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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on April 16, 2024. Claims 1-11, 13-14, 16-20 and 22-23 are pending and are currently examined.
Claim Objections
Claims 4 and 16 are objected to because of the following informalities:
Claims 4 and 16 recites abbreviation LCB1 without spelling it out the first time it appears in the claims set.
Claim Rejections - 35 USC § 112 (b)
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 2, 4, 5, 6, 7, 8 10,11 and 17-19 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.
Claims 2, 4, 5, 6, 7, 8 10 and 11 recite the limitation “composition” in reference to claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 5 and 17 recite a term “…is about the distance…” that renders the claim indefinite. It is not clear what the “about” here stands for. It is unclear if it means a same distance or a distance with difference. This rejection is also extended to claims 7 and 19. The term “less than about 5 nM” renders the claims indefinite. It is unclear if the claimed Kd is less than 5nM or not. Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claims.
Regarding claims 6 and 18, they recite a term “greater affinity” that renders the claims indefinite. The term “greater” is a relative term and is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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.
Claims 1, 5, 6, 11, 13, 17-18 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (WO 2018/215660 A1, published on Nov. 29, 2018, hereinafter, “Smith”) and in view of Tan et al. (CN112999333A, published on June 22, 2021, hereinafter, “Tan”).
The base claim 1 is directed to a DNA-peptide hybrid molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein the one or more target-specific binding peptides are specific for SARS-CoV-2.
The base claim 13 is directed to a method of treating a subject in need thereof, the method comprising administering to the subject a DNA-peptide hybrid molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein the one or more target specific binding peptides are specific for SARS-CoV-2, in an amount sufficient to treat SARSCoV-2 infection.
Smith teaches a nucleic acid-based nanostructure, which display virus-binding peptides. Such nanostructures are quick and cheap to produce, because both the peptide moieties as well as the nucleic acid carrier system can be easily synthesized. Nucleic acids can also be easily synthesized and chemically manipulated to contain molecules for attaching peptides or additional features such as fluorescence detection molecules. (See page 2, lines 9-20). For example, in Figure 5b, Smith teaches a DNA-peptide structure designed for influenza Hemagglutinin, where each arm of a symmetric DNA trimer structure carries a HA binding peptide that binds to one monomer of a HA protein (See Figure 5b, page 34 and below). Here the stability of a natural nucleic acid hybrid can for example be increased by adding non-natural nucleotides such as LNA and PNA. These offer more stability both because they allow stronger binding between two strands of nucleic acids and/or because they are less likely to be degraded by enzymes (See page 5, lines 9-19).
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Smith also teaches a method of treatment or prophylactic treatment of a viral infection comprising administering to a subject suffering from a viral infection an appropriate amount of a nanostructure according to the invention (See page 3, lines 5-7) and it will be clear to the skilled person that in order for the treatment to work, the peptide moieties of the nanostructure used in the method of treatment have to specifically bind to a molecule expressed on the surface of the virus to be targeted (See page 22, lines 10-15).
Accordingly, Smith teaches a DNA-peptide and DNA nanostructure, where they can be chemically linked to target-specific binding peptides for virus such as virus binding peptides for binding to the surface of measles, SARS-CoV and influenza viruses (See page 11, lines 5-16), and also teaches a method to administer the stable, cheap and easy production of nanostructures of the invention to treat the viral infection.
As for the claimed “the one or more target-specific binding peptides are specific for SARS-CoV-2”, Smith teaches that the peptide can be specific for SARS-COV, therefore, it would be obvious for one of ordinary skill in the art to set up an experiment to test a specific binding peptide being specific to SARS-COV-2 based on the teaching of SARS-COV above.
Nevertheless, Tan teaches using of multi-target blocking peptides for the prevention and treatment of new coronavirus infections and the multi-target blocking peptide can block the interaction of SARS-CoV-2-S protein RBD and its receptor, and finally prevent the new coronavirus from invading target cell (See page 1, claims 1 and 3).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce Tan’s one or more target-specific binding peptides for SARS-COV-2 into Smith’s designs to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to modify Smith’s invention to develop a target-specific binding peptides for SARS-COV-2 to prevent and treat of SARS-COV-2 infections. There would be a reasonable expectation of success to develop such as a DNA-peptide-based DNA nanostructure as claimed, and further develop a method to administer to a subject with the DNA-peptide hybrid molecule to treat SARS CoV-2 infection.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 5 and 17, they require the distance between the target-specific binding peptides on the fully assembled DNA-peptide hybrid molecule is about the distance between the sites where the target-specific binding peptide binds to the native SARS-CoV-2 homotrimer spike protein.
