DETAILED ACTION
Receipt of Arguments/Remarks filed on December 30 2025 is acknowledged. Claims 1-22, 24 and 40-54 were/stand cancelled. Claims 23, 25-31 and 55 were amended. Claims 23, 25-39 and 55 are pending. Claims 32-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 1 2025. Claims 23, 25-31, 36-39 and 55 are directed to the elected invention.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 2 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23, 25-31 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Gale JR. et al. (USPGPUB No. 20180104325, cited on PTO Form 1449) in view of Sato et al. (Immunity, 2015, cited on PTO Form 1449).
Applicant Claims
The instant application claims a method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of composition that induces interferon regulatory factor 3 (IRF3) activation in infected cells of the subject, wherein the composition is or comprises a nucleic acid molecule comprising a pathogen-associated molecular pattern (PAMP), wherein the PAMP comprises: a 5'-arm region comprising a terminal triphosphate; a poly-uracil core comprising at least 8 contiguous uracil residues; and a 3'-arm region comprising at least 8 nucleic acid residues, wherein the 5'-most nucleic acid residue of the 3'-arm region is not a uracil and wherein the 3'-arm region is at least 30% uracil residues.
The examiner notes that the recitation composition is or comprises is interpreted as comprising as the rest of the claim recites “a nucleic acid molecule comprising” and “the PAMP comprises”. Therefore the use of comprising throughout the claim results in “composition is or comprises” as being interpreted as not limiting and the composition open to any additional sequences or components.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Gale JR et al. is directed to methods and compositions for activation of innate immune responses through RIG-I like receptor signaling. Claimed is a method of treating a condition in a subject treatable by inducing RLR signaling, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a synthetic nucleic acid pathogen-associated molecular pattern (PAMP), wherein the synthetic PAMP comprises:
a 5′-arm region comprising a terminal triphosphate;
a poly-uracil core comprising at least 8 contiguous uracil residues;
and a 3′-arm region comprising at least 8 nucleic acid residues,
wherein the 5′-most nucleic acid residue of the 3′-arm region is not a uracil and wherein the 3′-arm region is at least 30% uracil residues (claim 1).
The poly-uracil core consisting of between 8 and 30 uracil residues (claim 11). The 5′-most nucleic acid residue of the 3′-arm region is a cytosine residue or a guanine residue (claim 12). The 3’-arm region is at least 90% uracil residue (claim 13). The 3’-arm region comprises at least 7 contiguous uracil residues (claim 14). The 5′-arm region further comprises one or more nucleic acid residues disposed between the terminal triphosphate and the poly-uracil core (claim 15). The 5′-arm region consists of the terminal triphosphate, and wherein the terminal triphosphate is linked directly to the 5′-end of the poly-uracil core (claim 20).
The PAMP is capable of inducing retinoic acid-inducible gene (RIG-I) like receptor activation (claims 17-28). The method further comprises administering an anti-viral therapeutic (claim 19).
A specific construct taught is SEQ ID NO: 1:
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As shown in the figures, the Con1 pU/UC (i.e. SEQ ID NO: 1) shows RIG-1 activation (Fig. 1C, 2A) wherein EC10, EC50, EC90 are reported with high signaling (Fig. 2C). Shown in Fig. 5B pU/UC shows IRF-3 activation.
It is taught that various classes of pathogens, such as viruses and bacteria, contain pathogen-associated molecular patterns (PAMPs) in structural or genetic components (paragraph 0005). Fig. 6 demonstrates the antiviral activity of the polyU-UC PAMP RNA constructs (paragraph 0025).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Gale, JR et al. teaches administering to a subject in need thereof a compound which a synthetic nucleic acid pathogen-associated molecular pattern (PAMP) and teaches these compounds activate RIG-1/IRF-3 and that the constructs possess antiviral activity, Gale JR. et al. does not expressly teach that the subject has a hepatitis B virus (HBV) infection. However, this deficiency is cured by Sato et al.
