DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s response to restriction requirement filed on October 23, 2025 have been received and entered. Claim 18 has been amended, while claims 1-17, 19 and 20 have been canceled. Claims 21-33 are new.
Claims 18, 21-32 and 33 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claim 18 (group III) in the reply filed on October 23, 2025 is acknowledged. Claims 21-33 are drawn to elected invention.
Priority
This application is a Continuation of US application no 15/877,705 filed on 01/23/2018, which is a Continuation of US application no 14/485,472 filed on 09/12/2014, which is a Continuation of PCT/US2013/031002 filed on 03/13/2013, which claims priority from US provisional application no 61/610,416 filed on 03/13/2012
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/02/2024, 10/23/2025 and 11/06/2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 18, 21-33 are under consideration.
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 18, 21-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: an in vitro method of method of targeting a cancer cell , said method comprising
contacting a cancer cell with a recombinant adenovirus to produce an adenoviral infected cancer cell; under in vitro condition wherein the recombinant adenovirus comprising a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein encoded by the SEQ ID NO: 69 inserted into the H1 loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein, wherein said insertion of the FRB protein into the H1 loop of the adenoviral fiber protein does not inhibit replication and assembly of the adenovirus, and wherein the ligand is capable of binding to the cancer cell,
allowing the adenoviral infected cell to express the recombinant nucleic acid, thereby forming the ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising the capsid-dimerizing agent binder conjugate;
contacting the cancer cells the dimerizing agent selected from the group consisting of rapamycin or a rapalog;
allowing the recombinant adenovirus and the ligand-dimerizing agent binder conjugate to bind to the dimerizing agent, thereby forming an adenoviral cancer cell targeting construct; and
allowing the adenoviral cancer cell targeting construct to bind to the cancer cell;
does not reasonably provide enablement for in vivo targeting any cancer cell of different etiology and pathology in a cancer patient, using any nucleic acid encoding any other capsid-dimerizing agent binder conjugate and any other ligand- dimerizing agent binder conjugate, any adenoviral fiber protein and a FRB protein of any length inserted any other location of the adenoviral fiber protein or using any ligand targeting any other cell type capable of binding to cancer cell and any other dimerizing agent binder as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
Claims are directed to a method that comprises administering a cancer patient of any etiology and pathology a recombinant adenovirus of claim comprising a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand- dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral capsid protein and a dimerizing agent binder, and the ligand-dimerizing agent binder conjugate comprises a ligand and a dimerizing agent binder to produce a ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate; administering to the cancer patient a dimerizing agent; allowing the recombinant adenovirus and the ligand-dimerizing agent binder conjugate to bind to the dimerizing agent, thereby forming an adenoviral cancer cell targeting construct. Dependent claims limit ligand is an antibody, capable of binding any tumor cells, and the antibody is a single domain antibody. Dependent claim also limits the adenoviral capsid protein is any fiber protein of any length and wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein of any length inserted into the HI loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein. Dependent claims further limit the FKBP protein to human FKBP protein subsequently limiting to FKBP12.
. Breadth of the claims
The breadth of independent claim encompasses use of a recombinant adenovirus of comprising a recombinant nucleic acid encoding any capsid-dimerizing agent binder conjugate and any ligand -dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral capsid protein of any size and any dimerizing agent binder, and the ligand-dimerizing agent binder conjugate comprising a ligand and a dimerizing agent binder to produce a ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate. The claim as written read on any adenoviral capsid protein comprising any fiber protein of any length and any dimerizing agent binder of the capsid agent binder conjugate that is inserted into any part of fiber protein. Further, independent claims recite a broad genu of ligand-dimerizing agent binder conjugate, wherein ligand is not even required to bind a tumor cell. Claims 24-25 limit the ligand to any antibody or any single domain antibody or yet to be identified antibody against any unknown or yet to identified target.
