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 .
Claim status
The preliminary amendments filed on November 7, 2023 amended claims 4, 7, 9, 11, 12, 19, 22, 27, 28, 30-32, 51, 55, 56, 58, 60, 63, and 66; canceled claims 1, 3, 5, 6, 8, 10, 13-18, 20, 21, 23-26, 29, 33-50, 52-54, 57, 59, 61, 62, 64, 65, 67, and 68 . Consequently claims 2, 4, 7, 9, 11, 12, 19, 22, 27, 28, 30-32, 51, 55, 56, 58, 60, 63, and 66 are pending and will be examined on the merits.
Priority
The instant application claims benefit of provisional applications, Application No. 63332386 (filed 19 April, 2022), Application No. 63347120 (filed 31 May, 2022), Application No. 63357953 (filed 1 July, 2022). The effective filing date of instant claims 2, 4, 7, 9, 11, 12, 19, 22, 27, 28, 30-32, 51, 55, 56, 58, 60, 63, and 66 is 19 April, 2022.
Information Disclosure Statement
The information disclosure statement filed on November 7, 2023 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, each information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 88, paragraph [0242], of the specification recites the following hyperlink which comprises the following browser-executable codes:
https://doi.org/10.1097/00029330-200703020-00012
https://doi.org/10.1038/sj.gt.3301419
https://doi.org/10.1016/S0006-291X(02)02486-5
Appropriate correction to remove the non-top level domain portion of the hyperlink is required.
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.
Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for incorporating a reference to Table 3. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parteFressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). See MPEP 2173.05(s). In the instant case, there is a practical way to define the claim limitation by referencing to the Sequence Identifiers presented in Table 3.
Claim 51 is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 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 51 is indefinite since it recites the system of a “claim 1”, which has been canceled.
Based on the examiner’s interpretation of the claims and the specifications of the application, claim 51 should read: “A method of inducing antibody production in the subject, comprising administering to the subject the system of Claim 2”. Therefore, claim 51 is examined accordingly.
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 32 and claim 2 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al 1997, see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding.
Claim 32 is drawn to “the antibody or antigen binding fragment thereof comprising at least 80%, at least 90%, at least 95%, or at least 98% sequence identity to an antibody set forth in Table 3”, which lists the heavy chain variable region (HCVR) and light chain variable region (LCVR) and the CDRs in these regions of 15 antibodies, without specifying the location of possible sequence variations. The location of sequence variations is not described in the specification of the instance case. Therefore, the claimed antibody or antigen binding fragment include those with variations in the CDR region, which would not preserve antigen-binding function based on the art at the time of filing. Therefore, a person with ordinary skill of the art would not reasonably expect all antibodies with at least 80% of sequence identity to the listed HCVR and LCVR to maintain the antigen binding function. Thus, the inventors have not shown possession of the full scope of the claim.
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.
Claims 2, 7, 22, 27, 28, 51 and 55 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Mucker et al. "Lipid nanoparticle formulation increases efficiency of DNA-vectored vaccines/immunoprophylaxis in animals including transchromosomic bovines." Scientific reports 10.1 (2020): 8764, as evidenced by Mucker et al. "Intranasal monkeypox marmoset model: Prophylactic antibody treatment provides benefit against severe monkeypox virus disease." PLoS Neglected Tropical Diseases 12.6 (2018): e0006581.
Regarding claim 2, Mucker teaches the use of lipid nanoparticle technology originally developed for mRNA in vivo delivery to deliver antibody encoding DNA constructs in a subject (rabbit) and induced antibody production in vivo. As described in the specification of the instant application, paragraph [0150], lipid nanoparticle (LNP) compositions and compositions wherein an LNP encapsulates a polynucleotide constructs) are included in the lipid vesicles described in claim 2. Mucker et al recites on page 5 and in Figure 5, “rabbits were injected with 1mg of LNP-formulated Mab-encoding DNA… The rabbit receiving LNP-formulated Mab-encoding DNA had detectable levels of antibody approximately one day after injection and peaked on Day 4.” As shown in Figure 5, the rabbit injected with LNP-formulated monoclonal antibody (MAb) encoding DNA produced the DNA encoded antibody.
