenberghe. ignores the teachings of the of Simons and Bennicelli. There is no requirement for Vandenberghe. to teach that which is clearly taught by Simons and Bennicelli. Thus, absent some demonstration of unexpected results from the claimed parameter, the optimization of concentration of Na2HPO4 , K2HPO4 , NaCl within PBS would have been obvious to optimize the concentration of each at the time of applicant's invention. "Where 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). Further, 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) See MPEP 2144.05. A person of skill in the art would be motivated to optimize the buffer of Vandenberghe and Simons to further include PF-68, because such would allow for better stability of AAV particle at room temperature, with a reasonable expectation of success.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Maintained- Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 51, 54-58, 60-62 and 71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass a coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof, wherein the coding sequence comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent, wherein (a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 16, (b) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or both (a) and (b). . Instant rejection is in part based on claim recite presence of either SEQ ID NO: 16 or SEQ IDNO: 20
Thus, the claims encompass a known genus of known or yet to be identified a vascular endothelial growth factor (VEGF) binding agent. The specification further contemplated using a soluble VEGF receptor can include one or more (e.g., two, three, four, five, six, or seven) immunoglobulin-like domains in the extracellular region from wildtype human VEGFR-1 and one or more (e.g., two, three, four, five, six, or seven) immunoglobulin-like domains in the extracellular region from wildtype human VEGFR-2 (see para. 281). The guidance provided in the specification is limited to construction rAAV-Bevacizumab, rAAV-Bevacizumab-GFP, rAAV-Aflibercept-PC, and rAAV-Aflibercept construct (see example 1.2).
The claims as such encompass vascular endothelial growth factor (VEGF) binding agent or any antibodies whose structure cannot be envisioned because the claims encompass generically antibodies defined solely by binding affinity. The genus of VEGF trap or antibodies as claimed includes unlimited variations in the entire polypeptide. Mutation of even a single amino acid residue affects antigen binding. The specification lacks support for a construct encoding only an immunoglobulin light chain or only one of HC or LC of ranibizumab. The length, structure or sequence of said "portion thereof" is not disclosed for the genus of antibodies encompassed by the claims. Wu et al (Journal of Molecular Biology, 1999, 294, 151-162, IDS) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152, left column) but certain residues have been identified as important for maintaining conformation. Additionally, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Maccallum et al (Journal of Molecular Biology, 1996, 262, 732-745, IDS) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (See page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (See page 735, left column).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d. Additionally, "a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated." Noelle v. Lederman, 355 F.3d 1343, 1350 (Fed. Cir. 2004).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only limited species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the genus." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
It has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure one of skill in the art would not know which residues are essential, which residues are non-essential and what particular sequence lengths identify essential sequences for identifying an antibody that binds to the epitope encompassed by the claimed specificity of function. Mere idea of function is insufficient for written description; isolation and characterization at a minimum are required. Skolnick et al (Trends in Biotechnology Vol. 18, pp 34-39, 2000, IDS) teach that the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based on sequence homology is inaccurate, in part because of the multifunctional nature of proteins (e.g., Abstract and Sequence based approaches to function prediction, page 34). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to function of the structurally related protein (See in particular abstract and box 2).
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of a given antibody. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites. The fact that not just one CDR is essential for antigen binding or maintaining the
conformation of the antigen binding site, is underscored by Casset et al (Biochemical and Biophysical Research Communications Vol. 307, pp 198-205, 2003, IDS) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (See entire document). Casset et al also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.). Vajdos et al (Journal of Molecular Biology Vol. 320, pp 415-428, 2002, IDS) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left column). Wu et al (Journal of Molecular Biology Vol. 294, pp 151-162, 1999) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity dues in part to large conformational change in antibodies that accompany antigen binding (page 152, left column) but certain residues have been identified as important for maintaining conformation.
Vas-Gath Inc. v. Mahurkar, 19 USPQ2d 111, clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." Therefore, Applicant was not in possession of the genus of coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent other than the first polypeptide consisting of the amino acid sequence of SEQ ID NO: 16, and the second polypeptide comprising of the amino acid sequence of SEQ ID NO: 20 as encompassed by the claims.
Response to arguments
Applicants disagree with the rejection arguing the present claims are directed to an AAV particle comprising an AAV Anc80 capsid and a nucleic acid construct comprising a coding sequence that encodes a VEGF binding agent comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 16 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 20. Applicant continue to argue that the application as filed, the amino acid sequences of SEQ ID NO: 16 and SEQ ID NO: 20 correspond to the Ranibizumab light chain and heavy chain. Thus, the present claims clearly specify the sequence of the claimed VEGF binding agent corresponding to Ranibizumab. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that none of the claims are limited to a first polypeptide comprising the amino acid sequence of SEQ ID NO: 16 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 20 as argued by the applicant. It is emphasized that independent claim limits the either first polypeptide comprising the amino acid sequence of SEQ ID NO: 16 or second polypeptide comprising the amino acid sequence of SEQ ID NO: 16 or both. Therefore, claims encompass vascular endothelial growth factor (VEGF) binding agent that is an antibody whose complete structure cannot be envisioned because the claims encompass at least in one embodiment either a defined first polypeptide or a second defined polypeptide. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of a given antibody. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites for the reasons of record. Therefore, Applicant was not in possession of the genus of combination of coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent other than the first polypeptide consisting of the amino acid sequence of SEQ ID NO: 16, and the second polypeptide comprising of the amino acid sequence of SEQ ID NO: 20 that correspond to the Ranibizumab light chain and heavy chain.