Guidance of the Specification and The Existence of Working Examples
The specification discloses viral compositions that express polypeptide binding pairs (as listed in Table 2, e.g. FKBP and FRB) capable of dimerizing in the presence of a chemical dimerizing agent (e.g. rapamycin) and thereby forming a ternary complex. The ternary complex enables the virus to bind to a specific cellular surface receptor. The components of the ternary complex may completely or partially be encoded by the adenoviral genome and are therefore not lost during viral replication providing for the ability of the virus of subsequent re-infection. A dimerizing agent binder is an agent capable of binding a dimerizing agent. A dimerizing agent binder includes is a compound or a small molecule. In some embodiments, the dimerizing agent binder is FRB protein. The examples of dimerizing agent binders are set forth in Table 2. Binding of the dimerizing agent binder to the dimerizing agent may occur through non-covalent intermolecular interactions such as hydrogen bonding, electrostatic interactions, hydrophobic and Van der Waals forces. The capsid-dimerizing agent binder conjugate includes a viral capsid protein. The specification refers the term capsid to any component (e.g. capsid proteins or polypeptides) forming the shell of a virus, wherein the capsid can include one or more of these components. The capsid includes any appropriate structural components of the viral shell. In some embodiments, the capsid protein is an adenoviral capsid protein. Examples of capsid proteins are L3 II (hexon) (e.g. encoding major structural proteins that form the triangular faces of the capsid), L1 IIIa (e.g. encoding minor structural proteins that help to stabilize the capsid), L2 III (penton) (e.g. encoding major structural proteins that form the vertex of the capsid where the fiber protrudes), L2 pVII (e.g. encoding core structural proteins with homology to histone H3 and associate with viral DNA in the capsid), and L5 IV (Fiber) (e.g. encoding major structural proteins that extend from the penton base and are responsible for receptor binding). In some embodiments, the adenoviral capsid protein is a fiber protein (see para. 79 of the specification).
The specification discloses that fiber protein which infers tropism to adenovirus is generally not permissible to large insertions or modifications, because the correct folding and assembly of fiber trimers into adenovirus particles are critical for viable progeny. To date, insertion of sequences in the C-terminal Ad5 fiber knob-domain has been effectively limited to peptides. The specification contemplates using Adsembly (described in FIG. 5) the 90 amino acid FRB domain that is inserted into the flexible H1 loop of fiber, which accommodates insertions of up to 100 amino acids without deleterious effects (see para. 109). The expression of FKBP from the virus genome would ideally have similar timing and levels matching that of fiber, to enable efficient dimerization with fiber in the presence of rap (see para. 114). The specification teaches out of three distinct approaches only one strategy that utilizes adenovirus transcriptional architecture to express FKBP worked. It is noted that the E3 component (E3-048) was cloned and used Adsembly with E1-009, wild type E2, L3, and E4 to generate Ad-178 (FIG. 8). This virus was able to replicate in 293 E4 cells, as evidenced by fluorescence and CPE and therefore, this strategy was used to create novel viruses that express FRB-fiber and FKBP retargeting moieties (see para. 166, 117). Based on the structural modeling (FIG. 13), the VHH domains (CEAVHH, EGFRVHH) are fused to the N terminus of FKBP for the least steric hindrance for VHH/target interactions and the FKBP/rap/FRB dimerization interface. It is further disclosed that using SLIC, the VHH sequences are fused to the N-terminus of FKBP with an inserted GSGSGST linker sequence. These fusion proteins are cloned into E3 components with the approach to generate Ad-177 and Ad-178 (Table 1). FIG. 11 shows the expression the EGFRVHH-FKBP fusion protein from the Ad-178 infected cells, which is similar to CEAVHH-FKBP expression from Ad-177 (data not shown). The guidance is limited to 90 amino acid FRB domain encoded by the nucleic acid sequence as set forth in SEQ I DNO: 69 that is inserted into the flexible H1 loop of fiber, which accommodates insertions of up to 100 amino acids without deleterious effects. The specification contemplates "FKBP protein or