Regarding claim 7, Mucker further teaches that the plasmid encoding the c7D11 antibody, pWRG/c7D11(H+L), contains polynucleotide sequences encoding both heavy and light chain which include variable domains of the antibody. As stated by Mucker et. al (2020), page 10, paragraph 6 under “DNA plasmids”, “The heavy chain and light chain sequence (including the signal sequence) were cloned into a unique NotI and BglII site of separate plasmids. The plasmid containing the light chain was then PCR amplified with forward primer GCA GGT TCT AGA CGA CAA TAT TGG CTA TT and reverse primer AAG CAA TAC ATG TGT CGA GCT GT so as to introduce XbaI and PciI restriction sites and amplify the CMV promotor, light chain and through the Xba1 restriction site present on the plasmid. The fragment was electrophoresed, band excised and digested with PciI and XbaI. The plasmid containing the heavy chain insert was digested with Xba1 and PciI, gel purified, dephosphorylated, and ligated with the PCR fragment using common techniques.”
Regarding claims 22, 27 and 28, Mucker et al further teaches that the antibody produced in Figure 5 is c7D11, a poxvirus specific antibody, that contains a human IgG1 heavy chain, as evidenced by Mucker et al. (2018). “a model for the study of human monkeypox (and smallpox) and present the first application of any marmoset (Callithrix jacchus) model for the treatment of poxvirus disease. More specifically, we used a cocktail of two human-chimeric monoclonal antibodies, c7D11 and c8A and evaluated the ability of the antibodies to prophylactically protect against a lethal dose of monkeypox virus. The antibodies, (c)7D11 and c8A, target two morphologically distinct forms of the virus known as the mature virion (MV) and the extracellular virion (EV), respectfully.” (page 3, paragraph 2) Mucker et al (2018) teaches that c7D11 antibody contains human IgG1 heavy constant sequences (page 3, paragraph 4).
Regarding claims 51 and 55, Mucker et al teaches the method of inducing expression of an antibody in a rabbit (see Page 5 and Figure 5, as described above) , comprising administering to the rabbit the LNP formulated antibody encoding DNA plasmid by intramuscular injection, Mucker et al recites that “intramuscular injection(s) (IM) were performed utilizing a PharmaJet Stratis® device in a volume of 0.5 mL. NHPs and rabbits were anesthetized before the tricep or lateral thigh, respectively, were clipped and subsequently injected (IM) with the test material.” (Page 12, Paragraph 3, “ DNA administration).
Pharmajet Stratis is a Needle-free Injection System commercialized and evaluated by Pharmajet (https://pharmajet.com/) that “deliver a spring-powered injection in 1/10 of a second by means of a narrow stream of fluid that penetrates the skin with a precise dose and depth. There is no need for an external power source and there is no needle.” Pharmajet Stratis is used for intramuscular or subcutaneous injection that delivers a fixed dose of 0.5 ml.
Pharmajet delivery of DNA utilized by Mucker et al is distinct from either electroporation or hydroporation which use electric field or a highly pressured solution injected into a subject to generate membrane pores, respectively. Electroporation utilizes ion movement in an electric field to generate membrane pores. As evidenced by Zhang et al. "Hydroporation as the mechanism of hydrodynamic delivery." Gene therapy 11.8 (2004): 675-682., hydroporation is achieved by “a rapid tail vein injection of a large volume of DNA solution. This method, called the hydrodynamics based procedure, has been widely utilized by the gene therapy community for evaluating therapeutic activities of various genes” (page 1, column 1, paragraph 3). “Similar to the mechanism of electroporation where membrane pores are generated by ion movement in an electric field, the hydrodynamics-based procedure generates membrane pores by a highly pressured solution in the liver. Thus, we propose the term ‘hydroporation’ (pores generated by aqueous solution) to describe this process as an analogous term to the technique of electroporation.” (page 6, column 2, paragraph 2).
Therefore, the method utilized by Mucker et al is performed without electroporation or hydroporation.