Sato et al. is directed to the RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus (HBV). RIG-I is a key PPR (pattern-recognition receptors) that can detect virus-derived RNAs in the cytoplasm during infection with a variety of viruses. Binding of RIG-I to its ligand ultimately leads to the induction of the IFN regulator factor-3 (IFR-3) and the subsequent production of IFNs and inflammatory cytokines. Thus, RIG-I sensing of viral RNA is a crucial process to activate the antiviral innate responses to limit viral replication and the activation of adaptive immunity (pages 123-124, bridging paragraph). HBV infection predominantly induces type III, but not type I, IFN gene induction, which is mediated by RIG-I through its recognition of the 5’-ε region of pgRNA in an RNA-binding dependent manner, resulting in the suppression of HBV replication. Findings demonstrate the innate defense mechanisms based on the viral RNA-RIG-I interaction, whereby RIG-I functions not only as a HBV sensor for the activation of IFN response but also as a direct antiviral factor (page 124, left column). As is the case with this, several viral PAMPs known to be recognized by RIG-I, for example, the poly-U/UC tract in the 3′ nontranslated region of HCV genome and 5′ terminal region of influenza virus genome were previously reported to be directly or indirectly critical for viral replication. In this respect, one could envisage that such an exquisite targeting by RIG-I would confer a unique machinery to ensure efficient antiviral activities of RIG-I. Therefore, RIG-I is likely to play dual roles as an innate sensor and as a direct antiviral effector for host defense during viral infection (page 130, paragraph bridging left and right columns).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Gale JR et al. and Sato et al. and utilize the PAMP of Gale JR et al. and administer to a patient with an HBV infection in order to activate RIG-I. One skilled in the art would have been motivated to administer the PAMP to this patient population as Sato et al. teaches that RIG-I is both an innate sensor and direct antiviral effector for HBV. Administration of a PAMP, which is taught by Sato et al. as activating RIG-I would therefore be expected to aid in treating the HBV viral infection. As shown by Gale JR et al., the pU/UC shows IRF-3 activation. Therefore, administration of the PAMP with the pU/UC would be expected to induce IRF3 activation.
Regarding claim 24, Gale JR et al. recites the same PAMP (see claim 1 of Gale JR et al.).
Regarding claim 25-31, Gale JR et al. teaches the same limitations. See claims 1, 11, 12, 13, 14, 15 and 20 of Gale JR et al.
Regarding claim 55, a specific PAMP taught is Con1 pU/UC (i.e. SEQ ID NO: 1) (Db) which is 100% identical to instantly claimed SEQ ID NO: 34 (Qy) as shown in the alignment below.
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Claims 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Gale JR. et al. in view of Sato et al. as applied to claims 23, 25-31 and 55 above and in further view of Dimou et al. (Therapeutics and Clinical Risk Management, 2007, cited on PTO Form 1449).
Applicant Claims
The instant application claims further comprising administering to the subject a therapeutically effective amount of a nucleoside reverse transcriptase inhibitor (NRTI). The NRTI as elected is entecavir.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Gale JR et al. and Sato et al. are set forth above. Gale JR et al. teaches that the method further comprises administering an anti-viral therapeutic (claim 19).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Gale JR et al. suggests further administering an anti-viral therapeutic, Gale JR et al. does not expressly teach this anti-viral is entecavir. However, this deficiency is cured by Dimou et al.
Dimou et al. is directed to the role of entecavir in the treatment of chronic hepatitis B. Six drugs have been approved for the treatment of chronic hepatitis B and one includes entecavir (page 1077). Entecavir has high anti-HBV potency (page 1085, conclusions).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Gale JR et al., Sato et al. and Dimou et al. and additionally administer entecavir with the PAMP of Gale JR et al. to patients with a HBV infection. One skilled in the art would have been motivated to administer entecavir as it has high anti-HBV potency and has been approved for treatment of chronic hepatitis B as taught by Dimou et al. One skilled in the art would have a reasonable expectation of success as Gale JR et al. suggests the PAMP can be administered with additional therapeutics such as anti-virals.