polypeptide" and “FRB protein or polypeptide" as referred to herein includes any of the naturally-occurring forms of the FKBP or FRB protein, or variants thereof that maintain FKBP and FRB protein activity respectively. Thus, claims as such embrace variant that within at least 50-100% activity compared to FKBP or FRB and variant have at least 90%, amino acid sequence identity across the whole sequence or a portion of the sequence compared to a naturally occurring FKBP or FRB protein as set forth in SEQ ID NO: 66 and 69 respectively (see para. 64 and 65). The guidance provided in the specification is limited to administration of Ad-177 and Ad-178 (Table 1). FIG. 11 shows the expression the EGFRVHH-FKBP fusion protein from the Ad-178 infected 294E4 cells (see para. 151-153 of the specification). The in vitro teaching of retargeting virus in a 294E4 fails to provide any reasonable correlation between the disclosed in vitro production of infected cells and an in vivo targeting of any cancer cell in a cancer patient using the adenovirus as broadly claimed. The specification provides no teaching of administering to the cancer patient of different etiology and pathology any recombinant adenovirus as broadly claimed and administering to the cancer patient any via route any dimerizing agent to produce any adenoviral cancer cell targeting construct that could bind to any cancer cell as broadly claimed in the cancer patient in vivo.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The independent claim recites administering to the cancer patient a recombinant adenovirus comprising a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand- dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral capsid protein and a dimerizing agent binder, and the ligand-dimerizing agent binder conjugate comprises a ligand and a dimerizing agent binder. The state of art summarizes by the reference of Green (Cancer Gene Therapy (2002) 9, 1036 – 1042) teaches challenges in (i) systemically administering adenovirus and targeting cancer cells due to rapid clearance of virus from the blood, (ii) effective expression in target tissue(see page 1036, col. 1, para. 2) and (iii) anti-adenovirus - neutralizing antibodies (see page 1036, col. 2, last para.). The limitation of poor systemic administrability or suboptimal intertumoral retainment of the virus remains a major challenge toward maximizing the antitumor activity of Ad was also suggested as post filing art of Thambi (abstract, Cancer Gene Therapy (2022) 29:1321 – 1331). The in vitro teaching of retargeting virus in a 294E4 fails to provide any reasonable correlation between the disclosed in vitro production of infected cells to an in vivo targeting of any cancer cell in a cancer patient delivered via different route the adenovirus as broadly claimed. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
The state of the art further reported unpredictability of small molecule dimerizer-controlled binding between capsids and ligands that stems from the complex, non-linear relationship between dimerization, ligand binding, and the resulting structural dynamics. For instance, Bessman (Cell Reports 2014, 9, 1306–1317) reported unexpected relationships between ligand binding and receptor dimerization. Bessman states “Surprisingly, dimerization does not enhance ligand binding (although ligand binding promotes dimerization). We further show that simply forcing EGFR ECRs into preformed dimers without ligand yields ill-defined, heterogeneous structures. Finally, we demonstrate that extracellular EGFR-activating mutations in glioblastoma enhance ligand-binding affinity without directly promoting EGFR dimerization, suggesting that these oncogenic mutations alter the allosteric linkage between dimerization and ligand binding” (see abstract). Further, Waehler et al (Nature Review, 2007, 8, 573-587, IDS) teaches potentially suboptimal stability of the vector–adaptor complex, especially in vivo, which might result from unforeseen interactions with factors that perturb the non-covalent binding. Systems that rely on either the BAP, with their strong binding of the targeting complex, or on chemical conjugation are the least likely to be affected by this. In addition, difficulties can arise in terms of scaling up adaptor protein production, and the coupling efficiency might vary between different batches (see page 581, col. 1, para. 3). Waehler continue to teach problems in “introduction of large proteins can be deleterious to the structure of the