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 .
Status of Application
Applicants' arguments/remarks filed 07/16/2025 are acknowledged. Claims 1 and 3 are currently amended. Claims 17 and 18 are newly canceled. Claims 1-6, 10-13, 15-16, 19 and 21-25 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 12/12/2024 and with respect to the applicant’s arguments/remarks:
The rejection under 35 U.S.C. 102(a)(1) of claim 17 is withdrawn in view of the cancellation of the claim.
The rejection under 35 U.S.C. 103 of claim18 is withdrawn in view of the cancellation of the claim.
The rejection under 35 U.S.C. 102(a)(1) of Claims 1-6, 10-13, 17, 21-25 is withdrawn due to the amendment of Claim 1.
The rejection under 35 U.S.C. 102(a)(1) of Claims 15-16 is withdrawn due to the amendment of Claim 15.
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.
Claims 1-6, 10-13, 21-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lanzavecchia (US 20110159001Al) in view of Meulen et al. (US 20100172917 A1).
Claims 1, 2, 3, 6, and 21-23,
Lanzavecchia teaches methods of treating a coronavirus-related disease or disorder in a
patient. In one embodiment, the method involves administering an agent (e.g., an antibody or monoclonal antibody), or combination of agents that neutralize the coronavirus to a patient suffering from the disease or disorder, (0166). These can include vectors, liposomes, naked DNA, adjuvant-assisted DNA, gene gun, etc., which include chemical conjugates, which has targeting moiety (e.g. a ligand to a cellular surface receptor), and a nucleic acid binding moiety, fusion proteins containing a target moiety (e.g. an antibody specific for a target cell). (0085). A large variety of possible moieties can be coupled to the resultant antibodies or to other molecules. (0096). Antibodies including polyclonal, monoclonal, humanized and fully human antibodies, may be used as therapeutic agents to treat or prevent a coronavirus-related disease or pathology (e.g., SARS) in a subject. An antibody for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Administration of the antibody may abrogate or inhibit or interfere with the binding of the target (e.g., ACE2) with an endogenous ligand (e.g., S1 region of SARS-CoV spike protein) to which it naturally binds. The antibody binds to the target and masks a binding site of the naturally occurring ligand, neutralizing SARS CoV by inhibiting binding of S1 to ACE2, (0103), like mAbs that inhibit binding of SARS-Co V S glycoprotein to ACE-2 (0190) (anti-ACE-2 antibody) and the mAb neutralizes SARS-CoV by directly blocking the interaction with its receptor ACE2. (0200). A pharmaceutical composition is formulated to be compatible with the following excipient components: sterile diluents; antibacterial agents; antioxidants; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers; pH adjusters. (0112). An antibody that abrogates, inhibits, or interferes with the binding of a target is considered an anti-target antibody. An antibody that blocks the binding of the ACE2 target is an anti-ACE2 antibody. The active ingredients can also be entrapped in colloidal drug delivery systems for example, liposomes, nano-particles, and nanocapsules, (110), or combination of agents that neutralize the coronavirus to a patient suffering from the disease or disorder, (0166).
Lanzavecchia does not teach an anti-viral agent selected from remdesivir, chloroquine, hydroxychloroquine, lopinavir, ranitidine bismuth citrate, and ritonavir.
Meulen et al. teach the binding molecules are capable of specifically binding to SARS-CoV, and can be used in the diagnosis, prophylaxis, and/or treatment of a condition resulting from SAR. (Abs). SARS is the abbreviation of severe acute respiratory syndrome. Antigen-binding fragments include antibodies, polypeptides. (0036). Antibody neutralizes SARS-CoV, by preventing the interaction of the S protein to cellular receptors such as ACE2. (0180). The binding molecules may be administered to a subject in an appropriate carrier, for example, liposomes. (0107). The binding molecule can be part of an immune-conjugate. A binding molecule is intended to refer to a binding molecule operatively linked, or otherwise physically or functionally associated with an effector moiety or tag, such as, a liposome. (0037). The composition includes pharmaceutically acceptable excipient, any inert substance that is combined with an active molecule such as a drug, agent, or binding molecule for preparing an agreeable or convenient dosage form. (0053). Examples of anti-viral agents include, but are not limited to ritonavir. (0103).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to treat a coronavirus-related disease or disorder in a patient. by method involving administering an agent e.g., an antibody or monoclonal antibody, which are to abrogate or inhibit or interfere with the binding of the target (e.g., ACE2) or combination of agents that neutralize the coronavirus, with targeting moiety, active ingredients entrapped drug delivery systems like liposomes or nanoparticles; taught by Lanzavecchia, or molecules binding to and neutralize SARS-CoV, to treat of a condition resulting from SAR, including antibodies, polypeptides, to preventing the interaction of the S protein to cellular receptors such as ACE2 to be administered to a subject in an appropriate carrier like liposomes, associated with an effector moiety combined with an active molecule such as a drug, agent, like ritonavir, taught by Meulen et al., since they have proven it would be feasible to do so.