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 non-obviousness.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al (Scientific reports 10.1 (2020): 8764) as applied to claim 2, in view of Vermeire et al. "DNA-based delivery of anti-DR5 nanobodies improves exposure and anti-tumor efficacy over protein-based administration." Cancer Gene Therapy 28.7 (2021): 828-838 (published 30 July 2020).
Claim 2 and the teaching of Mucker regarding claim 2, are discussed above.
Claim 4 limits the antibody described in claim 2 to a VHH antibody.
Mucker does not teach a VHH antibody.
However, Vermeire et al (2020) teaches a DNA based in vivo delivery of anti-DR5 VHH antibody into mice. Vermeire et al demonstrated that intramuscular transfer of a tetravalent (Nanobody) NbDR5-encoding plasmid (pNbDR54) provided functional DR5 antibody with antitumor activity in mice (Fig. 3).
As evidenced by Vincke et al, "Introduction to heavy chain antibodies and derived Nanobodies." Single domain antibodies: methods and protocols (2012): 15-26, Chapter 2, first paragraph, VHH antibody (variable heavy chain domain of a heavy chain antibody) or nanobody is devoid of a light chain and associates with its cognate antigen via a single domain. Vermeire et al (2020) teaches that “Due to their small size they have improved tissue penetration properties and can easily be engineered into multivalent formats capable of binding multiple targets. These features make them excellent drug candidates in oncology space”. However, “their reduced dimension and lack of an Fc region results in faster clearance from circulation due to renal excretion”, therefore, “Combining Nanobodies with DNA-based gene transfer could be a good strategy to address the inherent limitations of Nanobodies for therapeutic use.” (page 828, column 2, paragraph 1). Vermeire provides “pre-clinical proof of concept for DNA-based Nanobody gene transfer. Intramuscular delivery of DNA-based half-life engineered Nanobodies led to prolonged and substantially higher Nanobody plasma exposure. Furthermore, Nanobody gene transfer showed improved therapeutic efficacy over conventional protein delivery. Overall, the reported data highlight the potential of DNA-based Nanobodies in oncology and broaden the application range of DNA-based therapeutics”. (page 837, column 1, paragraph 3)
Therefore, it would have been obvious for a person with ordinary skills in the art at the time of invention to use the LNP formulated protein encoding DNA plasmid system to induce VHH antibody production in a subject to combine the advantage of VHH antibody and the LNP formulated DNA antibody therapy system taught by Mucker.
Claims 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al (Scientific reports 10.1 (2020): 8764) as applied to claim 2 and 7, in view of Esquivel et al. "In vivo delivery of a DNA-encoded monoclonal antibody protects non-human primates against Zika virus." Molecular Therapy 27.5 (2019): 974-985, as evidenced by Flingai et al. "Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy." Scientific reports 5.1 (2015): 12616.
Claim 2 and claim 7 and the teaching of Mucker are discussed above.
Claim 9 is drawn to the polynucleotide sequence in claim 2 and the polynucleotide sequences in claim 7, wherein the polynucleotide sequences encoding the Hc variable domain and the polynuleotide sequence encoding the Lc variable domain are coupled such that the sequences are transcribed as a single transcript.
Claim 11 is drawn to that the system of claim 2 wherein the system further comprises a second plasmid comprising a second polynucleotide sequence encoding a light chain of the antibody.
Mucker teaches that the plasmid encoding the c7D11 antibody, pWRG/c7D11(H+L), contains polynucleotide sequences encoding both heavy and light chain.
Mucker does not teach specifically that the heavy chain and light chain polypeptides are transcribed as a single transcript.
Mucker does not teach a second plasmid comprising polynucleotide sequences encoding a light chain.