viral protein into which they are inserted, or can impede the correct folding of the incorporated polypeptide. Incorporation of a single-chain antibody fusion into an Ad vector was initially impeded because of the different biosynthetic pathways that are used to produce the scFv (which is synthesized in the rough endoplasmic reticulum (ER), facilitating formation of di-sulphide bridges) and the Ad capsid proteins (which are synthesized in the cytosol, interfering with the formation of these bridges)”. Further, art teaches, “incorporation of such large proteins into the Ad fiber can impede proper folding trimerization) of the fiber and hence viral rescue. The use of cytosolically stabilized scFvs (intrabodies) and the generation of an artificial fiber allowed genetic coupling of the fiber and scFv in the Ad system. ..One challenge in using this system relates to identifying scFvs that will fold correctly in the cytosol, requiring expertise in scFv technology and complex fiber. The guidance is limited to 90 amino acid FRB domain encoded by the nucleic acid sequence as set forth in SEQ I DNO: 69 that is inserted into the flexible H1 loop of fiber, which accommodates insertions of up to 100 amino acids without deleterious effects. The specification contemplates "FKBP protein or polypeptide" and “FRB protein or polypeptide" as referred to herein includes any of the naturally-occurring forms of the FKBP or FRB protein, or variants thereof that maintain FKBP and FRB protein activity respectively. Thus, claims as such embrace variant subsequently limiting to a variant that has at least 90%, amino acid sequence identity across the whole sequence or a portion of the sequence compared to a naturally occurring FKBP protein as set forth in SEQ ID NO: 66 (see para. 64 and 65). In view of foregoing, only a 90 amino acid FRB domain encoded by the nucleic acid sequence as set forth in SEQ I DNO: 69 that is inserted into the flexible H1 loop of fiber could be demonstrated as enabled for the claimed method of targeting a cancer cell under in vitro condition.
The specification lacks teaching of any relationships between ligand binding and receptor dimerization in cancer cell of different etiology and pathology. Given that distinct subclonal population in a cancer patient may have divergent mutation and variable antigen expression that is expected to contribute to an uneven binding and resistance even with in same tumor. For instance, Larose (Cancer Drug Resistance 2025, 8 (11), 1-24) teaches HER2 positive cancer subclones with low her2 expression show reducing antibody-drug conjugates (ADC) binding leading to inconsistent ADC binding, allowing cells with low or absent target antigens to survive (see page 9, para. 1). The specification does not provide any specific guidance to target any type of cancer cells using any ligand to overcome this art recognized unpredictability. The lack of guidance in the specification would force the skilled practitioner to guess and try different ligand targeting tumor of different etiology and pathology by using different combination of capsid-dimerizing agent binder conjugate and ligand-dimerizing agent binder conjugates. Such guessing would require extensive unpredictable and undue experimentation. It is noted that the unpredictability of a particular art area may alone provide reasonable doubt as to the accuracy of the broad statement made in support of enablement of claims. See Ex parte Singh, 17 USPQ2d 1714 (BPAI 1991). It is also well established in case law that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991).A person of skill in the art would have to perform undue experimentation to make use of the adenovirus as broadly claimed, without reasonable expectation of success.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope. An artisan of skill would have required undue experimentation to practice the invention without reasonable expectation of success.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim 18, 21-23, 26-29, 31-32 and 33 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Clackson (US patent no. 6506379, dated 01/14/2003, IDS) as evidence by NCBI accession no CV110986/ BF118061, 2011, IDS), Herman et al (EP1413586, 04/28/2004, see sequence search report), Chen et al (Proc. Natl. Acad. Sci. USA, 1995, 4947-4951, IDS) and Fang et al (Molecular Therapy , 2007, vol. 15 no. 6, 1153–1159, IDS), McClelland et al (USP 5543328, 08/06/201996) and Belousova et al (Journal of Virology, 2002, 8621,-8631, IDS), .
