DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 07/19/2021, is a 371 filling of PCT/US2019/039939, filed 06/28/2019, and claims domestic benefit to US provisional applications 62/713,066, filed 08/01/2018, and 62/692,514, filed 06/29/2018.
Status of Application, Amendments, and/or Claims
Applicant’s response of 01/23/2026 is acknowledged. Claims 1 and 53-54 are amended and claims 4, 7-18, 20-22, 24-40, 42, 44-46, 48-52, and 57-69 are cancelled. Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 07/31/2025,
Claims 65 and 67-69 were rejected under 35 USC 112(d). The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 1-3, 5-6, 19, 23, 41, 43, 47, 53-56, 65, and 67-69 were rejected under 35 USC 103 over US’000 in view of US’287 and Hollevoet. Applicant’s amendment to the claims to recite that the HSV genome comprises an inactivating mutation in one or both copies of ICP4 and in an ICP22 gene has overcome the rejections and the rejections are withdrawn.
Claims 1-3, 5-6, 19, 23, 41, 43, 47, 53-56, 65, and 67-69 were rejected on the grounds of nonstatutory double patenting over US’438, US’090, US’660, App’416, App’878, and App’501, all in further view of Hollevoet, US’000, and US’287. Applicant’s amendment to the claims to recite that the HSV genome comprises an inactivating mutation in one or both copies of ICP4 and in an ICP22 gene has overcome the rejections and the rejections are withdrawn.
The following grounds of objection and rejection are new as necessitated by applicant’s amendment to the claims.
Claim Objection
Claim 43 is objected to for the following informality: the claim has an underline between “the” and “replication” in line 2. The claim, however, is not amended. Amendment to remove the extraneous underline is suggested.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016 in view of US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006, and Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19 as evidenced by Nguyen, N.P., et al (2010) Molecular biology of breast cancer stem cells: Potential clinical applications Cancer Treatment Reviews 36; 485-491.
US’000 discloses herpes simplex virus (HSV) vectors that do not express toxic HSV genes in non-complementing cells and which comprises a genome comprising one or more transgenes, where the vector is capable of expression of a transgene for at least 28 days in non-complementing cells. The disclosed vectors include vectors having deletions in the genes ICP0, ICP4, ICP22, ICP27, and ICP47, or alternative inactivating mutations, or vectors which express one or more of these genes with modified kinetics (abstract). US’000 further discloses the use of the HSV for gene transfer and expression of therapeutic proteins and polypeptides (abstract; page 6, [0057]).
US’000 teaches that among many viral and non-viral genetic vector systems, Herpes Simplex Virus (HSV)-based vectors have been investigated for use as gene transfer vectors, including for possible therapeutic use in human patients. HSV is a complex, non-integrating DNA virus capable of infecting a very wide range of human and animal cells. The viral genome contains more than 80 genes and is composed of two unique segments, UL and US. Removal of the essential immediate-early (IE) genes ICP27 and ICP4 renders the virus completely defective and incapable of expression of early (E) genes involved in viral genome replication and late (L) genes function in progeny virion assembly. These replication-defective viruses can be grown on complementing cells that express (complement) the missing ICP4 and ICP27 gene products and then can be used to infect non-complementing cells where the viral genome takes residence as a stable nuclear episome. However, vectors that preserve the ICP0 and ICP22 IE genes remain toxic to cells (page 1, [0003]). US’000 teaches HSV vector that do not express any toxic viral genes in non-complementing cells, yet are capable of vigorous, persistent, transgene expression (page 1, [0005]).
The HSV vectors of US’000 have been modified such that the vector does not express toxic viral genes in non-complementing cells (page 1, [0005]). The vectors taught by US’000 are described as meeting the need for an HSV vector capable of expressing a transgene in any tissue or cell in vitro or in vivo without harming the cell or tissue (page 1, [0004]). In the absence of a definition for “non-oncolytic” in the instant specification, the term is interpreted using the art recognized definition as evidenced by Nguyen. Nguyen defines “oncolytic virus” as “a virus used to treat cancer due to its ability to specifically infect and lyse cancer cells while ideally sparing normal cells” (page 488, left column, paragraph 3). As US’000 teaches that the HSV vectors do not express toxic viral genes and that the vectors do not harm the cell or tissue that is infected, the vectors are non-oncolytic, meeting the instant claim limitation. Additionally, US’000 does not teach that the HSV genome is oncolytic, further suggesting that the viruses of US’000 are non-oncolytic viruses.
US’000 teaches herpes simplex virus (HSV) vectors that do not express toxic HSV genes in non-complementing cells and which comprise a genome comprising one or more transgenes, wherein the vector is capable of expressing a transgene in non-complementing cells. The inventive vector can comprise a transgene inserted in operable connection with one or more insulator sequences within the genome wherein the vector does not express ICP0, ICP4, ICP22, ICP27, and ICP47 as immediate early genes. Depending on the activity of the promoter controlling the transgene, the inventive vector can express the transgene in any type of mammalian cell, especially human, that it can infect without the cytotoxicity associated with viral gene expression (page 1, [0006]). US’000 further teaches viral stocks of the inventive vectors, compositions thereof suitable for use therapeutically or for in vitro applications, and methods related thereto (abstract).