With regard to claims 4, and 23, 24, Meulen et al. teach a pharmaceutical composition can further comprise at least one other therapeutic, prophylactic and/or diagnostic agent. Preferably, the further therapeutic and/or prophylactic agents are agents capable of preventing and/or treating an infection and/or a condition resulting from SARS CoV. Therapeutic and/or prophylactic agents include, but are not limited to, anti-viral agents. Such agents can be binding molecules, small molecules, polynucleotide. (0102). Examples of anti-viral agents include, but are not limited to ritonavir. (0103).
With regard to claims 5, and 25
Lanzavecchia teaches transmucosal administration can be accomplished through the use of nasal sprays. (0116). For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. (0116).
Meulen et a. teach the route of administration can be transmucosal, inhalation. (0108). The pharmaceutical compositions of the invention can also be formulated for parenteral administration. (0110).
With regard to claims 10-11, Lanzavecchia teaches the antibody binds to the target and masks a binding site of the naturally occurring ligand, neutralizing SARS-CoV by inhibiting binding of S1 region of SARS-Co V spike protein to ACE2. (0103), which would reduce more infection of human cells by virus through ACE2.
With regard to claim 12,
Lanzavecchia teaches antibodies including polyclonal, monoclonal, humanized and fully human antibodies, may be used as therapeutic agents. Such agents are generally employed to treat or prevent a coronavirus-related disease or pathology ( e.g., SARS) in a subject. An antibody preparation, preferably one having high specificity, high affinity, and/or high neutralizing potency for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Administration of the antibody may abrogate or inhibit or interfere with the binding of the target (e.g., ACE2) with an endogenous ligand (e.g., S1 region of SARS-Co V spike protein) to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, thereby neutralizing SARSCoV by inhibiting binding of S1 to ACE2. (0103), which means that the levels of ACE-2 to be susceptible to infection by the virus are higher in cells infected by the virus that are not protected by the antibody.
Meulen et al. teach flow cytometry analysis was used to assay binding of the fragments of the S protein to angiotensin-converting enzyme 2 (ACE2), the natural receptor for SARS-CoV infectivity. Vero cells expressing ACE2. As a control, the Vero cells were incubated with a myc-tagged bivalent schv 02-006. Alternatively, the S565 fragment was incubated with the IgG antibodies 03-014 (anti-SARS-CoV S protein antibody), 03-018 (anti-SARS-CoV N protein antibody) or 02-027 (anti-EPCAM control antibody) prior to incubation with the Vero cells. As shown in FIG. 15, preincubation of fragment S565 in the presence of 0.5µM antibody 03-014 resulted in complete loss of S565 binding to Vero cells, whereas in the presence of antibody 0.5 µM antibody 03-018 (see, FIG. 16) or 0.5 µM antibody 02-027 (see, FIG. 17), S565 binding to Vero cells remained unaffected. In conclusion, monoclonal antibody 03-014 blocked binding of S565 to Vero cells, whereas antibodies 03-018 and 02-027 did not. These data suggest that antibody 03-014 neutralizes SARS-CoV, by preventing the interaction of the S protein to cellular receptors such as ACE2. (0180). For methods of treatment and/or prevention of SARS, the binding molecules are preferably capable of specifically binding to surface accessible proteins. (0059), by binding to carriers. (0062). The invention includes immunoconjugates, i.e., molecules comprising at least one binding molecule or functional variant thereof and further comprising at least one tag, detectable moiety/agent. Also contemplated in the invention are mixtures of immunoconjugates described herein or mixtures of at least one immunoconjugates and
another molecule. Such as a therapeutic agent or another binding molecule or immunoconjugate. In a further embodiment, the immunoconjugates of the invention may comprise more than one tag. These tags can be the same or distinct from each other and can be joined/conjugated non-covalently to the binding molecules. (0071).