Response to Arguments
Applicants’ arguments filed December 30 2025 have been fully considered but they are not persuasive.
Applicants argue (page 7-9) that (1) the cited publications, Gale and Sato, provide no teaching or suggestion that would motivate a skilled artisan to substitute HBV innate sensor with HCV innate sensor with any reasonable expectation of success.
Regarding Applicants’ first argument, the rejection is not based on replacing one sensor for another. The rejection is based on administering the PAMP of Gale JR et al. to a different patient population, specifically patients with an HBV infection.
Applicants argue (page 6-8) that (2) Gale is exclusively focused on activation of innate immune responses through RIG-I like receptor signaling by recognition of PAMPs derived from hepatitis C virus genome. Gale explains that PPRs are critical components of the innate immune response and function to recognize PAMPs in pathogen proteins or nucleic acids associated with viral infection. Gale notes that RIG-I is a cytoplasmic PRR that senses viral RNA within an infected cell. The examples described in Gale are focused on structure and use of PAMP derived from hepatitis C virus for inducing type I interferon mediated innate immune responses. Gale discloses that HCV PAMP is recognized by RIG-I like receptor, which, through downstream signaling, triggers type I interferon production and direct innate immune response limiting virus (e.g. HCV and West Nile virus) replication and spread. These examples of Gale are focused on RNA virus derived PAMP. In contrast the instant claims related to the use of the RNA virus derived PAMP for targeting a DNA virus infection, specifically HBV. Sato discloses that innate immune activation is impaired and the induction of type I IFNs is hardly detected in animal models of HBV infection as compared with HCV infection. HBV infection predominantly induced type III, but not type I, IFN gene induction with is mediated by RIG-I. It is argued that Sato teaches a different type of innate immune response is needed for treating HBV infection.
Regarding Applicants’ second argument, It is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV).
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991)
In In re Lintner, the claimed invention was a laundry composition consisting essentially of a dispersant, cationic fabric softener, sugar, sequestering phosphate, and brightener in specified proportions. The claims were rejected over the combination of a primary reference which taught all the claim limitations except for the presence of sugar, and secondary references which taught the addition of sugar as a filler or weighting agent in compositions containing cationic fabric softeners. Appellant argued that in the claimed invention, the sugar is responsible for the compatibility of the cationic softener with the other detergent components. The court sustained the rejection, stating "The fact that appellant uses sugar for a different purpose does not alter the conclusion that its use in a prior art composition would be [sic, would have been] prima facie obvious from the purpose disclosed in the references." 173 USPQ at 562.
