DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 7-20-26.
Claims 1-13, 16 and 17 are pending in the instant application.
Election/Restrictions
Claims 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) and have been canceled, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7-20-26.
Applicant’s election without traverse of Group I, SEQ ID Nos. 001 and 011, claims 1-13, 16 and 17, in the reply filed on 7-20-26, is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2-5, 8, 10, 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the vague phrase “the sialidase is derived from the influenza virus” in line 4. It is unclear what “derived from” represents. The metes and bounds of this genus of sialidases cannot be determined.
Claims 2-5, 8, 10, 12 recite the term “particularly” or “more particularly”. The metes and bounds of these terms are unclear. Appropriate clarification is required.
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 1-13, 16 and 17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the treatment of cancer comprising the administration of an AAV vector comprising SEQ ID No. 1, and in combination with an antagonist of PD-1, does not reasonably enable methods for treating cancer using the multitude of sialidases listed in claim 2, and encompassed within claim 1.
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/or use the invention commensurate in scope with these claims.
The following factors have been considered in determining that the specification does not enable the skilled artisan to make and/or use the invention over the broad scope claimed.
The breadth of the claims:
The claims are drawn to methods of treating cancer or of inhibiting recurrence of cancer in a patient comprising administering an adeno-associated virus comprising a transgene encoding any sialidase (AAV-Sia) derived from the influenza virus, which sialidase is optionally a neuraminidase selected from an influenza virus Type A-derived neuraminidase optionally comprising an N1, N2,N3, N4, N5, N6, N7, N8, N9, N10, or N11 neuraminidase, an influenza Type B Victoria, or a Yamagata lineage-derived neuraminidase, or which optionally comprises an N! neuraminidase having an identity of >85%-95% with SEQ ID NO 001 or SEQ ID No. 010, which adeno-associated virus is a replication deficient recombinant adeno-associated virus, which patient is optionally scheduled to receive, is currently receiving, or has recently been administered a checkpoint inhibitor agent optionally comprising an antibody with specificity for PD-1.
Teachings in the art
The following references address the varying cleavage specificities of sialidases (a.k.a. neuraminidases):
Baum et al (Virology, Vol. 180, pages 10-15 (1991)) discuss a survey performed of 10 human influenza A viruses of the N2 serotype and isolated between 1957 and 1987 that showed a drift in neuraminidase linkage specificity from the cleavage of NeuAcα2,3Gal to NeuAcα2,6Gal (see the Abstract and Introduction on page 10). Baum also teaches that an examination of over 60 influenza virus strains from 1947 to 1987 (H1N1, H2N2 and H3N2 strains) illustrates a shift in specificity to hydrolysis of both NeuAcα2,3Gal to NeuAcα2,6Gal, providing a selective advantage to the virus by its ability to destroy cell surface receptors on the infected cell, allowing release of newly formed virus particles (first full para on page 11).
Onsirisakul et al (World J. Virol. Vol. 3, No. 4, pages 30-36 (2014)) characterized neuraminidase substrate specificity of avian influenza H5N1 strains from humans and birds, and compared them to seasonal influenza virus, H3N2. H5N1 neuraminidase showed greater activity on α2,3-linked sialic acid than on α2,6-linked sialic acid. Neuraminidase activity of H5N1 had higher activity against α2,3-linkage than that of the H3N2 virus, and the activities on the α2,6-linkage were comparable (Abstract and Results on page 30).
Onsirisakul also teaches that avian and early human isolated N2 showed higher activity on α 2, 3-linked sialic acid than on α2,6-linked sialic acid. Late human N2 isolation had increased substrate specificity for α 2,6-linked SA and maintained α 2,3-linked activity. Similar to N2 activity, N1 isolated from avians showed higher activity on α 2,3-lnked SA than on α 2,6-linked SA. N1 isolated from humans reduced activity to α 2,3-linked SA and had increased activity to α 2,6-linked SA (Introduction on page 31).
Munkley et al (Medicines, Vol. 6, pages 1-10 (2019)) teach that key changes in cancer glycosylation include upregulation in the levels of sialylation and the expression of cancer associated sialoglycans. Munkley teaches that the upregulation of cancer associated sialylated glycans occurs in tumor growth. Abnormal sialyation is integral to tumor growth, metastasis and immune evasion (Abstract). Munkley teaches that cell surfaces of cancer cells are covered with dense layers of sialoglycans, including the Sialyl Lewis antigens (SLeA and SLeX), the truncated O-glycan, sialyl-Tn (Stn), and the sialylated ganglioside, GM2 (Introduction on page 1, Section 4 on page 3).