With regard to claim 13,
Lanzavecchia teaches a novel Coronavirus caused an outbreak of Severe Acute Respiratory Syndrome (SARS-Co V). (0003). Several lethal SARS-CoV challenge models have
been developed in BALB/c mice that recapitulated the age-related clinical signs, weight loss exceeding 20% as well as severe lung pathology, by using recombinant SARS-Co V bearing the S glycoprotein of early human and zoonotic strains (39). Virus titers were examined in the lungs on days 2 and 4. By day 2 post challenge, complete protection against virus replication in lungs of BALB/c mice treated with mAb 1 day prior to challenge was observed ( AN OVA; p<0 .01; FIG. 6B). In contrast, a 5 log reduction in virus titers was observed when treated on the day of challenge ( detectable virus in only 1 out of 4 animals, ANOVA; p<0.01). Consonant with the
development of severe clinical disease, no reduction in viral titers was observed when treated 1 day post challenge (FIG. 6B). By day 4 post challenge, virus was no longer detectable in lungs of mice treated -1, 0, 2 or 3 days post challenge (ANOVA; p<0.01) and only detectable in 1 out of5 BALB/c\ mice treated with mAb on day 1 post challenge (FIG. 6B). (0209). These data suggest that the lethal course of SARSCoV infection in the mouse model may well be set within the
first 24h post infection, as this mAb was not capable of reducing the clinical course of disease. (0210).
Meulen et al. teach the 03-014 group were accompanied by a complete protection
from macroscopic lung pathology in the group treated with 03-014 compared to the control group, who all showed multifocal lesions (p=0.029). Upon microscopic analysis, these
lesions showed alveolar changes resembling diffuse alveolar damage as well as peribronchial, peribrochiolar, and perivascular lymphocytic cuffing. (0215). These results demonstrate that passive transfer of the 03-014 anti-SARS-CoV antibody was able to abolish SARS-CoV induced pulmonary lesions as well as SARS-CoV excretion in animals that had obtained sufficient 03-014 IgG serum titers. (0216).
Claims 15, 16 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kulp (US 20230137756 A1) (us-provisional-application US 63001882 20200330) in view of Zhang et al. (US 20200165594 A1).
Kulp teaches compositions comprising cellular receptor mimics and methods for treating or preventing coronavirus infection or a disease or disorder associated with coronavirus infection such as COVID-19. (Abs). Exemplary delivery vehicles include, but are not limited to, nanoparticles, liposomes. For example, in some embodiments, the delivery vehicle is loaded with synthetic soluble receptor mimic polypeptide, or a nucleic acid molecule encoding a synthetic soluble receptor mimic polypeptide. In some embodiments, the delivery vehicle comprises a targeting moiety that targets the delivery vehicle to a treatment site. (0198). The composition can comprise a recombinant ACE2 polypeptide. (0109). The pharmaceutical compositions may combine other active agents. (0203). The composition further comprises a pharmaceutically acceptable excipient. In one embodiment, the composition further comprises an adjuvant. (0021). In certain embodiments, a synthetic soluble receptor mimic polypeptide, or nucleic acid molecule encoding the same as described herein, may be coated along the surface of the scaffold, substrate, or device. (0200).
Kulp does not teach the nanoparticle further comprises an anti-viral agent selected from remdesivir, chloroquine, hydroxychloroquine, lopinavir, ranitidine bismuth citrate, and ritonavir.
Zhang et al. teach antiviral therapies that can be used in combination with existing antiviral compounds for viruses. (Abs). Particle delivery systems include but not limited to, e.g., lipid-based systems, liposomes. (0288). In one embodiment, particles based may be applied to nasal delivery. (0292). One of the antiviral drugs to be delivered is ranitidine. (0298).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the invention, to prepare pharmaceutical compositions comprising a recombinant ACE2 polypeptide by nanoparticles or liposomes, for nasal delivery a targeting moiety taught by Kulp, and to combine an antiviral drug ranitidine, taught by Zhang et al., since the antiviral drug can help to destroy virus after the nanoparticles targeting and penetrating virus.
Response to Arguments
With Regard to 35 U.S.C. § 102 Rejection:
Applicant argues that Lanzavecchia and Meulen disclosing a method of using a nano-particle with an anti-ACE antibody targeting moiety. However, Lanzavecchia nor Meulen teach or suggest an anti-ACE-2 antibody. In contrast, Lanzavecchia discloses monoclonal antibodies that inhibit binding of SARS-CoV S glycoprotein to ACE-2. As described, for example paragraph 0190, the antibodies of Lanzavecchia, specifically inhibit binding of S protein to ACE-2, and therefore does not teach an anti-ACE antibody as required by claim 1. Meulen merely describes a human monoclonal anti-SARS-Cov antibody (see paragraph 0011) and does not disclose an anti-ACE antibody.
Applicant's arguments have been fully considered but they are not persuasive. An antibody that abrogates, inhibits, or interferes with the binding of a target is considered an anti-target antibody. In biology, to abrogate means to suppress, block, or put an end to a biological function or process, especially in the context of the immune system or cellular mechanisms. Lanzavecchia teaches administration of the antibody may abrogate or inhibit or interfere with the binding of the target (e.g., ACE2) with an endogenous ligand (e.g., S1 region of SARS-CoV spike protein) to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, thereby neutralizing SARS CoV by inhibiting binding of S1 to ACE2. (0103). Therefore, an antibody that blocks the binding of the ACE2 target is indeed an anti-ACE2 antibody because its action is directed against ACE2.