With respect to claims 18, 21-22, Clackson teaches a method of targeting a cell (HT1080, fibrosarcoma cells), said method comprising, introducing a viral vector including adenovirus into the target cell in to produce a population of transduced muscle cells (see col. 14, lines 59-67, col. 33, line 48, claim 7 of ‘379, example 8) , wherein the adenovirus comprises a nucleic acid encoding a fusion of FKBP and FRB to receptor tyrosine kinase cytoplasmic domain (see example 8), wherein the nucleic acid construct may be incorporated into vectors designed for integration into the host cells' chromosomes. The constructs may be integrated and packaged into non-replicating, defective viral genomes like Adenovirus (see col. 31, lines 53-56). Clackson discloses a complex of FRB: rapamycin: FKBP12 which acts as a biological switch to regulate transcription process in a cell. The art teaches FKBP/FRB domains can be placed either C-terminal or NH2-terminal to the cytoplasmic domain of the receptor tyrosine kinase. The vectors are constructed such that (i) the cytoplasmic domain of a given receptor is fused to both FKBP and FRB (for e.g., EGFR cytoplasmic domain fused to either FKBP or FRB) or (ii) can be constructed such that cytoplasmic domains of two different receptors are fused to FKBP and FRB (for e.g., EGFR cytoplasmic domain fused to FKBP and erbB-2 cytoplasmic domain fused to FRB). In the former case (i) addition of the drug, rapamycin, will induce the formation of homodimers (e.g., EGFR/EGFR) while, in the latter (ii) addition of the drug will induce heterodimer (e.g., EGFR/erbB-2, capable of binding to tumor cells as evidenced by ) and result in activation of the signal transduction cascade (see example 8, col. 89, lines 25-55). Clarkson further teaches administering subject a pharmaceutical composition containing the rapamycin or rapalog by a route of administration and in an amount effective to cause multimerization of the chimeric proteins in at least a portion of the cells by detecting cell death; or other objective for which the chimeras were designed (see col. 15, lines 40-52) (limitation of claim 18, , 21-23, 26-28). It is further disclosed that the FKNP protein is human FKBP protein12 protein (see col.9, lines 57-60) (limitation of claim 31-32)
With respect to claims, 21-22, Clackson discloses 89 amino acid regions essentially corresponding to the minimal ` FRB` domain as necessary and sufficient for FKBP-rapamycin binding (see col. 51, lines 5-10). Chen provided guidance with respect to the protein identified as FRB domain within the C-terminal 730 aa of the protein. Further analysis utilizing an in vitro transcription/translation system shows minimal binding domain to a fragment composed of only 90 aa, residues 2025-2114 (see page 4950, col. 2, para. 1). CBI accession number teaches at least 98% identical to SEQ ID NO: 69 encodes FRB and Herman provide the relevant sequence comprising of FKBP (SEQ IDNO: 11) (limitation of claims 1, 35). Clackson discloses FRB protein comprises a mutant FRB domain including FRB peptide sequence but bearing amino acid substitutions for one of more of the residues Tyr2038, Phe2039, Thr2098, Gln2099, Trp2101 and Asp2102. Exemplary mutations include Y2038H, Y2038L, Y2038V, Y2038A, F2039H, F2039L, F2039A, F2039V, D2102A, T2098A, T2098N, and T2098S (see col. 24, lines 27-38).
Regarding claims 18, 26-28, Clackson teaches that the nucleic acid encoding a fusion of FKBP and FRB to receptor tyrosine kinase cytoplasmic domain may be incorporated in the adenoviral vector (see col. 31, line 56, example 8). Clarkson further teaches ability of expression of a protein containing Fas and FRAP domains and a protein containing Fas and FKBP domains to activate Fas and trigger cell death upon addition of rapamycin that is tested in either transiently or stably transfected cells (example 8 and fig., 13).
Regarding 31-33, Clackson teaches FKNP protein is human FKBP protein12 protein (see col.9, lines 57-60) (limitation of claim 31, 32). It is disclosed that the dimerizing agent is rapamycin (example 8).
Clackson differs from claimed invention by not explicitly disclosing (i) FRB and FKBP from the adenovirus genome by co-translationally expressing it from the fiber transcript(ii) wherein the ligand is a re-targeting protein to target tumor cell type and (iii) adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein. .
Fang et al vector cassette encoding a single open reading frame (ORF) for the DC101 monoclonal antibody (mAb) in which mAb heavy and light chains are linked by a furin cleavage site and the 2A sequence. It is further disclosed that two distinct polypeptides in equimolar amount is produced (see fig. 1, page 1156, col. 2, para. 5). The combination of references differs from claimed invention by not explicitly disclosing wherein the ligand is a re-targeting protein to target tumor cells and adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein.