Alkhateeb et al (WO 2020/142727) describes various sialidases in para 0055-0063. The human neuraminidases include Neu1, a lysosomal neuraminidase enzyme, Neu2, a cytosolic sialidase enzyme, Neu3, a plasma membrane sialidase, and Neu4 with two isoforms, comprising a peripheral membrane protein and a second isoform that localizes to the lysosome lumen (para 0056-0060). Alkhateeb also teaches other eukaryotic neuraminidases, as well as prokaryotic neuraminidases (para 0061-0064).
Teachings in the specification:
The specification teaches the following:
Example 1: Methods Viral construct
A neuraminidase 1 polypeptide derived from influenza was inserted into a AAV serotype 2 (AAV2) virus, comprising both a capsid and an ITR from AAV2 as shown in Fig. 1… In short, HEK293 cells were co-transfected with AAV plasmid bearing a Gene-of-Interest (GOI), together with replication helper-plasmid DNA comprising AAV2 capsid and replication genes. The GOI chosen was Neuraminidase 1 (Influenza A virus H1N1-derived N1, SEQ ID NO 011, RefSeq#NC_026434.1) under control of the CMV (promoter SEQ ID NO 21) (Fig. 1). In the AAV plasmid, the REP and CAP genes of wild type AAV were deleted, leaving 2 copies of ITRs (~145 bp/each). AAV2-null empty control vectors were prepared in tandem… 2 days after transfection, HEK293 cell pellets were harvested, and viruses released through 3 freeze/thaw cycles. Viruses were purified by CsCl-gradient ultra-centrifugation, followed by desalting. Viral titre (GC/ml - genome copies/ml) was determined through real-time PCR.
Cell culture Tumour cell lines were cultured in DMEM …at 37 °C and 5% CO2. B16D5, EMT6, MC38 and Hela cells lines were seeded at 10⁴ cells/ well in a 6 well plate (n-1). The AAV-Sia was added at different concentration /cell (multiplicity of Males C57BI/6 mice, 8-10 weeks old were used to perform in vivo experiments. MC38 or B16D5 cells suspension (5x10⁵) in 200 µl of PBS were injected subcutaneously into the flanks of mice. Tumour growth and general health was monitored 3 times per week until tumours reached a maximum size of ~1500 mm³ (late tumour stage). AAV2-Sia treatment started when tumours reached ~ 50 mm³, four doses (10⁹ GC) were administered each 3-4 days. Empty vector was used as a control (AAV2-null). All the viruses were injected intratumourally (i.t.), diluted in 50 µl of PBS. In indicated experiments, an anti-PD1 antibody, clone RMP1-14…, was also used as a combination treatment in four doses (10 mg/kg, i.p.). The a-PD1 treatment started with the second dose of the AAV, also every 3-4 days.
Primary tumour cells Primary samples were obtained from the Division of thoracic surgery of the University hospital authorized be the local ethical committee (EKNZ 2018-01990). For the preparation of single cell suspensions, tumors were collected, surgical specimens were mechanically dissociated and subsequently digested using accutase …, collagenase IV…, hyaluronidase…, and DNase type IV (for 1 h at 37°C under constant agitation The digested primary tumours were cultured in 24-well plates overnight at 5x10⁴ cells per well, at the same day samples were transduced with AAV-Sia over 5 days with 2 different concentrations (10⁴ or 10⁵ Virus /cell). Both adherent and non-adherent cells were harvested on day 5, and stained with biotinylated PNA for flow cytometry analysis....
Example 2: Design of an AAV2-NA An adeno-associated virus (AAV2-Sia) was engineered such that upon transduction of mammalian cells it may produce a sialidase. The influenza neuraminidase N1 gene (SEQ ID NO 011, encoding SEQ ID NO 001) was amplified/synthesized and inserted by ligation into a commercial replication-deficient AAV serotype 2 virus in an expression cassette under control of the constitutive CMV promotor (Fig. 1). A vector lacking the N1 gene insert was used as a control (AAV2-null).