Applicants argue that the Examiner considers Kulp as teaching a nanoparticle comprising a recombinant ACE polypeptide as a targeting moiety. However, Kulp does not teach or suggest an anti-viral agent selected from remdesivir, chloroquine, hydroxychloroquine,
lopinavir, ranitidine bismuth citrate, and ritonavir, as encompassed by independent claims 1 and 15. More specifically, Kulp does not disclose a nanoparticle with a recombinant ACE polypeptide as a targeting moiety and loaded with an anti-viral agent selected from remdesivir, chloroquine, hydroxychloroquine, lopinavir, ranitidine bismuth citrate, and ritonavir.
This argument has been fully considered, but is not found persuasive, because with the amendment, adding the anti-viral agent selected from remdesivir, chloroquine, hydroxy-chloroquine, lopinavir, ranitidine bismuth citrate, and ritonavir, the 102 rejection of claim 15 is modified in this office action to 103 rejection with Zhang’s teachings that antiviral therapies that can be used in combination with existing antiviral compounds for viruses. Particle delivery systems include but not limited to, e.g., lipid-based systems, liposomes. One of the antiviral drugs to be delivered is ranitidine. (0298).
Applicants argue that further, if it is necessary to select portions of teachings within a reference and combine them to arrive at a species, then anticipation can only be found if one of ordinary skill in the art is able to "at once envisage" the species.1 Lanzavecchia, Meulen, and Kulp merely disclose a nanoparticle or a liposome as a potential carrier for the disclosed active ingredients. Therefore, a person of ordinary skill in the art could not have readily envisaged a nanoparticle comprising an anti-ACE antibody or a nanoparticle comprising ACE-2 polypeptide as a targeting moiety and comprising an anti-viral agent based on the disclosures of Lanzavecchia, Meulen, and Kulp. Accordingly, none of the cited publications does not anticipate the instant claims, and Applicant respectfully requests that the Examiner reconsider and withdraw the claim rejection under 35 U.S.C. § 102.
This argument has been fully considered, but is not found persuasive, because the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. In fact, so many references teach preparation methods and characterizations of nanoparticles, liposomes or lipid-nanoparticles carrying biologic materials that one with skill in the art can learn from to apply for this application.
With Regard to 35 U.S.C. § 103 Rejection:
Applicants argue that the cited publications do not teach a composition comprising a
nanoparticle with a recombinant ACE-2 polypeptide as a targeting moiety and an antiviral
agent. The Examiner considers Zhang as teaching a nanoparticle carrying an antiviral agent. However, Zhang merely discloses ranitidine as one of the medications to reduce the risk of infusion-related reactions (see paragraph 0298). Nowhere does Zhang disclose a nanoparticle as a carrier for ranitidine.
This argument has been fully considered, but is not found persuasive, because the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. Zhang teaches antiviral therapies that can be used in combination with existing antiviral compounds for viruses. Particle delivery systems include but not limited to, e.g., lipid-based systems, liposomes. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
Applicants argue that nanoparticle coated with recombinant-ACE-2 and loaded with antiviral medications can bind to the virus and act as a sink to remove viral particles and at the same time deliver loaded antiviral drug specifically to the infected cells/tissue. Moreover, increases in ACE-2 by using the composition encompassed by the claims will prevent and help resolving acute lung injury in subjects. This effect is unexpected based on the teachings of cited publications and therefore outweigh any prima facie obviousness. none of the publications cited by the Examiner teaches or suggests a composition encompassed by the pending claims.
This argument has been fully considered, that applicant has amended claims 1 and 15, to combine with the antiviral, to help resolving acute lung injury in subjects, but is not found persuasive, because Lanzavecchia teaches active ingredients can also be entrapped in colloidal drug delivery systems for example, liposomes, nano-particles, and nanocapsules, or combination of agents that neutralize the coronavirus to a patient suffering from the disease or disorder. Meulen teaches The composition includes pharmaceutically acceptable excipient, any inert substance that is combined with an active molecule such as a drug, agent, or binding molecule for preparing an agreeable or convenient dosage form. Examples of anti-viral agents include, but are not limited to ritonavir. Zhang teaches antiviral therapies that can be used in combination with existing antiviral compounds for viruses. Particle delivery systems include but not limited to, e.g., lipid-based systems, liposomes. And the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
Conclusion
Applicants' amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Correspondence
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615