US’000 teaches that any suitable method can be employed to render the inventive vector incapable of expressing ICP0, ICP4, ICP22, ICP27, and ICP47 as immediate early genes within non-complementing cells. For example, the genome of the vector can be engineered to comprise inactivating mutations, for example deletions, of one or all of these genes. Alternatively, one or more of these HSV genes can be engineered to be expressed as an early or late gene (page 4, [0043]). US’000 teaches that the vector desirably comprises a deletion of the internal repeat, or joint, region, comprising IRS and IRL. Deleting this region can contribute to the stability of the vector genome, and deleting this sequence of HSV DNA also allows for the vector to accommodate large transgenes and still be packaged correctly to mature virions. Deletion of the joint eliminates one copy of each of the IE genes ICP0 and ICP4 such that the remaining copies can be easily manipulated. It also deletes the promoter for the ICP22 or ICP47 immediate early gene. If desired, expression of the ICP47 gene can be restored by insertion of an immediate early promoter, preferably the ICP0 promoter or the HCMV major IE promoter to minimize immune recognition of the infected cells (page 7, [0060]).
US’000 teaches compositions comprising the HSV vector and a carrier, including a pharmaceutically acceptable carrier such as an excipient (page 8, [0071]).
US’000 teaches that when used in vivo, the inventive method can treat a disease or a condition within a subject, when the transgene of the vector encodes one or more prophylactically or therapeutically active proteins, polypeptides, or other factors. US’000 teaches a method of treating a disease or condition in a subject, comprising administering the vector of the invention to the subject in an amount and at a location sufficient to infect cells of the subject such that the transgene is expressed within the cells of the subject, and wherein the transgene encodes one or more prophylactically or therapeutically active proteins, polypeptides or ncRNA. An example of the disease or condition can be a type of cancer, in which the transgene encodes an agent that enhances tumor killing activity (page 9, [0076]).
As discussed above, US’000 teaches inactivating mutations, for example deletions, in one or more of ICP0, ICP4, ICP22, ICP27 and ICP47. US’000 also teaches that ICP4 and ICP27 genes are essential immediate early (IE) genes and removal of them renders the virus completely defective. ICP0 and ICP22 are taught to be genes associated with toxicity to cells.
US’000, however, does not expressly disclose that the genome comprises inactivating mutations in ICP4 and ICP22 but not in an ICP27 or tk gene as is instantly claimed. Additionally, US’000 does not disclose that the encoded protein or polypeptide is an antibody.
US’029 teaches an isolated HSV or HSV genome with an inactivating mutation in each copy of the gene encoding ICP4 (col. 17, claim 1). US’029 also teaches that the HSV comprises a further inactivating mutation in at least one of ICP0, ICP22, ICP27, ICP47, ICP6, or UL41 loci (col. 17, claim 2) and teaches an embodiment in which the HSV comprises an inactivating mutation in each copy of ICP4 and in ICP22 (col. 18, claim 20).
US’029 teaches that ICP4, ICP0, ICP27, ICP22, and ICP47 are the immediate early gene products and show varying degrees of essentiality to HSV function. These phosphoproteins possess regulatory activities thought to prime the host cell for the efficient cascade of subsequent viral gene expression. US’029 teaches that ICP22 promotes efficient late gene expression in a cell-type dependent manner and is involved in the production of a novel modified form of RNA Pol II. ICP4 is a large multifunctional protein and can act as a transcription factor that either represses or activate transcription through contacts with the general transcriptional machinery. ICP4 is absolutely required for both virus infectivity and the transition from IE to later transcription (col. 1, line 41 – col. 2, line 2).
US’029 teaches that a need exists for defective herpes simplex virus strains exhibiting efficient growth in a controlled laboratory complementing system, a reduced level of wild-type virus regeneration, and lower cytotoxic effect (col. 3, lines 25-30).
US’029 further exemplifies an HSV strain that is ICP4(-) and ICP22(-) and teaches that infected cells behaved similarly to d92 (defective in ICP4 and ICP27) infected Vero cells with respect to the longevity of protein synthesis (col. 14, lines 17-13). US’029 does not teach that the HSV strains comprise inactivating mutations in tk, and, therefore, the strains meet the instant claim limitation of not having such mutations.
Hollevoet teaches that recombinant monoclonal antibodies (mAbs) are one of today’s most successful therapeutic classes in inflammatory diseases and oncology. A wider accessibility and implementation, however, is hampered by the high production cost and prolonged need for frequent administration. To address these issues, antibody gene transfer seeks to administer to patients the mAb encoding polynucleotide sequence rather than the mAb protein, allowing the body to produce its own medicine in a cost- and labor-effective manner, for a prolonged period of time. Expressed mAbs can be secreted systemically or locally depending on the production site. Hollevoet provides a review of the state of play and clinical prospects of antibody gene transfer, highlighting recent innovations, opportunities, and remaining hurdles (abstract).
Hollevoet teaches that the history of pre-clinical and clinical studies of antibody gene transfer spans more than two decades and has been used in a myriad of indications including cancer, infectious diseases, inflammatory diseases, and central nervous system diseases. In addition to full-length IgG, in vivo expressed mAb products include antibody-fusion products such as immunoadhesins, bispecific antibodies, and fragments including antigen-binding fragments (Fab), single chain variable fragments (scFv), and single-domain antibodies (paragraph bridging pages 4-5). Hollevoet also teaches that therapeutic mAb applications include diseases such as asthma and rheumatoid arthritis (page 1, right column, paragraph 1).
Hollevoet further teaches viral vector mediated antibody gene transfer teaching that viral vectors are currently used as a delivery vehicle in the vast majority of pre-clinical and clinical gene therapy trials. The main driver thereto is their exceptional gene delivery efficiency, which reflects a natural evolutionary development. Hollevoet teaches that most often applied for gene therapy applications are adenoviruses and adeno-associated viruses (page 6, left column, paragraph 2). Hollevoet further teaches that in 2015, the FDA and EMA approved talimogene laherparepvec (T-VEC, Imlygic™), an oncolytic herpes virus armed with the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) (page 8, left column, paragraph 1).