Example 3: AAV2-NA removes SA in vitro. In vitro analyses of tumour cell infection were performed. To determine whether the AAV-Sia induced functional expression of a sialidase in transduced cells, the level of desialylation was analysed by flow cytometry and direct PNA staining, to test the enzymatic activity, i.e. desialylation of in vitro transduced tumour cells. This demonstrated AAV2-Sia induced desialysation of tumour cells upon increasing exposure to AAV2-Sla, as shown by increased binding of the lectin PNA (peanut agglutinin) binding to desialylated glycan residues (Figure 2). The sialylation was also accessed using the lectins MAA II (Maackia amurensis) and SNA (Sambucus Nigra) that directly binding to sialic acid residues, transduced cells consistently decreased the binding (Fig. 2).
Example 4: AAV2-Sia inhibits tumour growth in preclinical mouse models
The efficacy of these AAV2-Sia viruses was tested by administering the virus intratumourally into subcutaneous transplanted BI6D5 melanoma and MC38 colon cancer-derived tumours. The AAV2-Sia virus was applied in a syngeneic tumour model of subcutaneously implanted tumour cells in C57BI6 mice, where an anti-tumour effect was observed compared the AAV2- Sia and AAV2-null treatment (Figure 3).
Example 5: AAV2-Sia has an additive benefit to checkpoint inhibitor treatment. Combination therapy of AAV2-sia and a-PD1 antibody was tested by co-administration of a- PD1 antibody after the second dose of the AAV2-Sia, in both the MC38 and B15D5 models. The combination showed additive benefit in the responsive MC38 tumour model, where a reduced rate of tumour growth and increased survival were observed comparing AAV2-Sia versus AAV2-Sia +aPD1, compared to control AAV2-null and AAV2-null + a-PD1 groups (Figure 3). At day 35, AAV-Sia treated animal showed a distinct 50% survival advantage compared to anti-PD-1 treatment alone. An unexpected synergistic survival advantage was conferred by combined treatment with both an AAV-Sia according to the invention, and non- agonist anti-PD-1 antibody. After day 40 approximately 80% of animals receiving systemic injections of anti-PD1 antibody combined with local AAV-Sia administration were alive, while no animals in groups receiving either treatment alone survived. Melanoma B16 tumours, a cancer model more resistant to immunotherapy, showed no significant decrease in tumour burden upon immune checkpoint blockade when paired with AAV2-null. However, AAV2-Sia drove a small but significant decrease in the rate of tumour growth, which was enhanced with the addition of anti PD-1 treatment, suggesting AAV2-Sia induced susceptibility of an immunotherapy-resistant cancer. Combination treatment also conferred a synergistic survival advantage at day 34 following implant of this treatment resistant tumour, with 50% of animals surviving to this timepoint, compared to just 20% in the control group, and none in the anti- PD1 treated group.
Example 6: AAV2-Sia limits abscopal tumour growth Intratumoural administration of AAV-Sia is demonstrated above to deliver local effects at the tumour where the injection is received. The inventors then asked if the AAV-Sia activates systemic adaptive immunity, with the potential to abrogate growth of secondary, metastatic tumours at distant sites within the host. The efficacy AAV2-Sia viruses in non-treated distant tumours was tested by administering the virus intratumourally into subcutaneous transplanted MC38 tumours (treated) while the contralateral tumours (distant) were left untreated. AAV2- Sia injection directly into a tumour was confirmed to have the expected anti-tumour effect compared to AAV2-null (vehicle) control animals (Fig. 4 A). Importantly, growth of the contralateral tumour that was had not directly received the virus was also inhibited, showing a systemic anti-tumour immune response generated by local AAV-Sia application can counter tumour growth throughout the host to control metastatic cancer (Fig. 4 B).
Example 7: AAV-Sia safety profile Having demonstrated that immune cells were mediating local and systemic protection against tumours in AAV-Sia treated animals, the investigators considered what effect sialidase expression by virus-infected cells might have on immune cells. T cells are a vital component of anti-tumour immune responses, particularly in patients receiving checkpoint inhibition. Like tumour cells, the membrane lipids of T cell are decorated with glycans comprising terminal sialic acid residues, and such residues are involved in almost every aspect of T cell fate and function, from cell maturation, differentiation, and migration to cell survival and cell death. Ideally, an AAV-Sia composition for use in treating cancer, will induce specific desialylation of cancer cells upon AAV-Sia of primary tumours, with limited enzymatic effect on bystander cells, such as infiltrating immune cells, in order not to perturb protective immune cell migration and acquisition of effector functions. To assess any bystander effects of sialidase expressed within tumours, AAV-Sia was used to infect a mixed cell culture of CD45+ immune cells and CD45- cancer cells obtained from tissue samples derived from digested tumours samples from 3 different patients with lung cancer in vitro using the lectin PNA. The primary tumour cells were transduced over 5 days with 2 different concentrations of the AAV2-Sia virus (10⁴ or 10⁵ Virus /cell). Flow cytometry analysis of PNA levels following viral transduction demonstrated cancer cells, within the CD45 negative compartment (Fig. 5 A) were effectively desialylated upon treatment, while CD45+ cells (immune cells) were not affected (Fig. 5 B). AAV-Sia thus exhibits a high level of specificity of sialidase action for tumour cells, and has less effect of immune cells within a mixed primary cell population obtained from patient
samples. This specific action makes AAV-Sia a desirable alternative to other forms of sialidase administration in the context of cancer, due to a lack of bystander effects on the recruitment and effector functions of local protective immune cell responses. infection, MOI), and detached after 72 hours the cells with trypsin and stained with PNA (Peanut Agglutinin…).