Smith in view of Tan teaches that in one embodiment of the nanostructure, the length of each of the branches of the nucleic acid scaffold is selected so as to provide the nanostructure with the optimal binding geometry to bind its target. In one embodiment, different ranches of the nucleic acid scaffold are of different lengths. However, in a preferred embodiment, all of the branches of the nucleic acid scaffold are of the same length (See page 8, lines 15-20), where the target virus can be the SARS-COV or SARS-COV-2 virus and it is a common knowledge in the art that the native SARS-CoV-2 spike protein is a homotrimer.
Regarding claims 6 and 18, they require the DNA-peptide hybrid molecule has greater affinity for SARS-CoV-2 spike protein than the target-specific peptide alone.
Smith teaches that they have surprisingly also found that the nanostructures of the invention can bind to viruses even at low valency, with a much higher affinity than individual short peptides. This realisation implements the stable, cheap and easy production of nanostructures of the invention, which can be used in the diagnosis and treatment of infections (See page 2, lines 16-20).
Regarding claims 11 and 23, they require the chemical linkage of the one or more target specific binding peptides to the DNA nanostructure is cleavable.
Smith teaches that the peptide moieties can be attached to the nucleic acids of the nucleic acid scaffold directly or via a linker. The linker can optionally be cleavable (See e.g., page 18, paragraph 13).
Claims 2-3 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Schwarz et al. (Nanoscale. 2017 Jun 1;9(21):7047-7054).
Claims 2-3 and 14 require a specific DNA nanostructure group.
Based on the description above, Smith in view of Tan teaches a nanostructure comprising a) a nucleic acid scaffold; and b) at least two peptide moieties, wherein the at least two peptide moieties specifically bind to a molecule expressed on the surface of a virus such as SARS-COV-2 virus. However, Smith does not explicitly disclose the claimed nanostructure groups.
Schwarz describes a four-helix bundle DNA nanostructure with binding pockets for pyrimidine nucleotides and the binding affinity depends on the position in the structure, as expected for recognition beyond simple base pairing. The folding motif reported here can help to expand DNA nanotechnology into the realm of selective molecular recognition that is currently dominated by protein-based enzymes and receptors (See Abstract). Schwarz also discloses that the designed four-helix bundle motif presented is a robust folding platform that is suitable for setting up one or several intrahelical binding sites without a loss of conformational integrity (See 7050, right column, paragraph 3).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the four-helix bundle DNA nanostructure of Schwarz into Smith’s design and arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Schwarz teaches the benefit to use the four-helix bundle motif as described above and also states that the small DNA four-helix bundle, approx. 50 kDa in size, that folds readily and in high yield that was found to be suitable for setting up artificial binding sites (See page 7048, right column, paragraph 2). There would be a reasonable expectation of success to develop a method to design the DNA nanostructure containing a group of four-helix bundle as claimed.
Claims 4 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Schutz et al. (Adv Drug Deliv Rev. 2020 Dec; 167:47-65).
Claims 4 and 16 require the target-specific binding peptide is LCB1.
Based on the description above, Smith does not explicitly teach the target-specific binding peptide is LCB1.
Schutz studies the peptide and peptide-based inhibitors of SARS-CoV-2 entry and teaches two candidates, LCB1 and LCB3 (Fig. 3B, Table 1), were identified that bind the RBD with lower dissociation constants and neutralized SARS-CoV-2 in the picomolar range (See page 50, right column, paragraph 2). Schutz further discloses that the S protein-targeting peptides EK1C4, [SARSHRC-PEG4]2-chol, LCB1, and LCB3 show promising antiviral potency against SARS-CoV-2 without affecting the function of the host protein. Thus, oral, intranasal or inhalative applications might unfold the activity of these peptides directly at the site of replication without the need for optimization of properties such as tissue-penetration, plasma stability, or half-life (See page 60, left column, paragraph 3).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the LCB1 peptide of Schutz into Smith’s design and arrive at an invention as claimed. One of skill in the art would have been motivated to do so based on the benefit for using the LCB1 to against SARS-COV-2 infection. There would be a reasonable expectation of success to develop a LCB1 as a target-specific binding peptide as claimed.
