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 Mar. 6, 2026. Claims 1, 9, 38-39, 42-43, 48-49, 52-53 and 56 are pending and currently examined.
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.
(Previous Rejection - Maintained) Claims 1, 9, 38-39, 42-43, 48-49 and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Jadhav et al. (US 2021/0332365 A1, published on Oct. 28, 2021, claiming priority to US provisional application 62/718,314, filed on Aug. 13, 2018), of record in the previous Office actions, in view of Yeh et al. (PLoS ONE, 2015, 10(4): e0122259).
This rejection is extended to new claim 56.
The amended claims specify that six or more doses of 200 mg siRNA are administered over a period of at least 20 weeks with each dose separated by 4 weeks, and that the PEG-IFNa is administered at a weekly dose of 180 ug.
Jadhav teaches an invention relating to double stranded RNA agents (i.e. siRNAs) targeting the hepatitis B virus (HBV) genome, and methods of using such agents to inhibit expression of one or more HBV genes and methods of treating subjects having an HBV infection or HBV-associated disorder, e.g., chronic hepatitis B infection. See Abstract.
Table 2 Jadhav shows modified nucleotide sequences of GalNAc (L96)-conjugated HBV dsRNAs. Table 2 discloses a dsRNA with duplexID AD-81890 that comprises the same sequences as the ones of the instant claims. See below:
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Jadhav teaches that the dsRNA agent can be administered to the subject at a dose of 0.01 mg/kg to 10 mg/kg, 0.5 mg/kg to 50 mg/kg, or 3 mg/kg to 10 mg/kg; at a dose of 3 mg/kg to 10 mg/kg; or at a fixed dose of 50 mg to 200 mg. See [0050]. Jadhav teaches that, in some embodiments, a dsRNA agent can be administered at a dose of 50 mg to 900 mg. See [0245]. Jadhav teaches that the dsRNA agent can be administered to the subject in two or more doses. See [0052]. Jadhav teaches that the standard duration of therapy is considered 16 weeks. See [0283]. Jadhav teaches that the dsRNA agent can be administered to the subject subcutaneously. See [0051]. Jadhav teaches that patients to be treated may be HBeAg positive or negative. See claims 33-34.
Jadhav teaches that the additional therapeutic agents can be administered, including a reverse transcriptase inhibitor (e.g., Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, or AGX-1009) and an immune stimulator (e.g., pegylated interferon alfa 2a (PEG-IFN-a2a), Interferon alfa-2b, a recombinant human interleukin-7, or a Toll-like receptor 7 (TLR7) agonist). See [0056]. Jadhav teaches that the methods for treatment described therein can also be useful for treating a subject having an HDV infection or an HDV-associated disorder. See [0262]. Jadhav teaches that the disclosure provides compositions that are formulated for organ-specific (e.g., hepatic) intraarterial, intratumoral, intradermal, intravitreal injection, ocular topical, ophthalmic (eye drops), nebulization, ocular topical or other topical routes, suppository, or oral administration. In preferred embodiments, compositions are administered subcutaneously. See [0244].
Jadhav teaches siRNA dose schedules in mouse models. See Example 6 and Table 7 (shown below).
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Q2Wx6 refers to a dosing schedule of once every two weeks for 6 doses. QMx3 refers to a dosing schedule of once every month for 3 doses (equivalent to Q4Wx3).
Accordingly, Jadhav teaches a method of treating chronic HBV infection or an HBV-associated disease in a subject, comprising administering to the subject an siRNA and a pegylated interferon-alpha (PEG-IFNa), as specified in claim 1. However, Jadhav is silent on the claimed siRNA dosing schedule of six or more doses of 200 mg siRNA administered over a period of at least 20 weeks with each dose separated by 4 weeks, and that the PEG-IFNa is administered at a weekly dose of 180 ug. Instead, Jadhav teaches different dosing schedules for the siRNA reagents in a mouse model study.
Yeh teaches a study on pegylated-interferon alpha therapy for treatment-experienced chronic hepatitis B patients. It teaches that a total of 57 treatment-experienced CHB patients at two medical centers were enrolled. All of the patients were treated with Peg-IFN α-2a at 180 μg weekly for 24 or 48 weeks. The hepatitis B serological markers and viral loads were tested every 3 months until 1 year after stopping Peg-IFN therapy. Yeh concludes that Peg-IFN re-treatment is effective for a proportion of HBeAg-positive treatment-experienced patients; it has limited efficacy for HBeAg-negative treatment-experienced patients. Peg-IFN might facilitate HBsAg loss in HBeAg-negative treatment-experienced patients. See Abstract.
Accordingly, teachings of Yeh indicate that Peg-IFN α can be used in the treatment of human chronic HBV infection at a dosage value of 180 μg weekly for more than 20 weeks.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to arrive at the claimed dose, administration schedule and route conditions based on clinical needs or through routine experimental optimization, unless there is evidence that the claimed conditions are critical.