While HCV is an RNA virus and HBV is a DNA virus, this in and of itself would not motivate one skilled in the art to administer the PAMP of Gale JR et al. to a patient with an HBV infection. While Gale JR et al. does exclusively focus on administration to subjects with an HCV or west Nile viral infection, the rejection is not based on Gale Jr et al. only. The question to one of ordinary skill in the art is would it have been obvious to administer the RAMP to treat other viral infections, the examiners position is of the position that it would have been obvious. Nothing in Applicants arguments, nor the claims, establish a structural difference between the composition of the instant claims and the composition of Gale Jr et al. As shown by Gale JR et al. (Fig. 5B), the pU/UC (PAMP) shows IRF-3 activation. Sato et al. teaches that RIG-I dependent IRF-3 activation and the 5’-end of the HBV pgRNA confers PAMP motif for RIG-I recognition (page 123). Sato teaches that induction of IFN-3 leads to the subsequent production of type I and type III IFNs and inflammatory cytokines. RIG-I is the major PRR that initiates innate immune responses against HCV. In HBV infection, a type III IFN gene interferon is induced which is mediated by RIG-I (page 124). Thus, the combination of Gale Jr et al. and Sato et al. suggest that mediation of RIG-I can be used to treat both HCV or HBV infections. Therefore, while one is RNA viral infection and the other is a DNA viral infection both are mediated by RIG-I. Applicants arguments clearly recognize that HBV infection is mediated by RIG-I. Based on these teachings one skilled in the art would recognize that use of any composition which can mediate RIG-I would be potentially useful in treating either type of infection. While Gale Jr et al. specifically discusses type I IFN, Gale Jr et al. is silent to the type III. Therefore, the examiner cannot agree that Sato’s teaching of HBV infection predominantly induces type III but not type I is a teaching away from using the PAMP of Gale Jr et al. As evidenced by Bruening et al. (J Immunol Res, 2017), which establishes the state of the art, in HCV infected cells dsRNA replication intermediates are recognized by the cytosolic RNA sensors RIG-I and MDA5, leading to the activation of MAVS. Endosomal dsRNA is recognized by TLR3, leading to the activation of TRIF. MAVS and TRIF signal via the kinases IKK and TBK1, resulting in translocation of the transcription factors NF-κB and IRF3 to the nucleus. Here they trigger the expression of type I and type III IFNs, which are secreted and bind to their receptors in an auto- or paracrine manner (Figure 3). This is further supported in Sato et al. which states “as for the mechanism for the preferential induction of type III IFNs in hepatocytes in response to HBV, as well as HCV…” (page 130, left column, middle of paragraph).
Applicants argue (pages 9-10) that (3) the PAMPs disclosed in Gale and Sato are not interchangeable. It is argued that it was shown in Sato that εRNA was not able to block replication of HCV. It is argued that it was observed that Huh-7.5 cells induced by a vector designed to express εRNA did not how any effect of HCV replication as compared to control (Figure 6B, right).
Regarding Applicants’ third argument, it is not clear to the examiner where it shows in Fig. 6 that the PAMP from Gale would not work to treat HBV infection. Sato et al. teaches that Huh-7.5 cells carry a dominant-negative mutant RIG-I allele that prevents RIG-1 signaling. (page 124, right column, last paragraph). While page 130 states that the εRNA-MEND has specific effect on the replication of HBV but not HCV in Huh-7.5 cells (page 130, right column, last paragraph). And Figure 6b shows HCV replication in Huh-7.5.1/Rep-Feo-1b cells expressing εRNA, as determined by luciferase assay. This just states that the εRNA of Sato et al. would not decrease HCV replication not that the PAMP of Gale would not work with a subject with HBV infection. The examiner maintains since the PAMP of Gale mediates RIG-I and RIG-I mediation is taught as having an effect on both HCV and HBV, one skilled in the art would have been motivated to administer the PAMP of Gale to a subject with an HBV infection as well. Furthermore, even if the εRNA 5’end taught in Sato is required, it isn’t clear to the examiner why it could not be used with the PAMP of Gale. Both the instant claims and Gale merely recite a 5’-arm region comprising a terminal triphosphate. While the εRNA 5’ end would not be efficient in decreasing HCV replication, if one skilled in the art would recognize this and the desire is to treat a subject with HBV replication, then the combination of references and the state of the art would suggest that when desiring to treat an HBV replication a PAMP can be utilized. "where a rejection is predicated on two references each containing pertinent disclosure ... we deem it to be of no significance, but merely a matter of exposition, that the rejection is stated to be on A in view of B instead of on B in view of A, or to term one reference primary and the other secondary." In re Bush, 296 F.2d 491,496 (CCPA 1961).
Applicants argue (pages 10-11) that (4) Dimou does not cure the deficiencies of Gale and Sato.