Claims 7 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Kim et al. (bioRxiv preprint doi: https://doi.org/10.1101/2021.07.23.453598; this version posted July 26, 2021).
Regarding claims 7 and 19, they require the DNA-peptide hybrid molecule has a Kd of less than about 5 nM for each of the spike protein of SARS-CoV-2 alpha, beta, gamma, and delta variants.
Smith teaches that the binding affinity between peptide and virus is at a binding interaction "strong" (dissociation constant (Kd) in nM range or lower) or "weak" (above nM range, usually in µM range) (See page 13, lines 15-16), which indicates that the Smith teaches a method to detect the binding affinity of the DNA-peptide hybrid molecule. Furthermore, Smith teaches that this Kd is of less than 200 μM, more preferably less than 100 μM, even more preferably less than 50 μM, yet more preferably less than 40 μM, yet more preferably less than 30 μM, and most preferably less than 25 μM (See page 9, lines 1-7). Although the Kd value of Smith is not identical as claimed, it is common knowledge in the art that the Kd value can vary based on the experimental conditions such as pH, temperature and different targeted virus. One of skill in the art can test for an optimal Kd value as claimed through routine experimentation.
Nevertheless, Kim teaches a Differential Interactions Between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern. Kim discloses that performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). They report that the RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484K, and N501Y) or Delta (L452R and T478K) variant. Their study could help develop new drugs to inhibit SARS-CoV-2 entry effectively (See Abstract). Kim further teaches that the binding affinities of ACE2 and RBDWT were detected to be 27.5 ± 4.8 nM (Figure 4). This value is in agreement with a reported Kd range of 5-40 nM measured by surface plasmon resonance (See page 10, paragraph 1; Figure 4 and below). Here, although the Kd value is not identical to the Kd as claimed at “less than about 5 nM”, the Kd of 5 nM is comparable to the claimed limitation.
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the teaching of Kim’s affinity Kd of the SARS-CoV-2 RBDs to ACE2 into Smith’s affinity study to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Kim teaches that the study could help develop new drugs to inhibit SARS-CoV-2 entry effectively. There would be a reasonable expectation of success to develop a DNA-peptide hybrid molecule that has a Kd of less than about 5 nM for each of the spike protein of SARS-CoV-2 alpha, beta, gamma, and delta variants.
Claims 8 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Rosier et al. (Chem Commun (Camb). 2017 Jun 29;53(53):7393-7396).
Claims 8 and 20 require the synthetic DNA-peptide hybrid molecule further comprises an immunoglobulin Fc domain.
Smith teaches that in one embodiment of the nanostructure, at least one of the peptide moieties is derived from the complementarity determining region of an existing antibody. The way to do this is known in the art. For example, discloses the design of peptide moieties that bind to the influenza A hemagglutinin protein based on the HC19 antibody (See bridging pages 24-25). It would be obvious for one of ordinary skill in the art to include Fc domain in the synthetic DNA-peptide hybrid molecule, and the result would be predictable for selecting the Fc domain. For example, Smith teaches that this method allows one to screen peptides for their affinity to a particular target. It therefore allows the identification of new peptides that have the required binding affinity against a target of interest. Such peptides can then be used in the nanostructures of the invention (See bridging pages 24-25). Thus, one of skilled in the art can screen an immunoglobulin Fc domain that specifically bind to SARS-COV-2 spike protein and include it in the nanostructure because Smith already disclosed a method to use the PeB peptide (ARDFYDYDVFYYAMD) derived from antibody HC19 in the nanostructure (See page 17, lines 21-29).