Maintained -Double Patenting
Claims 51, 54-55, 58, 60-62 and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51-55, 57-61, 71-78 and 79 of copending Application No. 19095986 in view of Bennicelli et al (Molecular Therapy, 2008, 16 (3), 458-465)/ Simons (WO2019126329, dated 6/27/2019, IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims in both application encompass a composition comprising an adeno-associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof, and(ii) an AAV Anc80 capsid, wherein the coding sequence comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent. In the instant case, claims are directed to a pharmaceutical composition comprising an adeno-associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof, and(ii) an AAV Anc80 capsid, wherein the coding sequence comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent. Dependent claim limits the composition of claim 51, wherein (a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 16, (b) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or both (a) and (b) and wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid comprising the sequence of SEQ ID NO: 114. Claim 62 limits the pharmaceutical composition of claim 51, wherein the composition has a volume of 0.01 mL to 2.00 mL. In contrast, claims in ‘986 are directed to a composition comprising adeno-associated virus (AAV) particle, comprising (i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof; and(ii) an AAV Anc80 capsid, wherein the coding sequence includes comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent, wherein the concentration of AAV particles in the composition is 1 x 1011 vg/mL to 1 x 1015vg/mL.. Dependent claim 53 limit the tcomposition has a volume of about 0.01 mL to about 2.00 mL. Claims 56-58 limits the composition, wherein (a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 16, (b) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or both (a) and (b), and wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid and wherein the AAV Anc80L65 capsid comprises the sequence of SEQ ID NO: 114.
The ‘986 differs from claimed invention by not disclosing that that the composition comprises: .1 mM of Na2HPO4, 1.8 mM of K2HPO4, 172mM NaCl and 0.001% PF-68 (poloxamer-188)..
Simons teach a composition comprising the AAV r and a pharmaceutical carrier (see page 63, lines 1-20) and could be formulated in neutral-buffered saline, phosphate-buffered saline (see page 63, line 5) or perilymph solution includes 20-200 mM, NaCl; 1-5 mM KCl, 0.1-10 mM CaC12; 1-10 mM glucose; 2-50 mM HEPES, having a pH of between about 6 and about 9 (page 64, lines 19-21, limitation of claim 57).. Bennicelli cure the deficiency by disclosing AAV particle formulated in PBS180 (PBS + PF68 (0.001%) enable quantitative recovery of vector genome titer and functional activity of dilute AAV solutions following handling manipulations, incubation at room temperature (see page 459, col. 2, para. 3, fig. S1). Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to produce an AAV particle suitable for gene therapy for ocular or inner ear disorder would combine the teaching of prior art to modify the AAV particle composition of ‘986 by optimizing the perilymph solution with PF-68 as suggested in Bennicelli/Simons, for successful delivery and transduction of virus particle in inner ear cells, with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 51, 54-55, 58, 60-62 and 71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of USP 12365726 in view of Bennicelli et al (Molecular Therapy, 2008, 16 (3), 458-465)/ Simons (WO2019126329, dated 6/27/2019, IDS). It is noted that instant application is a divisional of ‘726, however, during the prosecution of ‘726 it was indicated that invention of group I drawn to a composition comprising AAV particle and group II drawn to a AAV particle formulated in a solution in a specific dose range are related as combination and subcombination. The office action explicitly stated if the composition comprising AAV particle is found allowable, any withdrawn product claim(s) depending from or otherwise requiring all the limitations of the allowable claims will be examined for patentability in accordance with 37 CFR 1.104. See MPEP § 821.04(a). Applicant was advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Applicant should note that composition comprising AAV particle claimed in the instant application encompass and construed as the AAV particle allowed in ‘726 and therefore an obviousness type double patenting rejection is proper and set forth below.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims in both encompass a composition comprising an adeno-associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof, and(ii) an AAV Anc80 capsid, wherein the coding sequence comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent. In the instant case, claims are directed to a pharmaceutical composition comprising an adeno-associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof, and(ii) an AAV Anc80 capsid, wherein the coding sequence comprises a first nucleic acid sequence that encodes a first polypeptide of the VEGF binding agent and a second nucleic acid sequence that encodes a second polypeptide of the VEGF binding agent. Dependent claim limits the composition of claim 51, wherein (a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 16, (b) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or both (a) and (b) and wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid comprising the sequence of SEQ ID NO: 114. Claim 62 limits the pharmaceutical composition of claim 51, wherein the composition has a volume of 0.01 mL to 2.00 mL