Regarding Applicants’ fourth argument, the arguments are not persuasive for the reasons set forth above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 23, 25-31 and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9775894 in view of Gale JR. et al. (USPGPUB No. 20180104325, cited on PTO Form 1449) and Sato et al. (Immunity, 2015, cited on PTO Form 1449). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of composition that induces interferon regulatory factor 3 (IRF3) activation in infected cells of the subject. The instant application claims a method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of composition that induces interferon regulatory factor 3 (IRF3) activation in infected cells of the subject, wherein the composition is or comprises a nucleic acid molecule comprising a pathogen-associated molecular pattern (PAMP), wherein the PAMP comprises: a 5'-arm region comprising a terminal triphosphate; a poly-uracil core comprising at least 8 contiguous uracil residues; and a 3'-arm region comprising at least 8 nucleic acid residues, wherein the 5'-most nucleic acid residue of the 3'-arm region is not a uracil and wherein the 3'-arm region is at least 30% uracil residues.
Patent ‘894 claims an isolated nucleic acid molecule with a non-naturally occurring sequence, the isolated nucleic acid comprising: a 5′-arm region comprising a terminal triphosphate; a poly-uracil core comprising at least 8 contiguous uracil residues; and a 3′-arm region comprising at least 8 nucleic acid residues, wherein the 5′-most nucleic acid residue of the 3′-arm region is not a uracil and wherein the 3′-arm region is at least 80% uracil residues, wherein the 5′-arm region and the poly-uracil core do not naturally occur contiguously together in a Hepatitis C virus. The polyuracil core consists of between 8 and 30 uracil residues. The 5′-most nucleic acid residue of the 3′-arm region is a cytosine residue or a guanine residue. The 3′-arm region is at least 90% uracil residues. The 3′-arm region comprises at least 7 contiguous uracil residues. The 5′-arm region further comprises one or more nucleic acid residues disposed between the terminal triphosphate and the poly-uracil core. The nucleic acid molecule is capable of inducing retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. RLR is RIG-I. A pharmaceutical composition comprising the isolated nucleic acid molecule is claimed. The composition further comprises an anti-viral therapeutic. The 5′-arm region consists of the terminal triphosphate, and wherein the terminal triphosphate is linked directly to the 5′-end of the poly-uracil core.
While Patent ‘894 claims an isolated nucleic acid molecule with a structure reading on the claims which activates RIG-I, Patent ‘894 does not claim administration to a subject with an HBV infection. However, these deficiencies are cured by Gale JR et al. and Sato et al.
Gale JR et al. is directed to methods and compositions for activation of innate immune responses through RIG-I like receptor signaling. Claimed is a method of treating a condition in a subject treatable by inducing RLR signaling, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a synthetic nucleic acid pathogen-associated molecular pattern (PAMP), wherein the synthetic PAMP is the same as the instant claims and Patent ‘894.
A specific construct taught is SEQ ID NO: 1:
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As shown in the figures, the Con1 pU/UC (i.e. SEQ ID NO: 1) shows RIG-1 activation (Fig. 1C, 2A) wherein EC10, EC50, EC90 are reported with high signaling (Fig. 2C). Shown in Fig. 5B pU/UC shows IRF-3 activation.
It is taught that various classes of pathogens, such as viruses and bacteria, contain pathogen-associated molecular patterns (PAMPs) in structural or genetic components (paragraph 0005). Fig. 6 demonstrates the antiviral activity of the polyU-UC PAMP RNA constructs (paragraph 0025).