McClelland teaches use of adenoviral vector containing a ligand that is specific for a receptor located on a desired cell type for targeting. It is generally known in the art that the ligand may include transferrin that binds to the transferrin receptor located on tumor cells, activated T-cells, and neural tissue cells or EGF (see claim 1, 9 and 18), Belousova provides motivation to improve the adenoviral vector system using tropism-modified or targeted Ad5 as a way to improve the efficiency and selectivity of Ad vectors by circumventing their dependency on CAR expression by a target cell (see page 8622, col. 1, para. 1). The combination of references differs from claimed invention by not explicitly disclosing adenoviral fiber protein and FRB protein inserted into the H1 loop of the adenoviral fiber protein (limitation of claim 29).
Belousova et al teach a recombinant nucleic acid encoding a capsid fiber protein- polypeptide inserts of incrementally increasing lengths to develop viral vectors capable of tissue-specific gene delivery (abstract). It is further disclosed that HI loop of the fiber knob domain as a preferred site for the incorporation of targeting peptide and hypothesized that the structural properties of this loop would allow for the insertion of a wide variety of ligands, including large polypeptide molecules. Belousova et al disclose generation of 8 different adenoviral 5 vector Ad5LucNNRGD vector incorporating within the H1 loops of the fiber cloned between codon Thr546 and Pro547 of the Ad5 fiber gene insert ranging in size from 13-83 amino acid residue without any significant reduction in key properties of virion (see page 8624, col. 1, para. 1, figure 4, page 8629, col. 1, para. 2). Belousova continue to teach increasing the size of the HI loop, “we have shown that heterologous protein sequences of over 100 amino acid (aa) residues can be configured into Ad5 fiber” (see page 8622, col. 2, para. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method of targeting a cancer cell by modifying the adenoviral vector comprising recombinant nucleic acid disclosed in Clackson by incorporating the minimal FRB` domain (~90aa) in the H1 loops of the fiber of the Ad5 fiber gene without any dramatic reduction in key properties of virion as suggested by Belousova, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. It would be further obvious to one of ordinary skill in the art to place FKBP sequence placed downstream of the fiber coding sequence following an inserted furin-2a sequence and an auto-cleavage site as described in Fang to produce two distinct polypeptides in equimolar amount; the FRB-Fiber molecule on its C-terminus, and the FKBP protein on its N-terminus, with a reasonable expectation of success. It would have been further obvious to use a ligand that specifically targets the cognate receptor on a cancer cell as disclosed by McClelland as targeting protein for fusion with FKBP as in Clackson, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to (i) use a transferrin or EGF as targeting protein because such ligand was known to target specific cell type expressing receptor for transferrin or EGFR in tumor cells, (ii) modify the adenoviral vector in order to improve the efficiency across cells type as suggested by Belousova. One of skill in the art would have been expected to have a reasonable expectation of success in because prior art successfully reported (i) incorporating ~100 amino acid within the H1 loops of the fiber without any significant reduction in key properties of virion as in Belousova, (ii) fusing to the terminus of FKRB with a ligand because Clarkson successfully reported producing FKBP-retargeting fusion proteins (see example 8), and (iii) using Furin-2a sequence is an optimized Furin protease recognition site to generate two distinct polypeptides in equimolar amount as in Fang. 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) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim 18, 24 and 25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Clackson (US patent no. 6506379, dated 01/14/2003, IDS) as evidence by NCBI accession no CV110986/ BF118061, dated Jan. 2011, IDS), Herman et al (EP1413586, 04/28/2004), Chen et al (Proc. Natl. Acad. Sci. USA, 1995, 4947-4951, IDS) and Belousova (Journal of Virology, 2002, 8621,-8631, IDS), Fang et al (Molecular Therapy , 2007, vol. 15 no. 6, 1153–1159, IDS) as applied above and further in view of Galsgow et al (PLoS One, 2009, 4, 12, e8355, 1-12) and Behar, G., et al., (FEBS Journal, 276(14): p. 3881-3893 (2009).