However, Esquivel et al (2019) teaches that the monoclonal antibody encoding DNA can be constructed as single or two (dual) plasmids format and produce functional antibodies (Suppl. Figure 1). Esquivel el al recites “DmAb (DNA-encoded monoclonal antibody) constructs encoding fully human IgG1k mAbs were designed and engineered into a modified-pVax1 mammalian expression vector under the control of a cytomegalovirus immediate-early promoter and bovine growth hormone poly(A) signal… In a dual-plasmid system, HCs and LCs were expressed from separate plasmids, resulting in three constructs: DMAb-ZK190-HC, DMAb-ZK190-LC, and DMAb-ZK190-LALAHC. In a single-plasmid system, HCs and LCs are expressed on the same plasmid, resulting in two constructs: DMAb-ZK190 and DMAb-ZK190-LALA.” (Page 981, column 2, paragraph 4). Esquivel et al cited the single plasmid format construct encoding full length IgG including both Hc and Lc described by Flingai et al (2015) on page 2, paragraph 4, and Figure 1a on page 3: “In order to express a full-length antibody from a single open reading frame, the heavy and light chain genes were separated by a furin cleavage site and a P2A self-processing peptide. Each transgene was genetically optimized, synthesized, and subcloned into a modified pVax1 mammalian expression vector (Fig. 1a).” Esquivel et al further “evaluated the expression of both single-plasmid and dual-plasmid constructs in mice, demonstrating protective efficacy even at low doses of the DMAb-ZK190 single-plasmid construct (Figure S7). Importantly, a single construct would be simpler for clinical translation, therefore, we moved the single plasmid into NHP study. It is likely that, similar to mice, higher expression levels would be observed with two-plasmid delivery in NHPs. Further studies investigating plasmid structure among other strategies to further increase expression levels in larger animals are important.” Based on this previous research, an ordinary artisan would be motivated to try both single and dual-plasmid formats to induce in vivo antibody production using the lipid nanoparticle formulated DNA antibody expression system taught by Mucket et al to identify a system that can generate desired results.
Claims 12 is rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al. ( Scientific reports 10.1 (2020): 8764) as applied to claim 2 and 11, in view of Esquivel et al (2019): Molecular Therapy 27.5 ): 974-985 and Heartlein et al. , patent WO 2014/152774 A1 (published 2014).
Claim 2 and 11 and the teachings of Mucker et al regarding claim 2 and Esquivel et al (2019) regarding claim 11, are discussed above.
Claim 12 limits the ratio of the plasmid encoding the Hc variable domain to the plasmid encoding the Lc of the antibody at about 1.7:1 (w/w).
Mucker et al teaches the LNP formulated DmAb system in a subject where Hc and Lc DNA sequences are cloned linearly (1:1) in a plasmid DNA vector (pWRG/c7d11(H+L) (page 10, paragraph 5).
Mucket et al does not teach a dual-plasmid system.
Esquivel et al (2019) teaches a dual-plasmid system without specifying a Hc:Lc ratio of 1.7.
However, Heartlein et al. (2014) teaches that production of fully assembled multi-chain antibodies can be accomplished in vivo by delivering exogenous mRNAs encoding a heavy chain and a light chain of an antibody, when encapsulated in liposome. Claim 4 of this patent is drawn to “the first mRNA encoding the heavy chain and the second mRNA encoding the light chain are present at a ratio ranging between approximately 4:1 to 1:4”. Heartlein et al recites that “it may be advantageous to deliver heavy chain (Hc) and light chain(Lc) encoding mRNA at varying ratios in order to optimize production of fully assembled functional antibodies.” [paragraph 0066]. Heartlein et al tested anti-CCL2 Hc and Lc mRNA (HC-antiCCL2:LC-antiCCL2 mRNA) at ratios of 4:1, 1:1 and 1:4 in vitro by transfecting two cell lines and found all of these conditions successfully induced antibody expression in both cell lines (Figures 1-3, Example 4 paragraphs [0145-0148]). Heartlein et al further demonstrated successful antibody production in mice by intravenous injection of anti-CCL2 Hc and Lc mRNA constructs at a ratio of 1:1 (wt:wt) encapsulated in lipid nanoparticles (Example 5, paragraphs [0149-0154]. In addition, Heartlein et al demonstrated successful antibody production in mice by intravenous injection of Hc and Lc mRNA constructs of another antibody, anti-VEGF, at 1:1 (wt:wt) ratio (Figures 5-7, Example 6, paragraphs [0155-0163]).