Hollevoet further teaches that therapeutic proof of concept has been demonstrated in mice and non-human primates, and intramuscular vectored mAb therapy is under clinical evaluation (abstract). Hollevoet teaches modes of delivery for viral vector antibody gene transfer teaching that the muscle and liver, via intravenous delivery, have been most often reported and others include the brain, intranasal route, trachea, tumors via direct injection or intravenous delivery, pleura, peritoneum, skin including intradermal and subcutaneous, and spinal canal, as well as into the eye (page 3, Figure 1b).
Hollevoet further teaches antibodies including adalimumab, infliximab, etanercept, rituximab, bevacizumab, and trastuzumab (page 2, left column, paragraph 1), as well as ipilimumab (page 2, right column, paragraph 1), and tocilizumab (page 11, right column, paragraph 2).
The antibodies disclosed by Hollevoet comprise the amino acid sequences of instant claims 67-69, as evidenced by the instant specification which defines the amino acid sequences of the antibodies as follows (pages 35-42, [0111]; Table 1, pages 44-47; Table 2, pages 50-54):
Adalimumab: VH-SEQ ID NO: 355; VL-SEQ ID NO: 420; defined as HSV-AB1 (Table 2); HVR-H1-H3: SEQ ID NOs: 1, 60, and 123, respectively, and HVR-L1-L3: SEQ ID NOs: 186, 243, and 295, respectively (Table 1);
Infliximab: VH-SEQ ID NO: 365; VL-SEQ ID NO: 430, defined as HSV-AB11 (Table 2); HVR-H1-H3: SEQ ID NOs: 11, 70, and 133, respectively, and HVR-L1-L3: SEQ ID NOs: 196, 253, and 305, respectively (Table 1);
Rituximab: VH-SEQ ID NO: 356; VL-SEQ ID NO: 421, defined as HSV-AB2 (Table 2); HVR-H1-H3: SEQ ID NOs: 2, 61, and 124, respectively, and HVR-L1-L3: SEQ ID NOs: 187, 244, and 296, respectively (Table 1);
Bevacizumab: VH-SEQ ID NO: 357; VL-SEQ ID NO: 422, defined as HSV-AB3 (Table 2); HVR-H1-H3: SEQ ID NOs: 3, 62, and 125, respectively, and HVR-L1-L3: SEQ ID NOs: 188, 245, and 297, respectively (Table 1);
Trastuzumab: VH-SEQ ID NO: 846; VL-SEQ ID NO:1097, (HVRs not defined in Tables 1 and 2);
Ipilimumab: VH-SEQ ID NO: 372; VL-SEQ ID NO: 437, defined as HSV-AB18 (Table 2); HVR-H1-H3: SEQ ID NOs: 19, 77, and 140, respectively, and HVR-L1-L3: SEQ ID NOs: 202, 260, and 312, respectively (Table 1); and
Tocilizumab: VH-SEQ ID NO: 367; VL-SEQ ID NO: 432 , defined as HSV-AB13 (Table 2); HVR-H1-H3: SEQ ID NOs: 15, 72, and 135, respectively, and HVR-L1-L3: SEQ ID NOs: 198, 255, and 307, respectively (Table 1);
As the antibodies disclosed by Hollevoet comprise the sequences claimed in instant claims 67-69, the teachings of Hollevoet meets the instant claim limitations.
Hollevoet teaches the use of viral vectors for the delivery of mAb encoding nucleotide sequences and also teaches that a herpes virus has been produced and approved with a gene for encoding GM-CSF, demonstrating that the use of herpes viruses for producing polypeptides/proteins was known in the prior art.
Hollevoet teaches that, while replication competence can boost mAb expression, it also carries biosafety concerns (page 9, left column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the HSV vectors disclosed by US’000 to comprise vectors in which the ICP4 and ICP22 genes comprise inactivating mutations but not the ICP27 or tk gene based on the combined teachings of US’000 and US’029. It would have further been obvious to modify the compositions and methods disclosed by US’000 to have the transgene comprise a monoclonal antibody (mAb)-encoding nucleotide sequence as disclosed by Hollevoet, including those that encode the mAbs disclosed by Hollevoet.
It would have been obvious to have the HSV vectors disclosed by US’000 comprise inactivated ICP4 and ICP22 genes, but not ICP27 or tk genes, as US’029 teaches inactivating mutations in HSV ICP4 and ICP22 genes as a means for generating a gene transfer vector that has reduced cytotoxicity in vivo and promotes more efficient transgene expression. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’000 and US’029 are teaching the modification of HSV vectors for gene delivery and transgene expression.
This conclusion of obviousness is further supported by KSR (E), obvious to try. See MPEP 2143.
In this case, US’000 and US’029 demonstrate infected cell protein (ICP) genes, including ICPs 0, 4, 22, 27, and/or 47, were known to play particular roles in HSV function. The references also teach the utilization of mutations or deletions in these genes to render them inactive for use in HSV transgene delivery and expression. As the genes and their functions were known in the art, it would have been obvious and predictable to try any of these mutations in any combination to arrive at an HSV for transgene delivery and expression that is both replication-defective and non-toxic to infected cells (non-oncolytic).