Sato et al. is directed to the RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus (HBV). RIG-I is a key PPR (pattern-recognition receptors) that can detect virus-derived RNAs in the cytoplasm during infection with a variety of viruses. Binding of RIG-I to its ligand ultimately leading to the induction of the IFN regulator factor-3 (IFR-3) and the subsequent production of IFNs and inflammatory cytokines. Thus, RIG-I sensing of viral RNA is a crucial process to activate the antiviral innate responses to limit viral replication and the activation of adaptive immunity (pages 123-124, bridging paragraph). HBV infection predominantly induces type III, but not type I, IFN gene induction, which is mediated by RIG-I through its recognition of the 5’-ε region of pgRNA in an RNA-binding dependent manner, resulting in the suppression of HBV replication. Findings demonstrate the innate defense mechanisms based on the viral RNA-RIG-I interaction, whereby RIG-I functions not only as a HBV sensor for the activation of IFN response but also as a direct antiviral factor (page 124, left column). As is the case with this, several viral PAMPs known to be recognized by RIG-I, for example, the poly-U/UC tract in the 3′ nontranslated region of HCV genome and 5′ terminal region of influenza virus genome were previously reported to be directly or indirectly critical for viral replication. In this respect, one could envisage that such an exquisite targeting by RIG-I would confer a unique machinery to ensure efficient antiviral activities of RIG-I. Therefore, RIG-I is likely to play dual roles as an innate sensor and as a direct antiviral effector for host defense during viral infection (page 130, paragraph bridging left and right columns).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘894, Gale JR et al. and Sato et al. and utilize the PAMP of Patent ‘894 and administer to a patient with an HBV infection in order to activate RIG-I. One skilled in the art would have been motivated to administer the PAMP to this patient population as Sato et al. teaches that RIG-I is both an innate sensor and direct antiviral effector for HBV. Administration of a PAMP, which is taught by Sato et al. as activating RIG-I would therefore be expected to aid in treating the HBV viral infection. As shown by Gale JR et al., the pU/UC shows IRF-3 activation. Therefore, administration of the PAMP of Patent ‘894 with the pU/UC would be expected to induce IRF3 activation.
Regarding claim 24-31, Patent ‘894 recites the same PAMP.
Regarding claim 55, a specific PAMP in Gale JR et al. (which has the structure as taught in Patent ‘894) taught is Con1 pU/UC (i.e. SEQ ID NO: 1) (Db) which is 100% identical to instantly claimed SEQ ID NO: 34 (Qy) as shown in the alignment below.
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Claims 23, 25-31 and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 9 and 11-20 of U.S. Patent No. 10434164 in view of Gale JR et al. and Sato et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘164 claims a method of inducing RLR signaling in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a synthetic nucleic acid pathogen-associated molecular pattern (PAMP), wherein the synthetic PAMP comprises: a 5′-arm region comprising a terminal triphosphate; a poly-uracil core comprising at least 8 contiguous uracil residues; and a 3′-arm region comprising at least 8 nucleic acid residues, wherein the 5′-most nucleic acid residue of the 3′-arm region is not a uracil and wherein the 3′-arm region is at least 80% uracil residues. An increase in IRF3 phosphorylation is claimed. RIG-I is claimed. he poly-uracil core consists of between 8 and 30 uracil residues. The poly-uracil core consists of between 8 and 30 uracil residues. The 3′-arm region is at least 90% uracil residues. The 3′-arm region comprises at least 7 contiguous uracil residues. The 5′-arm region further comprises one or more nucleic acid residues disposed between the terminal triphosphate and the poly-uracil core. The terminal triphosphate, the one or more nucleic acid residues of the 5′-arm region, and the poly-uracil core do not naturally occur together in a Hepatitis C virus. The 5′-arm region consists of the terminal triphosphate, and wherein the terminal triphosphate is linked directly to the 5′-end of the poly-uracil core. Further administering an anti-viral therapeutic is claimed.
While Patent ‘164 claims a PAMP with the same structure as instantly claimed and a method of administering, Patent ‘164 does not claim that the patient has an HBV infection. However, these deficiencies are cured by Gale JR et al. and Sato et al.
The teachings of Gale JR et al. and Sato et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘164, Gale JR et al. and Sato et al. and utilize the PAMP of Patent ‘164 and administer to a patient with an HBV infection in order to activate RIG-I. One skilled in the art would have been motivated to administer the PAMP to this patient population as Sato et al. teaches that RIG-I is both an innate sensor and direct antiviral effector for HBV. Administration of a PAMP, which is taught by Sato et al. as activating RIG-I would therefore be expected to aid in treating the HBV viral infection. As shown by Gale JR et al., the pU/UC shows IRF-3 activation. Therefore, administration of the PAMP of Patent ‘164 with the pU/UC would be expected to induce IRF3 activation.