In the instant application, since the DNA encoding heavy chain and light chain are constructed using the same vector as shown in Fig. 5B and 5C, they are expected to produce equivalent amount of transcripts. The Hc to Lc ratio of 1.7:1 ratio is within the range of Hc to Lc ratio of 4:1 to 1:4 which successfully gives rise to antibody production, as taught by Heartlein et al. (2014).
Therefore, it would have been obvious to an ordinary artisan to try this ratio using the LNP formulated DmAb system taught by Mucket et al as a step to optimize antibody expression.
Claims 19 is rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al. (Scientific reports 10.1 (2020): 8764) as applied to claim 2, in view of Nguyen et al. "Evaluation of gene promoters for liver expression by hydrodynamic gene transfer." Journal of Surgical Research 148.1 (2008): 60-66, and Vermeire et al. "Improved potency and safety of DNA-encoded antibody therapeutics through plasmid backbone and expression cassette engineering." Human Gene Therapy 32.19-20 (2021): 1200-1209., (published 18 October 2021).
Claim 2 and the teaching of Mucker regarding claim 2, are discussed above.
Claim 19 limits the promoter in the plasmid system of claim 2 to a CAG promoter.
Mucker et al teaches the usage of the CMV promoter in the plasmid vector (pWRG7077) to drive the expression of the antibody Hc and Lc (page 10, paragraph 5).
Mucker et al does not teach a CAG promoter.
However, Nguyen et al (2008) teaches that although “CMV is one of the strongest viral promoters in vitro. Unfortunately, in vivo the CMV promoter has been silenced at the mRNA level within several weeks in multiple organ systems. “ (page 6, paragraph 6). To see if there are other promoters that performs better than CMV promoter, Nguyen compared the activity of the luciferase reporter gene produced by the different promoters (including Human cytomegalovirus (hCMV), chicken beta-actin/CMV enhancer (CAG), elongation factor-1alpha (EF1α), and phosphoglycerokinase (PGK) promoters) with the high expressing CMV promoter by hydrodynamic injection of DNA constructs in to mice and whole animal bioluminescent imaging (page 5, paragraph 4). The results demonstrate that each luciferase plasmid could produce visible amounts of bioluminescence in the liver (figure 3, where CBA (chicken beta-actin/CMV enhancer (CAG), page 1, Abstract) was labeled, which represents CAG promoter). The CAG plasmid produced the highest levels of bioluminescence with 1.7×1010 ± 1.1×1010 photons emitted per second (p/sec) through the region of interest (figure 4). (page 5, paragraph 4). Nguyen further “tested two of these vector plasmids that contain promoters that are not silenced (CAG with the highest expression by reporter gene studies, and EF1α) in a clinical model of a human disease that affects the liver, hemophilia A… The data demonstrate that the CAG promoter produces high levels of reporter gene both in vivo and in vitro.” (page 6, paragraph 6). These data demonstrated the advantage of using CAG promoter over CMV promoter to achieve high level of gene expression in vivo.
Nguyen does not teach utilizing CAG promoter to drive antibody production in vivo.
However, Vermeire et al. (2021) teaches the use of CAG promoter to drive 4D5 antibody (the murine equivalent of trastuzumab (Herceptin), page 1201, column 1, paragraph 3) heavy or light chain expression in mAb-encoding plasmid backbones (Table 1, Figure 1). (page 1203, column 2, paragraph 4). These constructs successfully induced 4D5 production in vitro (Figure 2A, B) and in vivo in mouse serum after intramuscular electroporation of these constructs (Figure 2C, D).
Therefore, it would have been obvious for a person with ordinary skills in the art at the time of the invention to utilize CAG promoter to enhance antibody expression in the LNP formulated DmAb expression system taught by Mucker et al (2020).
Claims 30, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al ( Scientific reports 10.1 (2020): 8764) as applied to claim 2 and 27, in view of Parzych et al "Nucleic acid approaches to antibody-based therapeutics for COVID-19: A perspective." Journal of Allergy and Clinical Immunology 146.3 (2020): 537-540 and US patent 10787501 (2020).