Furthermore, the determination of the optimal HSV gene manipulation for the delivery and expression of transgenes, including antibodies, is considered to be routine optimization where conditions were known in the prior art. MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, as discussed above, US’000 and US’029 demonstrate infected cell protein (ICP) genes, including ICPs 0, 4, 22, 27, and/or 47, were known to play particular roles in HSV function and had been considered and tested in the prior art as potential genes for inactivating in HSV for transgene delivery. Hollevoet teaches that replication competency can boost mAb expression but carries biosafety concern and US’000 and US’029 demonstrate that, by manipulating replication competency and toxicity of the HSV vector, transgene expression can be modulated. As such, it would have been obvious to one of ordinary skill in the art to optimize the HSV vector, using deactivating mutations in the ICPs, as a means to optimize the vector for a desired transgene expression.
An ordinarily skilled artisan would have been motivated to have the transgene in the replication-defective recombinant HSV of US’000 comprise a mAb-encoding nucleotide as Hollevoet teaches that recombinant monoclonal antibodies are one of today’s most successful therapeutic classes in inflammatory disease and oncology and that using viruses for production allows for a wider accessibility and implementation. An ordinarily skilled artisan would have had a reasonable expectation of success as US’000 teaches that the HSVs disclosed encode polypeptides and antibodies are polypeptides. Additionally, Hollevoet discusses numerous studies in which viruses were used for antibody gene transfer and both Hollevoet and US’000 demonstrate that recombinant herpes viruses had been successfully used for the transfer of genes and the expression of proteins/polypeptides.
With regards to the limitations that the recombinant herpes virus genome does not comprise a polynucleotide encoding a collagen polypeptide, a fibronectin polypeptide, an elastin polypeptide, a lumican polypeptide, a vitronectin polypeptide, a vitronectin receptor polypeptide, a laminin polypeptide, a neuromodulator polypeptide, and a fibrillin polypeptide, and that the recombinant herpes virus genome does not comprise a polynucleotide encoding a transglutamine polypeptide, the rejection above relies on modification of the transgene of US’000 to comprise a mAb-encoding nucleotide as taught by Hollevoet in which case the polynucleotide would encode an antibody and would not encode the polypeptides claimed meeting the instant claim limitations. Additionally, US’000 does not teach the recited polypeptides further suggesting that the HSV of US’000 does not comprise a polynucleotide that encodes the recited polypeptides.
Response to Arguments
Applicant’s arguments in the response filed 01/23/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant argues that US’000, which is referred to as “Glorioso” in the response, is directed towards a herpes simplex virus genome that does not express all of ICP0, ICP4, ICP22, ICP27, and ICP47. Applicant argues that the reference does not teach or suggest that the genome comprises an inactivating mutation in ICP4 and ICP22 without an inactivating mutation in ICP27.
In response, it is first noted that the rejection relies on a combination of the applied references and what the combination would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. As such, US’000 is not required to teach each and every limitation of the claimed invention in order to demonstrate a prima facie case of obviousness. In the instant office action, the reference US’029 is also cited in order to demonstrate that various combinations of inactivating mutations had been considered, including HSVs in which inactivating mutations are present in ICP4 and ICP22 and not ICP27 or tk as claimed.
That said, while US’000 does study HSV genomes that do not express all of ICP0, ICP4, ICP22, ICP27, and ICP47, US’000 explicitly teaches that the genome of the vector can be engineered to comprise inactivating mutations, for example, deletions, of one or more of the ICP0, ICP4, ICP22, ICP27, and ICP47 genes (page 4, [0043]), demonstrating that US’000 considered inactivating mutations in one or more of the genes disclosed, not necessarily only all of the disclosed genes.
Additionally, in the rejections of the instant office action, the rejection is supported by obviousness rational KSR(E) as well as routine optimization. As discussed in the rejection, the teachings of US’000 and US’029 demonstrate that the genes of HSV had been studied and characterized, including in the context of transgene transfer and expression. Therefore, one of ordinary skill in the art would have been able to try various combinations with a reasonable expectation of success while optimizing for ideal properties for a particular application.
Applicant does not provide any evidence that the claimed HSV vector with activating mutations in ICP4 and ICP22, but not ICP27 or tk, results in an unpredictable outcome or that the claimed inactivating mutations are critical in any way. For instance see MPEP 2143 and MPEP 2144.05 II.
Applicant further argues that one of ordinary skill in the art would not be motivated to turn towards US’287, referenced by applicant as “Breakefield” because US’287 teaches HSV that comprise an inactivating mutation in tk.
The reference US’287 is no longer cited in the rejection rendering applicant’s arguments about the reference moot. That said, it is noted that explicit motivation in the art is not required in order to establish obviousness. Explicit motivation in the prior art is not required in order establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art.
Applicant further argues that one of ordinary skill in the art would not have been motivated to arrive at a recombinant HSV as recited in the instant claims because the state of the art at the time of the effective filing date of the claimed invention teaches the beneficial properties of engineering a herpes virus vector having inactivating mutations in ICP4, ICP22, and ICP27 for reducing cytotoxicity, rather than in ICP4 and ICP22 alone. Applicant cites Krisky as teaching the beneficial properties of including the ICP27 inactivating mutation. Applicant cites teachings of Krisky in which the HSV vector DHZ.1, which comprises inactivating mutations in ICP4 and ICP22 only, was more toxic than viruses deleted for all three IE genes including ICP4, ICP22, and ICP27. Applicant argues that, based on these teachings, one of ordinary skill in the art would have been motivated to engineer a herpes virus vector having inactivating mutations in ICP4, ICP22, and ICP27.