[Emphases added][Citations omitted]
The examples provided in the instant specification, of the treatment of cancer comprising the administration of an AAV vector comprising SEQ ID No. 1, and in combination with an antagonist of PD-1 are not representative or correlative of the ability to treat cancer using the multitude of sialidases listed in claim 2, or any sialidases derived from the influenza virus.
In light of the teachings in the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure as being correlative or representative of the ability to provide treatment effects using the multitude of sialidases encompassed by the claims. Since the specification fails to provide the requisite guidance for the adequate delivery and expression of the multitude of species of sialidases claimed in any subject, and further whereby any cancer is treated, and since determination of the factors required for accomplishing this in any subject is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For these reasons, the instant rejection for lacking enablement over the full scope claimed is proper.
Claims 1-13, 16 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are drawn to methods of treating cancer or of inhibiting recurrence of cancer in a patient comprising administering an adeno-associated virus comprising a transgene encoding any sialidase (AAV-Sia) derived from the influenza virus, which sialidase is optionally a neuraminidase selected from an influenza virus Type A-derived neuraminidase optionally comprising an N1, N2,N3, N4, N5, N6, N7, N8, N9, N10, or N11 neuraminidase, an influenza Type B Victoria, or a Yamagata lineage-derived neuraminidase, or which optionally comprises an N! neuraminidase having an identity of >85%-95% with SEQ ID NO 001 or SEQ ID No. 010, which adeno-associated virus is a replication deficient recombinant adeno-associated virus, which patient is optionally scheduled to receive, is currently receiving, or has recently been administered a checkpoint inhibitor agent optionally comprising an antibody with specificity for PD.
Teachings in the specification:
The teachings in the specification are described above in the scope of enablement rejection.
The specification fails to provide the requisite guidance for using the genus of sialidases instantly claimed, and further whereby treatment is provided in any subject. The specification describes the treatment of cancer comprising the administration of an AAV vector comprising SEQ ID No. 1, and in combination with an antagonist of PD-1.
The specification fails to provide evidence of any treatment effects using the large genus of sialidases claimed. The specification fails to provide a representative number of species describing an N! neuraminidase having an identity of >85%-95% with SEQ ID NO 001 or SEQ ID No. 010. The specification also fails to describe the cleavage specificities of teach member of the large genus of sialidases claimed, and the correlation between the sialidase targets and cancer. It is also unclear what is encompassed by the genus comprising any sialidases derived from the influenza virus.
Since the disclosure fails to describe the characteristics concisely identifying members of the proposed genus of therapeutic agents, and because the claimed genus is highly variant, the description provided is insufficient. One of skill in the art would reasonably conclude that the disclosure fails to provide a concise description of the broad genus of sialidases as therapeutic agents as instantly claimed.
Thus, Applicant was not in possession of the broadly claimed genus.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 7-13, 16 and 17 are is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Alkhateeb et al (WO 2020/142727).
Alkhateeb et al (WO 2020/142727) (See IDS filed 8-1723 teach the treatment of numerous cancers in a patient comprising the administration of compositions comprising an immune cell with increased sialidase activity, an engineered T-cell in combination with a sialidase, and engineered T cells pretreated with a sialidase (Abstract, para 0007, 00222-00225). The sialidases or neuraminidases optionally cleave α 2-3, α 2,6- and/or α 2,8- linkages. (para 0011). The human sialidases include Neu1, Neu2, Neu3 and Neu4 (para 0017).