Regarding claim 24-31, Patent ‘164 recites the same PAMP.
Regarding claim 55, a specific PAMP in Gale JR et al. (which has the structure as taught in Patent ‘164) taught is Con1 pU/UC (i.e. SEQ ID NO: 1) (Db) which is 100% identical to instantly claimed SEQ ID NO: 34 (Qy) as shown in the alignment below.
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Claims 23, 25-31 and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-13 and 19-26 of U.S. Patent No. 11324817 in view of Gale JR et al. and Sato et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘817 claims an isolated nucleic acid molecule with a non-naturally occurring sequence, the isolated nucleic acid comprising: a 5′-arm region comprising a terminal triphosphate; a poly-uracil core comprising at least 8 contiguous uracil residues; and a 3′-arm region comprising at least 8 nucleic acid residues, wherein the 5′-most nucleic acid residue of the 3′-arm region is an adenine residue, and wherein the 3′-arm region is at least 30% uracil residues, wherein the 5′-arm region and the poly-uracil core do not naturally occur contiguously together in a Hepatitis C virus. A method of inducing RLR signaling in a subject, the method comprising: administering to the subject an effective amount of a pharmaceutical composition comprising the isolated nucleic acid is claimed. The poly-uracil core comprises at least 18 contiguous uracil residues. The 3′-arm region is at least 40%, 50%, 60%, or 70% uracil residues. The 3′-arm region comprises a plurality of short stretches of between 2 and 15 contiguous uracil residues with one or more cytosine residues interspersed between the plurality of short stretches. The 3′-arm region is covalently linked directly to the 3′-end of the poly-uracil core. The 5′-arm region further comprises one or more nucleic acid residues disposed between the terminal triphosphate and the poly-uracil core. The nucleic acid molecule is capable of inducing retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. RIG-I is claimed. Further comprising a an anti-viral therapeutic is claimed.
While Patent ‘817 claims a PAMP with the same structure as instantly claimed and a method of administering, Patent ‘817 does not claim that the patient has an HBV infection. However, these deficiencies are cured by Gale JR et al. and Sato et al.
The teachings of Gale JR et al. and Sato et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘817, Gale JR et al. and Sato et al. and utilize the PAMP of Patent ‘817 and administer to a patient with an HBV infection in order to activate RIG-I. One skilled in the art would have been motivated to administer the PAMP to this patient population as Sato et al. teaches that RIG-I is both an innate sensor and direct antiviral effector for HBV. Administration of a PAMP, which is taught by Sato et al. as activating RIG-I would therefore be expected to aid in treating the HBV viral infection. As shown by Gale JR et al., the pU/UC shows IRF-3 activation. Therefore, administration of the PAMP of Patent ‘817 with the pU/UC would be expected to induce IRF3 activation.
Regarding claim 24-31, Patent ‘817 recites the same PAMP.
Regarding claim 55, a specific PAMP in Gale JR et al. (which has the structure as taught in Patent ‘817) taught is Con1 pU/UC (i.e. SEQ ID NO: 1) (Db) which is 100% identical to instantly claimed SEQ ID NO: 34 (Qy) as shown in the alignment below.
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Claims 23, 25-31 and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8 and 14-17 of U.S. Patent No. 12023375 in view of Gale JR et al. and Sato et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘375 claims a pharmaceutical composition, wherein the pharmaceutical composition comprises: an isolated nucleic acid molecule comprising the sequence of SEQ ID NO: 1; and a carrier, wherein the carrier comprises a nanoparticle. The composition further comprises an anti-viral therapeutic. The method of inducing RLE signaling comprising administering to a subject is claimed. An increase in IRF3 phosphorylation and RIG-I is claimed.