These arguments, however, are not persuasive. In order to compare the cytotoxicity properties of the IE gene products ICP4, ICP22, ICP27, and ICP47 in mitotic cell lines and primary post-mitotic neurons in culture, Krisky generated mutant viruses deleted for various combinations of the IE genes and examined the effects of the deletions on the cytotoxicity of the mutant viruses. The different isolates and IE genotypes studied by Krisky are provided in Fig. 1A on page 1595, where it is shown that Krisky studied various inactivating mutations and combinations thereof including ICP4 and ICP22 (DHZ.1) as well triple combination mutations of ICP4, ICP22, and ICP27 (THZ.1, THZ.3, and T0Z.1). In Fig. 2, Krisky provides results for the cytotoxicity of the HSV-1 mutants in rat glioblastoma cells. Krisky teaches that viruses deleted for two IE genes, including DHZ.1, were generally more toxic than viruses deleted for all three IE genes, but less than a single IE mutant (only ICP4-) (paragraph bridging pages 1599-1600).
The studies presented in Krisky do demonstrate that the triple combination of ICP4-, ICP22-, and ICP27- did result in a higher cytotoxicity compared to a double mutation of ICP4- and ICP22-; however, Krisky also demonstrates that inactivating mutations in ICP4 and ICP22 also result in a reduction in cytotoxicity. As such, the alternative, or even preferred, embodiments presented by Krisky do not teach away from the claimed invention nor do they demonstrate that one of ordinary skill in the art would not have a had a reasonable expectation of success in arriving at the instantly claimed invention.
See MPEP 2123 (II), which states “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). ‘A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.’ In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)… Furthermore, ‘[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”
Additionally, the teachings of Krisky act as further support for the rejection of the instant office action by further demonstrating that inactivating mutations in HSV IE including ICPs 4, 22, 27, and 47 had been considered and characterized in the prior art in the context of gene transfer even in 1998, which is 20 years prior to the effective filing date of the instantly claimed invention.
Applicant further argues that post-filing data provided by applicant shows limited in vivo toxicity of the claimed HSV encoding an antibody. Applicant cites Example 3 of the specification, which discloses an in vivo study establishing an atopic dermatitis (AD) murine model which was then treated either topically or intradermally with HSV-Ab1Fc1 (a single chain anti-human TNFα antibody). The example demonstrates that robust human IgG protein expression was detected in both the ear and dorsal tissues infected with HSV-Ab1Fc1, but not vehicle control, suggesting that the virus was capable of delivering its encoded antibody cargo into AD-like lesions after topical exposure. Applicant argues that post-filing histology data, which is provided in the response, shows limited toxicity of the HSV-Ab1Fc1 vector, which has an inactivating mutation in one or both copies of the ICP4 gene and an inactivating mutation in ICP22, without an inactivating mutation in ICP27 gene. Applicant argues that these results would not have been predicted based on the combination of applied references.
As detailed by applicant in the response, Example 3 of the instant disclosure studied HSV encoded antibodies in a mouse atopic dermatitis (AD) model. In the example, animals received topical or intradermal treatment with HSV-Ab1Fc or vehicle controls which comprised a methylcellulose gel carrier (page 104, [0271]; page 106, [0275]). The example concludes that the data presented demonstrates the successful establishment of an AD-like phenotype and the feasibility of robust local delivery of a virally encoded antibody into an AD-like lesion after topical administrations of the HSV-Ab1Fc1 vector. In the post filing results presented by applicant in the response, it is shown that the HSV-Ab1Fc1 vector had limited toxicities.
It is appreciated that applicant presents data demonstrating that the claimed HSV is capable of expressing a single chain antibody when applied topically compared to controls comprising a delivery vehicle only and that the HSV shows limited toxicity. Applicant, however, does not provide a comparison to the closest prior art, for instance, the HSV vector of US’000, in order to demonstrate unexpected properties compared to the closest prior art.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
In the example referenced, applicant compares HSV-Ab1Fc1 with a control that comprises only the carrier, which is not a closest prior art comparison. As such, it is not evident from the results provided that the HSV vector provides an unexpected result compared to the closest prior art.
Furthermore, as discussed in detail in the rejections of the instant office action, one of ordinary skill in the art would reasonably expect that an HSV with inactivating mutations in ICP4 and ICP22 would be capable of gene delivery and antibody expression with decreased cytotoxicity relative to unmodified, wild-type, HSV vectors.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
As discussed in detail above, the combination of applied references demonstrate that HSV vectors have been considered for transgene delivery and expression of polypeptides, including antibodies. Additionally, the IE genes within HSV vectors had been studied and characterized as a means to reduce cytotoxicity during gene delivery. The newly applied reference, US’029, also considers and exemplifies the use of an HSV vector that is ICP4- and ICP22-. US’029 teaches that ICP4 is absolutely required for both infectivity and the transition from IE to later transcription suggesting that a deactivation of the gene would be expected to interrupt replication of the virus. A concept which is supported by the teachings of US’000 which teaches that ICP4 is involved in replication. US’000 also teaches that if ICP0 and ICP22 are intact the virus will still be cytotoxic suggesting that the deactivation of ICP22 would impact cytotoxicity.
It is also noted that 716.02 states that “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
Additionally, even if the results presented by applicant were determined to be unexpected, which they are not, the claims are not commensurate in scope with the claimed invention.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
The currently claimed composition and methods encompass the use of any recombinant herpes virus, any administration route, and for the treatment of any disease. The results provided by applicant, however, do not demonstrate that the same results would be achieved over the entire scope of the claimed genus. For instance, the examples only demonstrate the use of the modified HSV-1 genome with topical or intradermal administration for the treatment of AD.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 10,786,438 B2
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. US 10,786,438 B2 in view of Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19, US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016, and US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006.