Alkhateeb teach the method of cancer treatment to include combination therapy in administering an immune checkpoint antagonist optionally comprising a PD-1 and/or PD-L1 antagonist optionally comprising an antibody (para 0033, 0099, Table 1 on pages 31-32, para 00140, 00226-00229). Sialidases are described in para 0055-0063. The human neuraminidases include Neu1, a lysosomal neuraminidase enzyme, Neu2, a cytosolic sialidase enzyme, Neu3, a plasma membrane sialidase, and Neu4 with two isoforms, comprising a peripheral membrane protein and a second isoform that localizes to the lysosome lumen (para 0056-0060). Alkhateeb also teaches other eukaryotic neuraminidases, as well as prokaryotic neuraminidases (para 0061-0064).
Alkhateeb teaches adeno associated virus (AAV) vectors and replication deficient viral vectors (para 00185-00192, 00198), which AAV vectors comprise a CMV promoter (para 00164, 00166, 0195-0199).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1-13, 16 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Alkhateeb et al (WO 2020/142727), Munkley et al (Medicines, Vol. 6, pages 1-10 (2019)), Dobie et al (British J. Cancer, Vol. Vol. 124, pages 76-90 (2020)), the combination in view of Bennett et al (US 2020/0261600).
The claims are drawn to methods of treating cancer or of inhibiting recurrence of cancer in a patient comprising administering an adeno-associated virus comprising a transgene encoding a sialidase (AAV-Sia), which sialidase is a neuraminidase selected from an influenza virus Type A-derived neuraminidase optionally comprising an N1 neuraminidase which optionally comprises an N! neuraminidase having an identity of >85%-95% with SEQ ID NO 001 or SEQ ID No. 010, which adeno-associated virus is a replication deficient recombinant adeno-associated virus, which patient is optionally scheduled to receive, is currently receiving, or has recently been administered a checkpoint inhibitor agent optionally comprising an antibody with specificity for PD-1.
Alkhateeb et al (WO 2020/142727) is relied upon as set forth in the 102 rejection above.
Munkley et al (Medicines, Vol. 6, pages 1-10 (2019)) teach that key changes in cancer glycosylation include upregulation in the levels of sialylation and the expression of cancer associated sialoglycans. Munkley teaches that the upregulation of cancer associated sialylated glycans occurs in tumor growth. Abnormal sialyation is integral to tumor growth, metastasis and immune evasion (Abstract). Munkley teaches that cell surfaces of cancer cells are covered with dense layers of sialoglycans, including the Sialyl Lewis antigens (SLeA and SLeX), the truncated O-glycan, sialyl-Tn (Stn), and the sialylated ganglioside, GM2 (Introduction on page 1, Section 4 on page 3).
Dobie et al (British J. Cancer, Vol. Vol. 124, pages 76-90 (2020) teach that the main cause of death in cancer patients is metastasis. Sialic acids at the terminal end of glycans are of critical importance. The most common sialic acid in humans is N-acetylneuraminic acid (Neu5Ac), and plays an essential role in cellular interactions. There are four human neuraminidase enzymes (NEU1-4) that cleave sialic acid from glycan chains, also regulating cell surface sialylation. Sialic acid presents as tumor hypersialylation with up to 40-60% increased sialic acid residues on the surface of cancer cells. This hypersialylation occurs via the upregulation of sialyltransferases and the downregulation of neuraminidases (Background on page 76). Neuraminidase 1 (NEU1) overexpression was found to result in significant reduction in liver metastasis (second full paragraph on page 82).
The primary references do not teach replication deficient AAV vectors for sialidase expression.
Bennett et al (US 2020/0261600) teach replication deficient AAV vectors (para 0075).
It would have been obvious to design and utilize the AAV vector instantly claimed for the expression of the well known neuraminidase, N1, for treating cancer in a patient because the role of sialic acids in cancer has been reported in the prior art as taught by Alkhateeb, Munkley and Dobie. The prior art also clearly taught the administration of sialidases for treating various forms of cancer. One of ordinary skill would have been motivated to utilize a CMV vector for expressing the N1 sialidase because the CMV promoter was well known and routinely used in the prior art for expressing recombinant enzymes and other therapeutic molecules, as taught by Bennett.
One of ordinary skill would have reasonably expected that the administration of expression vectors including AAV for the expression of recombinant N1 sialidase, and in combination with an antagonist of PD-1, would provide treatment effects for reducing tumor load and metastases in a subject.
For these and the aforementioned reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
9-11-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
Prosecution Insights