Claim 2 and 27 and the teaching of Mucker et al regarding these claims, are discussed above.
Claim 30 limits the viral protein described in claim 27 to a protein from SARS-CoV-2.
Claim 31 further limits the viral protein from SARS-CoV-2 to the spike protein.
Claim 32 is drawn to an antibody described in claim 2 that shares at least 80% of sequence identity with the antibodies listed in Table 3.
Mucker does not teach expression of an antibody against SARs-Cov2 protein or an antibody listed in Table 3.
However, Parzych et al (2020) teaches the use of in vivo mAb production against SARS-CoV-2 using the DmAb platform. Parzych et al recites “Antibodies directed against the S (spike protein) protein of SARS-CoV-2, a closely related coronavirus that previously caused a deadly outbreak in humans, conferred protection in vivo. One such neutralizing antibody, mAb CR3022, cross-reacts with a unique epitope in the receptor-binding domain of the SARS-CoV-2 S protein. As an exemplative use of this technology against SARS-CoV-2, CR3022 sequences were modified and optimized as previously described to generate a novel DMAb encoding humanCR3022, which was successfully expressed in mice (Fig 2,D).” (page 3, column 1, paragraph 1).
Parzych further recites that “Because of significant advancement over recent years, nucleic acid–based technologies hold increased potential to provide rapid and consistent antibody-mediated protection while avoiding the technical challenges associated with recombinant mAb production… DMAbs exhibit potent and durable expression kinetics, with functionality and in vivo efficacy comparable to those of their recombinant counterparts. Such biologics have been generated against a diverse set of infectious diseases”, and “ The preclinical data from these strategies support their further development as rapid response tools against emerging outbreaks such as COVID-19.”
Therefore, it would have been obvious for an ordinary artisan at the time of invention to utilize a DNA construct encoding an antibody against the spike protein of SARS-CoV-2, such as antibody 1 and 2 (Table 3) taught by US patent 10787501 (Regeneron Pharmaceuticals Inc.), and the LNP formulated DmAb expression system taught by Mucker to induce the expression of these receptor blocking antibodies as an effective therapy against SARS-Cov2 infection.
Claims 56, 58 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al. ( Scientific reports 10.1 (2020): 8764) as applied to claim 2 and 51.
Claim 2 and 51 and the teaching of Mucker, are discussed above.
Claim 56 limits the serum level of antibody production in a subject described in claim 51 to a range of at least 75ng/ml.
Claim 58 limits the method to administering 2 doses of antibody encoding DNA to a subject.
Claim 60 limits the peak serum level of the antibody after the second dose to more than 2-fold higher than the peak serum level achieved after the first dose.
Mucker teaches that administering a single dose of 1mg LNP formulated anti-poxvirus antibody encoding DNA plasmids into a rabbit successfully induced functional anti-poxvirus antibody in the serum, which peaked at 30ng/ml on day 4 after the intramuscular injection.
Although Mucker does not teach a serum antibody of 75ng/ml after the LNP formulated DmAb construct, Mucker depicts the c7D11 antibody expression study as a proof of concept experiment to demonstrate that LNP delivery of DmAb can increase protein production in vivo than naked DmAb (page 5, paragraph 1). Since the main goal of this research by Mucker et al (2020) is to test the feasibility of LNP formulated DNA vaccine, the LNP formulated DmAb system was not optimized such that a higher antibody serum level could be achieved. Mucker teaches that ANDV viral protein expression level (as indicated by higher antibody titre against the ANDV virus induced by the DNA vaccine) can be optimized by a “dose probing study” (page 2, paragraph 4-6, Figure 1A, B, C) and a boost (second dose) of the LNP formulated DNA vaccine (page 2, paragraph 5-6, Figure 1B, C, D). Mucker teaches after the ANDV DNA vaccine was dose optimized and administered the second time to the rabbits at 0.1mg/animal on day 27, the antibody titre against the viral protein GnGc (glycosylated glycoprotein present on the pseudovirions (PsV) increased more than two fold as indicted by the increased OD450 value from ~1 (Day 27) to more than 3 (D34, 41, 51). (Figure D, Page 2, paragraph 6).