The claims of US’438 are drawn to pharmaceutical compositions for topical, transdermal, superficial, or intradermal administration comprising a herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome that comprises a first and second polynucleotide encoding cosmetic proteins and a pharmaceutically acceptable excipient; wherein the recombinant HSV comprises an inactivating mutation in both copies of ICP4; where the first protein is a collagen protein, a fibronectin protein, a first elastin protein, a first lumican protein, a first vitronectin protein, a first vitronectin receptor protein, a first laminin protein, a first neuromodulator protein, and a first fibrillin protein (claims 1, 3, 5, 6-7, 11, and 23-28). US’438 further claims that the HSV is replication deficient, comprises an inactivating mutation selected from the group consisting of ICP0, ICP22, ICP27, and ICP47, and has reduced cytotoxicity as compared to a corresponding wild-type herpes simplex virus (claims 1-4, and 8). US’438 further claims that the composition is administered via intradermal or superficial injection (claims 9-10). US’438 further claims a method of improving a skin condition comprising administering an effective amount of the composition (claim 12-22).
The claims of US’438 differ from the instantly claimed invention in that the instantly claimed invention is drawn to polynucleotides encoding antibodies and use of the compositions in the treatment of one or more signs or symptoms of disease.
The teachings of Hollevoet, US’000, and US’029 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’438 to use the claimed compositions and methods for the delivery of antibodies as disclosed by Hollevoet by substituting the polynucleotides encoding the cosmetic proteins with a polynucleotide that encodes an antibody as further supported by US’000. It would have further been obvious to have the HSV be both replication-defective and non-oncolytic as disclosed by US’000 and US’029 which is further supported by the mutations described in the claims of US’438.
It would have been obvious to an ordinarily skilled artisan to modify the compositions and methods of US’438 by substituting the polynucleotides encoding the cosmetic proteins with the polynucleotides encoding antibodies as Hollevoet demonstrates that antibody expression in vivo by viral gene transfer had been studied and demonstrated in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as US’438 claims compositions and methods that express proteins and antibodies are proteins. Additionally, Hollevoet demonstrates the effective use of viral gene transfer for antibodies.
It would have been obvious to have the HSV be both replication-defective and non-oncolytic as US’000 teaches these types of HSV for the gene delivery of proteins/polypeptides, which antibodies are. Replication-defective and non-oncolytic HSVs are also supported by the claims of US’438 which includes mutation in both copies of ICP4 as well as ICP22, which, based on US’029 and US’000 results in replication-defective non-oncolytic HSVs.
With regards to the instant claim limitations that the recombinant herpes virus genome does not comprise a polynucleotide encoding a collagen polypeptide, a fibronectin polypeptide, an elastin polypeptide, a lumican polypeptide, a vitronectin polypeptide, a vitronectin receptor polypeptide, a laminin polypeptide, a neuromodulator polypeptide, and a fibrillin polypeptide, and that the recombinant herpes virus genome does not comprise a polynucleotide encoding a transglutamine polypeptide, the nonstatutory double patenting rejection relies on modification of the claims of US’438 to substitute the polynucleotides encoding the claimed polypeptides with a polynucleotide encoding an antibody. Upon this substitution, the polynucleotide of US’438 would not encode these polypeptides, meeting the instant claim limitations.
US 10,525,090 B2
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. US 10,525,090 B2 in view of Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19, US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016, and US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006.
US’090 claims a pharmaceutical composition comprising a herpes virus comprising a recombinant herpes virus genome, wherein the genome comprises one or more polynucleotides encoding a TGM1 polypeptide and a pharmaceutically acceptable excipient (claim 1, 4-8, and 10-11). US’090 further claims that the recombinant herpes virus genome is replication competent or replication defective and has inactivating mutations in a gene selected from ICP0, ICP4, ICP22, ICP27, tk, UL41, and UL55 (claims 2-6) and has reduced cytotoxicity compared to a corresponding wild-type herpes virus (claim 9). US’090 claims that the composition is suitable for topical, transdermal, or intradermal administration (claims 12-13). US’090 further teaches methods comprising administering to the subject an effective amount of a pharmaceutical composition comprising the composition (claims 14-30).
The claims of US’090 differ from the instantly claimed invention in that the instantly claimed invention is drawn to polynucleotides encoding antibodies and use of the compositions in the treatment of one or more signs or symptoms of disease.
The teachings of Hollevoet, US’000, and US’029 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’090 to use the claimed compositions and methods for the delivery of antibodies as disclosed by Hollevoet by substituting the polynucleotide encoding TGM1 with a polynucleotide that encodes an antibody. It would have further been obvious to have the HSV be both replication-defective and non-oncolytic as disclosed by US’000 and US’029 which is further supported by the mutations described in the claims of US’090.
It would have been obvious to an ordinarily skilled artisan to modify the compositions and methods of US’090 by substituting the polynucleotides encoding TGM1 with the polynucleotides encoding antibodies as Hollevoet demonstrates that antibody expression in vivo by viral gene transfer had been studied and demonstrated in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as US’090 claims compositions and methods that express proteins and antibodies are proteins. Additionally, Hollevoet demonstrates the effective use of viral gene transfer for antibodies.
It would have been obvious to have the HSV be both replication-defective and non-oncolytic as US’000 teaches these types of HSV for the gene delivery of proteins/polypeptides, which antibodies are. Replication-defective and non-oncolytic HSVs are also supported by the claims of US’090 which includes mutation in both copies of ICP4 as well as ICP22, which, based on US’029 and US’000 results in replication-defective non-oncolytic HSVs.