The teaching of Clackson, Belousova and Fang et al have been described above and relied in same manner here. While combination of reference teaches use of targeting a cell by introducing recombinant adenoviral vector comprising nucleic acid encoding a fiber-FRB capsid protein and FKBP-retargeting ligands fused proteins, wherein FRB and FKBP are dimerizing agent binders, but differs from claimed invention by not disclosing wherein the ligand is an antibody.
Galsgow et al teach producing scFv targeted adenoviral vectors that retains the native secretory biosynthetic pathway of standard available "off the shelf" scFv molecules. Galsgow et al disclose genetic tagging of the adenoviral capsid and the scFv with synthetic leucine zipper- like dimerization domains that provide high affinity, selective interaction between adenoviral particles and the scFv following lysis of the producer cells (see page 2, col. 1, para. 2). Galsgow et al disclose the configuration of heterodimeric zipper domains, wherein one zipper domain is genetically incorporated onto the C-terminus of the knobless 566FF fiber, and its counterpart is fused to the N-terminus of a recombinant scFv molecule (see figure 1b). Galsgow differs from claimed invention by not disclosing that the antibody is single domain antibody.
Behar et al disclose advantage of using single domain antibody in place of scFv because these minimal antibody domains exhibit affinities similar to those of conventional mAbs and are also capable of binding small molecules as haptens. It is disclosed that they often use complementarity determining region (CDR) 3 longer than the one of VH domains, which allow them to bind otherwise difficult-to-reach epitopes within the cavities on the antigen surface. It is further disclosed that the single-domain nature of VHH permits the amplification and subsequent straightforward cloning of the corresponding genes, without requiring an artificial linker peptide (as for single-chain Fv fragments) or bi-cistronic constructs (as for Fab fragments). This feature allows direct cloning of large sdAb repertoires, without the need to be concerned by the usual disruption of VHVL pairing faced when generating scFv and Fab fragment libraries (see page 3882, col. 1, para. 1). Behar disclose amino acid sequence of CEA-specific single domain antibody (see figure 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the method by substituting the ligand disclosed in Clackson with an antibody as suggested in Galsgow or more specifically a single domain VHH antibody as disclosed by Behar as targeting protein for fusion to FKBP within the H1 loops of the fiber insert, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use a single domain VHH antibody as targeting protein because VHHs are stable and do not require post-translational disulfide bond formation to function. One of skill in the art would have been expected to have a reasonable expectation of success in because prior art successfully reported fusing to the terminus of fiber protein a recombinant antibody molecule. 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) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 18, 21-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9913866 and Clackson (US patent no. 6506379, dated 01/14/2003, IDS) and further in view of McClelland et al (USP 5543328, 08/06/201996).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims in the instant application uses the recombinant adenovirus explicitly claimed in 866. For example, instant claims are directed to a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder 5conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the HI loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein. Dependent claims limit the ligand is capable of binding 10a tumor cell, wherein the ligand is an antibody, and wherein the antibody is a single domain 15antibody. Claims further limit the FRB protein comprises a wild-type mTOR FRB domain, wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69, wherein the FRB protein comprises a mutant mTOR FRB domain. Claims are also directed to a recombinant adenovirus comprising a capsid-dimerizing agent binder 10conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein, wherein the capsid-dimerizing agent binder conjugate is bound to a dimerizing agent, wherein the dimerizing agent is further bound to a ligand-dimerizing agent binder conjugate, wherein the dimerizing agent is 20rapamycin or a rapalog. In contrast, claims in ‘866 are directed to a recombinant adenovirus comprising a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein, wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69 and the FKBP protein, and wherein said insertion of the FRB protein into the H1 loop of the adenoviral fiber protein does not inhibit replication and assembly of the adenovirus. Dependent claims limit the recombinant adenovirus of claim 1, wherein the ligand is capable of binding a tumor cell and wherein the ligand is an antibody or a single domain antibody (claims 2-4). Claim 5 limits the the FKBP protein is a human FKBP protein subsequently limiting the human FKBP protein to FKBP12. Claim 7 is directed to a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein, wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69, and wherein said insertion of the FRB protein into the H1 loop of the adenoviral fiber protein does not inhibit replication and assembly of the adenovirus, wherein the capsid-dimerizing agent binder conjugate is bound to a dimerizing agent, and wherein the dimerizing agent is rapamycin or a rapalog. As such, the ‘866 claims represent a species of the instant broader independent claims. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978).