Mucker further teaches applying 3 doses of DNA vectored vaccine in Cynomolgus macaques (Figure 3), the ANDV neutralizing antibody titre increased from low 103 on day28 to high 103 or over 104 on day 56 after the second dose, which are greater than 2 fold increase in individual NHPs.
Therefore, it would have been obvious for an ordinary artisan to optimize the dose level of LNP formulated DmAb and apply the 2 dose regimen taught by Mucker to a subject to enhance the antibody production. Based on the positive results taught by Mucker et al, an ordinary artisan would predict that by optimizing the dose of DmAb constructs and administering an additional dose of DmAb into a rabbit, the serum antibody level can increase to the level claimed in claim 56, and that a more than 2 fold increase of serum antibody level can be achieved after the second dose. A prima facie case of obviousness exists.
Claims 63 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Mucker et al (Scientific reports 10.1 (2020): 8764) as applied to claim 2 and 51, in view of Esquivel et al. Molecular Therapy 27.5 (2019): 974-985.
Claim 51 and the teaching of Mucker regarding claim 51, are discussed above.
Claim 63 limits the serum level of antibody described in claim 51 to be sustained at a concentration of at least 50ng/ml for at least 4 weeks
Claim 66 limits the serum level of antibody described in claim 51 to be sustained at a concentration of at least 10% of the peak serum concentration for at least 4 weeks.
Mucker et al teaches in vivo antibody expression induced by LNP formulated DmAb over a period of 7-10 days (Figure 5).
Mucker et al does not teach sustained serum level of an antibody for more than 4 weeks.
However, Esquivel et al teaches in vivo delivery of a DmAb platform (dual-plasmid constructs) encoding a Zika virus neutralizing antibody (mAb-ZK190) using intramuscular injection followed by electroporation. Treated mice achieved average serum ZK190 concentration of 27ug/ml and persisted 10 weeks (page 975, paragraph 4, Figure 1A). The serum antibody level peaked at 30-40ug/ml 2 weeks after intramuscular dosing and sustained up to day 70 at ~10ug/ml (25-30% of the peak level), which exceeds the antibody level and a serum durability claimed in claims 63 and 66, respectively.
Therefore, it would have been obvious for an ordinary artisan to predict that after routine optimization of the LNP formulated DmAb system taught by Mucker et al, serum antibody level of at least 50ng/ml or at least 10% of the peak level can be sustained for at least 4 weeks.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Application 18/838,923
The instant application and the reference application name at least one inventor in common. Claims 2, 11, 12 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 2, 11 and 12 of copending Application No. 18838923 (herein App‘923). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
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.
Claims 4, 7, 9, 19,22, 51 and 56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 6, 9, 18, 20 and 48 of copending App’923. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 4, claim 3 of App’923 claims the antibody or antigen binding fragment described in claim 2 is a single-domain antibody (sdAb) or a VHH antibody. As evidenced by Qin et al. "Single domain antibody application in bacterial infection diagnosis and neutralization." Frontiers in Immunology 13 (2022): 1014377, heavy chain only antibodies ( or HCAbs) bind to antigen through only one variable region, they are referred to as VHH or sdAb or nanobody (page 2, column 1, paragraph 3). Therefore, claim 4 of the instant application is not patentably distinct from claim 3 of App’923.
Regarding claim 7, claim 6 of App’923 claims the plasmid in the identical system encodes a full length heavy chain and/or a full length light chain which includes a plasmid encoding a full length heavy chain and a full length light chain and a plasmid encoding both a heavy chain variable domain and a full length light chain. It would have been obvious to one of ordinary skill in the art to try the plasmid encoding a heavy chain variable domain and a light chain in the antibody system described in claim 2 of App’923 .
Claim 9 of the instant application and claim 9 of App‘923 application is drawn to the identical system of claim 2 wherein the plasmid comprises a polynucleotide sequence encoding a heavy chain variable domain and a polynucleotide sequence encoding a light chain variable domain and wherein these polynucleotide sequences are coupled such that the sequences are transcribed as a single transcript.