With regards to the instant claim limitations that the recombinant herpes virus genome does not comprise a polynucleotide encoding a collagen polypeptide, a fibronectin polypeptide, an elastin polypeptide, a lumican polypeptide, a vitronectin polypeptide, a vitronectin receptor polypeptide, a laminin polypeptide, a neuromodulator polypeptide, and a fibrillin polypeptide, and that the recombinant herpes virus genome does not comprise a polynucleotide encoding a transglutamine polypeptide, the nonstatutory double patenting rejection relies on modification of the claims of US’090 to substitute the polynucleotides encoding the claimed polypeptides with a polynucleotide encoding an antibody. Upon this substitution, the polynucleotide of US’438 would not encode these polypeptides, meeting the instant claim limitations.
US 11,779,660 B2
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. US 11,779,660 B2 in view of Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19, US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016, and US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006.
US’660 claims a pharmaceutical composition comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex genome comprises polynucleotides encoding an IL-2 polypeptide and an IL-12 polypeptide and a pharmaceutically acceptable excipient, wherein the genome comprises an inactivating mutation (claims 1, 3-6, 9-10, and 13-32). US’660 further claims that the virus is replication defective (claim 2) and that the virus is not oncolytic and has reduced cytotoxicity as compared to a corresponding wild-type herpes simplex virus (claims 7-8). US’660 further claims that the composition is suitable for topical, transdermal, subcutaneous, epicutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intramuscular, intraosseous, intracardial, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, intratumoral, local, or inhaled administration (claims 11-12). US’660 claims that the genome comprises an inactivating mutation in an ICP22 HSV gene (claim 1) and further in a gene selected from the group consisting of ICP0, ICP4, ICP25, ICP47, tk, UL41, and UL55 (claim 5).
The claims of US’660 differ from the instantly claimed invention in that the instantly claimed invention is drawn to polynucleotides encoding antibodies and use of the compositions in the treatment of one or more signs or symptoms of disease.
The teachings of Hollevoet, US’000, and US’029 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’660 to use the claimed compositions and methods for the delivery of antibodies as disclosed by Hollevoet by substituting the polynucleotides encoding IL-2/IL-12 with a polynucleotide that encodes an antibody. It would have further been obvious to include a mutation specifically in ICP4 based on the teachings of US’000 and US’287.
It would have been obvious to an ordinarily skilled artisan substitute the polynucleotides encoding IL-2/IL-12 with a polynucleotide that encodes an antibody as Hollevoet demonstrates that antibody expression in vivo by viral gene transfer had been studied and demonstrated in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as US’660 is teaching compositions and methods that express proteins and antibodies are proteins. Additionally, Hollevoet demonstrates the effective use of viral gene transfer for antibodies.
It would have been obvious to include a mutation specifically in ICP4 and ICP22 as US’000 and US’029 demonstrate that mutations in the ICP4 and ICP22 gene render the HSV replication-defective and non-oncolytic. A person of ordinary skill in the art would have had a reasonable expectation of success as US’660 claims that the HSV is replication defective and can have an inactivating mutation in ICP4. Additionally, US’000 and US’029 also teach gene delivery using HSV vectors.
Application 17/127,416
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45, 119-120, and 122-124 of copending Application No. 17/127,416 in view of Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19, US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016, and US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006.
App’416 claims a pharmaceutical composition comprising a HSV-1 comprising a recombinant HSV-1 genome wherein the genome comprises one or more polynucleotides encoding an inhaled therapeutic polypeptide and a pharmaceutically acceptable excipient. App’416 further claims that the HSV-1 is replication-defective, does not comprise a polynucleotide that encodes CFTR, and that the HSV-1 has reduced cytotoxicity compared to a corresponding wild type HSV-1. App’416 claims that the recombinant HSV-1 genome comprises an inactivating mutation in the ICP22 HSV-1 gene and that the inactivating mutation is a deletion of at least a portion of the coding of the gene. App’416 claims that the genome comprises an inactivating mutation in one or more essential immediate early genes, including ICP22.
The claims of App’416 differ from the instantly claimed invention in that the instantly claimed invention is drawn to polynucleotides encoding antibodies and use of the compositions in the treatment of one or more signs or symptoms of disease. Additionally, App’416 does not explicitly claim that the virus is non-oncolytic, or that the HSV has an inactivating mutation in ICP4.
The teachings of Hollevoet, US’000, and US’029, and are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’416 to use the claimed compositions and methods for the delivery of antibodies as disclosed by Hollevoet by substituting the polypeptide encoding polynucleotides of App’416 with a polynucleotide that encodes an antibody. It would have further been obvious to use the methods disclosed by US’000 and US’029, for instance an inactivating mutation in ICP4, to make the virus replication deficient, and to modify the HSV to have reduced cytotoxicity compared to a wild type virus, and be non-oncolytic.
It would have been obvious to an ordinarily skilled artisan substitute the polypeptide encoding polynucleotides of App’416 with a polynucleotide that encodes an antibody as Hollevoet demonstrates that antibody expression in vivo by viral gene transfer had been studied and demonstrated in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as App’416 is teaching compositions and methods that express therapeutic proteins and antibodies are therapeutic proteins. Additionally, Hollevoet demonstrates the effective use of viral gene transfer for antibodies.