While Patent ‘375 claims a PAMP with the same structure as instantly claimed and a method of administering, Patent ‘375 does not claim that the patient has an HBV infection. However, these deficiencies are cured by Gale JR et al. and Sato et al.
The teachings of Gale JR et al. and Sato et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘375, Gale JR et al. and Sato et al. and utilize the nucleic acid of SEQ ID NO: 1 of Patent ‘375 and administer to a patient with an HBV infection in order to activate RIG-I. One skilled in the art would have been motivated to administer the nucleic acid to this patient population as Sato et al. teaches that RIG-I is both an innate sensor and direct antiviral effector for HBV. Administration of a PAMP, which is taught by Sato et al. as activating RIG-I would therefore be expected to aid in treating the HBV viral infection. As shown by Gale JR et al., the pU/UC shows IRF-3 activation. Therefore, administration of the nucleic acid of Patent ‘375 with the pU/UC would be expected to induce IRF3 activation.
Regarding claim 24-31 and 55, Patent ‘375 claims SEQ ID NO: 1 which is 100% identical to instantly claimed SEQ ID NO: 34 (Qy) as shown in the alignment below and possess the structural requirement recited in claims 24-31.
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Claims 36-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9775894; claims 1, 8, 9 and 11-20 of U.S. Patent No. 10434164; claims 1-10, 12-13 and 19-26 of U.S. Patent No. 11324817; claims or 1-4, 6-8 and 14-17 of U.S. Patent No. 12023375 in view of Gale JR et al. and Sato et al. as applied to claims 23-31 and 55 above and in further view of Dimou et al.
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims further comprising administering to the subject a therapeutically effective amount of a nucleoside reverse transcriptase inhibitor (NRTI). The NRTI as elected is entecavir.
The claims of Patent ‘894, ‘164, ‘817 and ‘375 are set forth above.
While Patent ‘894, ‘164, ‘817 and ‘375 all claim further comprising an anti-viral agent, Patent ‘894, ‘164, ‘817 and ‘375 do not expressly claim entecavir. However, that deficiency is cured by Dimou et al.
Dimou et al. is directed to the role of entecavir in the treatment of chronic hepatitis B. Six drugs have been approved for the treatment of chronic hepatitis B and one includes entecavir (page 1077). Entecavir has high anti-HBV potency (page 1085, conclusions).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘894, ‘164, ‘817 OR ‘375; Gale JR et al., Sato et al. and Dimou et al. and additionally administer entecavir with the composition of Patent ‘894, ‘164, ‘817 or ‘375 to patients with a HBV infection. One skilled in the art would have been motivated to administer entecavir as it has high anti-HBV potency and has been approved for treatment of chronic hepatitis B as taught by Dimou et al. One skilled in the art would have a reasonable expectation of success as all Patent ‘894, ‘164, ‘817 and ‘375 claim the composition can be administered with additional therapeutics such as anti-virals.
Response to Arguments
Applicants’ arguments filed December 30 2025 have been fully considered but they are not persuasive.
Applicants argue that claim 23 of the present application recites a method of treating or preventing a hepatitis B virus infection in a subject in need thereof. Patent ‘894 does not claim administration to a subject with an HBV infection; Patent ‘164 does not claim administration to a subject with an HBV infection; Patent ‘187 does not claim administration to a subject with an HBV infection; and Patent ‘375 does not claim administration to a subject with an HBV infection. As explained above, Gale and Sato address fundamentally different viral systems, distinct PAMP structure and different innate immune pathways. Gale and Sato provide no teaching or suggestion that would motivate a skilled artisan to combine their teachings. It is argued that Dimou does not cure these deficiencies.
Regarding Applicants arguments, the arguments are not persuasive for the reasons set forth above.
Conclusion
Applicant's amendment necessitated the new ground(s) 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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636