Regarding claim 19, claim 18 of App’923 recites the promoter in the plasmid in claim 2 can be elected from CAG, CMV, EF1A, CBh, CBA and SFFV. It would have been obvious for an ordinary artisan to utilize CAG promoter in the plasmid described in claim 2 App’923.
Regarding claim 22, claim 20 of App’923 recites the antibody or antigen binding fragment thereof comprises an IgG1, IgG2a, IgG2b, IgG3, IgG4, IgD, IgM, IgA1, IgA2 and IgE heavy chain. It would have been obvious for an ordinary artisan to try IgG1 heavy chain in the antibody system described in claim 2 App’923.
Claims 51 and 56 recites the method of administering the antibody system in a subject and the administration of the system produces a peak blood plasma level of the antibody or antigen binding fragment thereof of at least 75ng/ml, at least 100 ng/mL, at least 150 ng/mL, at least 200 ng/mL, at least 250 ng/mL, at least 300 ng/mL, at least 400 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 800 ng/mL, at least 900 ng/mL, or at least 1000 ng/mL. Claim 48 of App’923 recites that administering the identical system produces the same blood plasma levels of the antibody or antigen binding fragment. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 27, 28, 30, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending App’923 in view of Mucker et al Scientific reports 10.1 (2020): 8764 and Parzych et al Journal of Allergy and Clinical Immunology 146.3 (2020): 537-540 and US patent 10787501 (2020), as evidenced by Mucker et al. PLoS Neglected Tropical Diseases 12.6 (2018): e0006581.
Regarding claims 27, 28, Mucker et al (2020) teaches the use of lipid nanoparticle technology to deliver antibody encoding DNA constructs in a subject (rabbit) and induced production of a poxvirus specific antibody, c7D11 (Mucker et al. (2018)).
Regarding claims 30, 31 and 32, Parzych et al (2020) teaches the use of in vivo mAb production against SARS-CoV-2 using the DmAb platform. As discussed above, Parzych et al recites “Antibodies directed against the S (spike protein) protein of SARS-CoV-2, a closely related coronavirus that previously caused a deadly outbreak in humans, conferred protection in vivo. Parzych et al further recites that “Because of significant advancement over recent years, nucleic acid–based technologies hold increased potential to provide rapid and consistent antibody-mediated protection while avoiding the technical challenges associated with recombinant mAb production… DMAbs exhibit potent and durable expression kinetics, with functionality and in vivo efficacy comparable to those of their recombinant counterparts.”
Therefore, it would have been obvious for an ordinary artisan at the time of invention to utilize a DNA construct encoding an antibody against the spike protein of SARS-CoV-2, such as antibody 1 and 2 (Table 3) taught by US patent 10787501 (Regeneron Pharmaceuticals Inc.), and the lipid vesicle formulated DNA encoded antibody expression system described in App’923 to induce the expression of these receptor blocking antibodies as an effective therapy against SARS-Cov2 infection.
Claims 55, 58, 60, 63 and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 48 of copending App’923 in view of Mucker et al Scientific reports 10.1 (2020): 8764.
Regarding claim 55, as discussed above, Mucker et al teaches the method of inducing expression of an antibody in NHPs and rabbits with intramuscular injection of the LNP formulated DmAb system with Pharmajet, which is distinct from electroporation and hydroporation. Therefore, it would have been obvious for an ordinary artisan to utilize Mucker’s administration method and the lipid vesicle formulated DNA encoded antibody system described in App’923 to induce antibody production in a subject.
Regarding claims 58, 60, 63 and 66, the teaching of Mucker et al (2020) regarding 2 doses of LNP formulated DNA in a subject, the expected serum levels of DNA encoded antibody, as well as the duration of the serum antibody level, are discussed above.
Therefore, it would have been obvious for an ordinary artisan to utilize the lipid vesicle formulated DNA encoded antibody system described in App’923 and the teachings of Mucker et al (2020) to achieve the results claimed in claim 58, 60, 63 and 66.
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/HONG REN/
Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647