A person of ordinary skill in the art would have been motivated to use the methods disclosed by US’000 and US’029, for instance an inactivating mutation in ICP4, to make the virus replication deficient, and to modify the HSV to have reduced cytotoxicity compared to a wild type virus, and be non-oncolytic in order to express the antibody in vitro or in vivo without harming the cells or tissues as disclosed by US’000. An ordinarily skilled artisan would have had a reasonable expectation of success as both App’416 and US’000 teach HSV as a means of expressing a protein encoding transgene.
With regards to the instant claim limitations that the recombinant herpes virus genome does not comprise a polynucleotide encoding a collagen polypeptide, a fibronectin polypeptide, an elastin polypeptide, a lumican polypeptide, a vitronectin polypeptide, a vitronectin receptor polypeptide, a laminin polypeptide, a neuromodulator polypeptide, and a fibrillin polypeptide, and that the recombinant herpes virus genome does not comprise a polynucleotide encoding a transglutamine polypeptide, the nonstatutory double patenting rejection relies on modification of the claims of App’416 to substitute the polynucleotides encoding the claimed polypeptides with a polynucleotide encoding an antibody. Upon this substitution, the polynucleotide of App’416 would not encode these polypeptides, meeting the instant claim limitations.
This is a provisional nonstatutory double patenting rejection.
Application 17/279,501
Claims 1-3, 5-6, 19, 23, 41, 43, 47, and 53-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 36, 39, 69, 72, and 80-83 of copending Application No. 17/279,501 in view of Hollevoet, K. and P.J. Declerck (2017) State of play and clinical prospects of antibody gene transfer J Transl Med 15(131); 1-19, US 2016/0153000 A1 (Glorioso, J.C.) 2 June 2016, and US 7,078,029 B2 (DeLuca, N.A.) 18 Jul 2006.
App’501 claims a pharmaceutical composition comprising a herpes simplex virus comprising a recombinant herpes simplex virus genome wherein the genome comprises one or more polynucleotides encoding a human filaggrin polypeptide and a pharmaceutically acceptable excipient (claims 1 and 69). App’501 further claims that the virus is replication defective (claim 4) and that the composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, sublingual, buccal, rectal, vaginal, inhaled, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, local, or epicutaneous administration (claims 36 and 39). App’501 further claims a method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of a skin disease in a subject comprising administering the composition (claims 72 and 80-83).
The claims of App’501 differ from the instantly claimed invention in that the instantly claimed invention is drawn to polynucleotides encoding antibodies and use of the compositions in the treatment of one or more signs or symptoms of disease. Additionally, App’501 does not claim that the herpes virus is non-oncolytic and has an inactivating mutation in one or both copies of ICP4 and ICP22.
The teachings of Hollevoet, US’000, and US’029, and are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’501 to use the claimed compositions and methods for the delivery of antibodies as disclosed by Hollevoet by substituting the filaggrin encoding polynucleotides of App’501 with a polynucleotide that encodes an antibody. It would have further been obvious to include inactivating mutations such as those described by US’000 and US’029, to render the HSV both replication-defective and non-oncolytic, including an inactivating mutation in one or both copies of ICP4 and ICP22.
It would have been obvious to substitute the filaggrin encoding polynucleotides of App’501 with a polynucleotide that encodes an antibody as Hollevoet demonstrates that antibody expression in vivo by viral gene transfer had been studied and demonstrated in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as App’501 is teaching compositions and methods that express proteins and antibodies are proteins. Additionally, Hollevoet demonstrates the effective use of viral gene transfer for antibodies. It would have further been obvious to use the methods disclosed by US’000 and US’029 to make the virus non-oncolytic and non-replicating by using ICP4 and ICP20 inactivating mutations. An ordinarily skilled artisan would have been motivated to make these modifications in order to express the antibody in vitro or in vivo without harming the cells or tissues as disclosed by US’000. An ordinarily skilled artisan would have had a reasonable expectation of success as both App’501 and US’000 teach HSV as a means of expressing a protein encoding transgene and US’029 teaches mutations in ICP4 and ICP22.
With regards to the instant claim limitations that the recombinant herpes virus genome does not comprise a polynucleotide encoding a collagen polypeptide, a fibronectin polypeptide, an elastin polypeptide, a lumican polypeptide, a vitronectin polypeptide, a vitronectin receptor polypeptide, a laminin polypeptide, a neuromodulator polypeptide, and a fibrillin polypeptide, and that the recombinant herpes virus genome does not comprise a polynucleotide encoding a transglutamine polypeptide, the nonstatutory double patenting rejection relies on modification of the claims of App’501 to substitute the polynucleotides encoding the claimed polypeptides with a polynucleotide encoding an antibody. Upon this substitution, the polynucleotide of App’501 would not encode these polypeptides, meeting the instant claim limitations.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments in the response filed 01/23/2026 concerning the nonstatutory double patenting rejections have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections over US’438, US’090, and US’660, applicant argues that, as remarked above, the combination of cited references does not teach or suggest the pending claims and one of ordinary skill in the art wouldn’t have had motivation to modify the cited references to arrive at the pending claims with a reasonable expectation of success.
Applicant’s arguments regarding the rejections under 35 USC 103 were not persuasive for the reasons discussed in detail above. The arguments concerning the same references used in the nonstatutory double patenting rejections are also not persuasive for the reasons discussed above regarding the 35 USC 103 rejections.
With regards to the provisional nonstatutory double patenting rejections over 17/127,416 and 17/279,501, applicant states that response is withheld until reconsideration of the claims in view of the amendments and remarks submitted. Applicant further submits that if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having an earlier patent term filing date, the examiner should withdraw the rejection citing MPEP 804.
As the nonstatutory double patenting rejections are not the only rejections remaining, the rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693