In contrast, claims in ‘726 is directed to n adeno-associated virus (AAV) particle comprising: (i) a nucleic acid construct that comprises the nucleotide sequence set forth in SEQ ID NO: 91, and (ii) an AAV Anc80 capsid. Dependent claims limit the AAV Anc80 capsid is an AAV Anc80L65 capsid and wherein the AAV Anc80 capsid comprises the amino acid sequence set forth in SEQ ID NO: 113. Claims are also directed to an adeno-associated virus (AAV) particle comprising: (i) a nucleic acid construct that comprises the nucleotide sequence set forth in SEQ ID NO: 92, and (ii) an AAV Anc80 capsid. Dependent claims limit the AAV Anc80 capsid is an AAV Anc80L65 capsid comprising the amino acid sequence set forth in SEQ ID NO: 114. The ‘726 differs from claimed invention by not disclosing that that the composition comprises: .1 mM of Na2HPO4, 1.8 mM of K2HPO4, 172mM NaCl and 0.001% PF-68 (poloxamer-188).. Simons teach a composition comprising the AAV r and a pharmaceutical carrier (see page 63, lines 1-20) and could be formulated in neutral-buffered saline, phosphate-buffered saline (see page 63, line 5) or perilymph solution includes 20-200 mM, NaCl; 1-5 mM KCl, 0.1-10 mM CaC12; 1-10 mM glucose; 2-50 mM HEPES, having a pH of between about 6 and about 9 (page 64, lines 19-21, limitation of claim 57).. Bennicelli cure the deficiency by disclosing AAV particle formulated in PBS180 (PBS + PF68 (0.001%) enable quantitative recovery of vector genome titer and functional activity of dilute AAV solutions following handling manipulations, incubation at room temperature (see page 459, col. 2, para. 3, fig. S1).. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to produce an AAV particle suitable for gene therapy for ocular or inner ear disorder would combine the teaching of prior art to modify the AAV particle composition of ‘726 by optimizing the perilymph solution with PF-68 as suggested in Bennicelli/Simons, for successful delivery and transduction of virus particle in inner ear cells, with reasonable expectation of success.
Response to arguments
Applicant disagree with the rejection arguing the First Restriction and the Second Restriction were not withdrawn by the Office and both restrictions were deemed final in the parent application ‘095. Accordingly, because both the Restriction Requirements were deemed final by the Office, the safe harbor protection afforded by 35 U.S.C. § 121 is applicable to one or more Divisional applications that claim priority to the US 095. Applicant assert that he claims in the present Divisional application (claiming priority to US ‘095) are directed to subject matter that was deemed to be patentably distinct compared to the subject matter elected and pursued in US’095. Furthermore, pending claims in US 19/095,919 which is also a Divisional application claiming priority to US ’095, focused on AAV formulations are similarly directed to subject matter that is patentably distinct over the present claims. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it should be noted that there was no restriction between claims of instant application and US application US 19/095,919 in any one of the prior applications. Therefore, while claims at issue are not identical, they are not patentably distinct from each other for the reasons of record. The claims in both applications encompass the same composition comprising an adeno-associated virus (AAV) particle, wherein the AAV particle comprises:(i) the nucleic acid construct. The ‘986 differs from claimed invention by not disclosing that that the composition comprises: .1 mM of Na2HPO4, 1.8 mM of K2HPO4, 172mM NaCl and 0.001% PF-68 (poloxamer-188), which would be obvious over modified perilymph solution of prior art. This would it would have been prima facie obvious for one of ordinary skill in the art seeking to produce an AAV particle suitable for gene therapy for ocular or inner ear disorder would combine the teaching of prior art to modify the AAV particle composition of ‘986 by optimizing the perilymph/PBS by further incorporating PF-68 as suggested in Bennicelli/Simons, for successful delivery and transduction of virus particle in ocular or inner ear cells, with reasonable expectation of success.
In response to applicant’s argument that claims in the present Divisional application (claiming priority to US °095) are directed to subject matter that was deemed to be patentably distinct compared to the subject matter elected and pursued in US’095, it is noted that instant application is a divisional of ‘726 (US’095), however, during the prosecution of ‘726 in the second restriction it was explicitly stated that invention of group I drawn to a composition comprising AAV particle and group II drawn to a AAV particle formulated in a solution in specified concentration ranges are related as combination and subcombination (as indicated in previous office action mailed on 7/29/2025, page 13, para. 2 of the office action). The final office action in US’095 (‘726 Patent) application explicitly stated if the composition comprising AAV particle is found allowable, any withdrawn product claim(s) depending from or otherwise requiring all the limitations of the allowable claims will be examined for patentability in accordance with 37 CFR 1.104. See MPEP § 821.04(a). Applicant was advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant applicat