It is noted that instant claims use the same adenovirus vector that is specifically disclosed in ‘866 that could be used to target any cell using cancer as disclosed in Clackson and . McClelland. Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of ‘866 to modify the method of targeting a cancer cell by modifying the ligand that specifically targets the cognate receptor on a cancer cell as disclosed by McClelland as targeting protein for fusion with FKBP as in Clackson, with a reasonable expectation of success, at the time of the instant invention. One of skill in the art would have been expected to have a reasonable expectation of success in because prior art successfully reported targeting cell using the recombinant adenovirus of ‘866.
Claims 18, 21-33 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-6, 8 and 32 and 33 of U.S. Patent no 12514887 in view of Belousova et al (Journal of Virology, 2002, 8621,-8631, IDS), Clackson (US patent no. 6506379, dated 01/14/2003, IDS) .
Although the claims at issue are not identical, they are not patentably distinct from each other because claims in the instant application uses the recombinant adenovirus explicitly claimed in 866. For example, instant claims are directed to a recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder 5conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the HI loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein. Dependent claims limit the ligand is capable of binding 10a tumor cell, wherein the ligand is an antibody, and wherein the antibody is a single domain 15antibody. Claims further limit the FRB protein comprises a wild-type mTOR FRB domain, wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69, wherein the FRB protein comprises a mutant mTOR FRB domain. Claims are also directed to a recombinant adenovirus comprising a capsid-dimerizing agent binder 10conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein, wherein the capsid-dimerizing agent binder conjugate is bound to a dimerizing agent, wherein the dimerizing agent is further bound to a ligand-dimerizing agent binder conjugate, wherein the dimerizing agent is 20rapamycin or a rapalog. In contrast, claims in ‘887 are directed to recombinant adenovirus, comprising: an adenovirus E1A promoter; an adenovirus E4 promoter, wherein the genome encodes an adenovirus fiber protein fused to the wild-type FKBP-rapamycin binding (FRB) protein or a mutant FRB protein comprising a T2098L substitution and genome further comprises encodes a targeting ligand fused to FK506 binding protein (FKBP). Dependent claims limit the targeting ligand is a single domain antibody. Claim 8 limits the adenovirus fiber protein is fused to the mutant FRB protein comprising the T2098L substitution. Claim 13 is directed to a composition comprising the recombinant adenovirus of claim 1, and a pharmaceutically acceptable carrier. Belousova et al teach a recombinant nucleic acid encoding a capsid fiber protein- polypeptide inserts of incrementally increasing lengths to develop viral vectors capable of tissue-specific gene delivery (abstract). It is further disclosed that HI loop of the fiber knob domain as a preferred site for the incorporation of targeting peptide and hypothesized that the structural properties of this loop would allow for the insertion of a wide variety of ligands, including large polypeptide molecules Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art use of the adenoviral vector as disclosed in ‘887 by incorporating the minimal FRB` domain (~90aa) in the H1 loops of the fiber of the Ad5 without any dramatic reduction in key properties of virion as suggested by Belousova, with a reasonable expectation of success, at the time of the instant invention. As such, the ‘877 claims represent a species of the instant broader independent claims. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978). It is noted that instant claims use the same adenovirus vector in view of Belousova and ‘887 that could be used to target any cell using cancer as disclosed in Clackson. Therefore, the recombinant nucleic acid of instant application encompasses the claims of '887.
Conclusion
No claims allowed.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632