Nevertheless, Rosier teaches the incorporation of native antibodies and Fc-fusion proteins on DNA nanostructures via a modular conjugation strategy and this has led to DNA and RNA nanostructures being employed as powerful tools to study enzymatic cascades, receptor activation and as in vivo delivery vehicles (See Abstract and title), and discloses that the Fc domain is often used as a fusion partner to biologically active proteins, increasing in vivo stability and circulation, and prolonging activity in therapeutic applications (See page 7395, left column, paragraph 2).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the Fc domain of Bosier into Smith’s design to arrive at an invention as claimed. Based on the modular conjugation strategy of the Fc domain and the benefit to include the Fc domain taught by Rosier, one of skill in the art would have been motivated to do so to include the Fc domain in Smith’s DNA-peptide based nanostructures. There would be a reasonable expectation of success to add the Fc domain to the DNA-peptide hybrid molecular as claimed.
Claims 9 is rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Tso et al. (PLoS One. 2021 Mar 4;16(3): e0247640).
Claim 9 requires the composition of claim 8, wherein the binding of the DNA-peptide hybrid molecule to SARS-CoV-2 spike protein induces immune cells to engage in antibody dependent cellular cytotoxicity (ADCC).
Smith teaches that the DNA-peptide nanostructure comprises a Peb peptide derived from antibody HC19, but Smith does not explicitly point out the induced antibody dependent cellular cytotoxicity (ADCC).
Tso teaches the presence of antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 in COVID-19 plasma and the NK92.05-CD16-176V effector cells will recognize those dye-labeled and Ab decorated antigen expressing target cells via its FcγRIII receptor that binds to the Fc region of the bound antibody (See Abstract and page 7, paragraph 2). Tso teaches that non-RBD-specific Ab which target the SARS-CoV-2 S could be less apt to neutralization, but nevertheless have important roles in viral control by coupling adaptive humoral responses to natural killer (NK) cells through the mechanism of Ab-dependent cellular cytotoxicity (ADCC) (See page 2, paragraph 3), and ADCC is an important factor in vaccine efficacy (See page 10, paragraph 1).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the teaching of ADCC of Tso into Smith’s design to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because the ADCC can be an important factor in vaccine efficacy. There would be a reasonable expectation of success to add the Fc domain to the DNA-peptide hybrid molecular to induces immune cells to engage in antibody dependent cellular cytotoxicity (ADCC) as claimed.
Claims 10 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Tan as applied to claims 1, 5, 6, 11, 13, 17-18 and 23 above and further in view of Stephanopoulos N. (Chem Commun (Camb). 2017 Jun 29;53(53):7393-7396).
Claims 10 and 22 requires the one or more target-specific binding peptides and the DNA nanostructure are linked through a disulfide bond or through copper-free click chemistry between a protein bearing the non-canonical amino acid 4-zidophenylalanine and DNA linked to cyclooctyne.
Smith teaches that the peptide moieties were attached to the nucleic acids of the nanostructure as follows. The peptides are each derivatized with an azide group and each DNA strand of the nucleic acid scaffold with a DBCO linker. Three peptide moieties are then coupled to each nucleic acid scaffold by copper-free Click chemistry (See page 30, paragraph 2). However, Smith does not teach the linkage is between the non-canonical amino acid 4-azidophenylalanine and DNA linked to cyclooctyne.
Stephanopoulos reviews the Hybrid Nanostructures from the Self-Assembly of Proteins and DNA and teaches the Bioconjugation Chemistry for Protein-DNA Hybrids (See Abstract and Figure 2 and below), which discloses the non-canonical amino acid 4-azidophenylalanine and cyclooctyne. Stephanopoulos teaches that they turned to copper-free click chemistry with the NCAA 4-azidophenylalanine. The NCAA was incorporated via the Schultz technique, and the cyclooctyne coupling partner was introduced into the DNA with a modified phosphoramidite. This strategy allowed them to place the modification at any location on the protein surface without any of the restrictions imposed by fusion tags or cysteine residues (See bridging pages 376-377), and the cyclooctyne used (appended directly to the 5’ end of the DNA) and the use of a NCAA on the protein resulted in a short linker between the molecules and thus allowed for tight coupling between the two components (See page 377, first paragraph).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the Copper-free
click chemistry techniques between NCAA 4-azidophenylalanine and cyclooctyne into Smith’s design to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because the technique allowed them to place the modification at any location on the protein surface without any of the restrictions imposed by fusion tags or cysteine residues. There would be a reasonable expectation of success to develop a method to link with the copper-free click chemistry between a peptide bearing the non-canonical amino acid 4-azidophenylalanine and DNA linked to cyclooctyne as claimed.
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Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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