(Previous Rejection - Maintained) Claims 1, 9, 38-39, 42-43, 48-49 and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Sepp-Lorenzino et al. (US 2020/0038506 A1, published on Feb. 6, 2020; PCT filed on Apr. 18, 2018) in view of Maiser et al. (US 2017/0275626 A1, published on Sep. 28, 2017), of record in the previous Office actions, and further in view of Yeh et al. (PLoS ONE, 2015, 10(4): e0122259).
This rejection is extended to new claim 56.
Sepp-Lorenzino teaches an invention relating to methods for the treatment of a subject having an HBV-associated disease using a combination of an RNAi agent that targets HBV and an HBV vaccine. The methods may comprise sequentially administering to the subject having an HBV infection: a) an RNAi agent that inhibits expression of at least three HBV transcripts, wherein the RNAi agent forms a double stranded region; b) a protein-based vaccine comprising a first HBV core antigen (HBcAg) polypeptide, and a first HBV surface antigen (HBsAg) polypeptide; and c) a nucleic acid-based vaccine comprising an expression vector construct encoding a second HBcAg polypeptide, and/or a second HBsAg polypeptide, wherein the second HBcAg polypeptide, and/or the second HBsAg polypeptide, shares at least one epitope with at least one of the first HBcAg polypeptide, and/or the first HBsAg polypeptide. See Abstract.
Sepp-Lorenzino teaches a siRNA embodiment, AD-66810, which comprises a sense strand of 5’-gsusguGfcAfCfUfucgcuucacaL96-3’, and an antisense strand of 5’-usGfsugaAfgCfGfaaguGfcAfcacsusu-3’. See [0390], shown below:
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Here, the sense strand of AD-66810 is identical to the sense strand of the instant invention, while the antisense strand of AD-66810 is identical to the antisense strand of the instant invention except that the (Agn), adenosine-glycol nucleic acid, of the claimed strand is replaced with Af on the antisense strand of AD-66810. On the other hand, Sepp-Lorenzino teaches that the modified nucleotide (Agn) may be included in siRNA of other sequences, e.g., in AD-64105, AD-64107, AD-64020, etc. See Table 3.
Sepp-Lorenzino teaches that the RNAi agent can be administered to the subject at a dose of 0.01 mg/kg to 10 mg/kg; or 0.5 mg/kg to 50 mg/kg; or 10 mg/kg to 30 mg/kg. In certain embodiments, the RNAi agent is administered to the subject at a dose selected from 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, and 30 mg/kg. In some embodiments, a dose of the RNAi agent is administered to the subject about once per week; about one every two weeks; about once every three weeks; about once every four weeks; or a dose of the RNAi agent is administered to the subject not more than once per week; or a dose of the RNAi agent is administered to the subject no more than once every four weeks. See [0015].
Sepp-Lorenzino teaches that the methods may further comprise administration of an immune stimulator to the subject. In certain embodiments, the immune stimulator is selected from the group pegylated interferon alfa 2a (PEG-IFNalpha-2a), Interferon alfa-2b, PEG-IFN-alpha-2b, Interferon lambda a recombinant human interleukin-7, and a Toll-like receptor 3, 7, 8 or 9 (TLR3, TLR7, TLR8, TLR9) agonist, a viral entry inhibitor, Myrcludex, an oligonucleotide that inhibits the secretion or release of HBsAg, REP 9AC, a capsid inhibitor, Bay41-4109, NVR-1221, a cccDNA inhibitor, IHVR-25) a viral capsid, an MVA capsid, an immune checkpoint regulator, an CTLA-4 inhibitor, ipilimumab, a PD-1 inhibitor, Nivolumab, Pembrolizumab, BGB-A317 antibody, a PD-L1 inhibitor, atezolizumab, avelumab, durvalumab, and an affimer biotherapeutic. See [0041]. Sepp-Lorenzino teaches that nucleot(s)ide analog selected from the group consisting of Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (TAF), Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, AGX-1009, emtricitabine, clevudine, ritonavir, dipivoxil, lobucavir, famvir, FTC, N-Acetyl-Cysteine (NAC), PC1323, theradigm-HBV, thymosin-alpha, and ganciclovir, besifovir (ANA-380/LB-80380), and tenofvirexaliades (TLX/CMX157) may also be included in the treatment. See claims 62- 63.
Accordingly, Sepp-Lorenzino teaches a method of treating an HBV-associated disease comprising administering to a subject in need an siRNA and a pegylated interferon alpha. It teaches that siRNA used in the treatment can be identical in sequence to the one as claimed in the instant invention, except for the difference of one modification in the antisense strand – Af in place of (Agn).
Maiser teaches an invention relating to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The dsRNAs may comprise various modifications. See Abstract. Maiser teaches designs of modified RNA sequence comprising glycol nucleic acid (Agn) or (Tgn) at various locations (almost all possible locations). See table on pages 98-102. Teachings of Maiser suggest that the placement of (Agn) can be tested and optimized through routine experimentation.
Yeh teaches a study on pegylated-interferon alpha therapy for treatment-experienced chronic hepatitis B patients. It teaches that a total of 57 treatment-experienced CHB patients at two medical centers were enrolled. All of the patients were treated with Peg-IFN α-2a at 180 μg weekly for 24 or 48 weeks. The hepatitis B serological markers and viral loads were tested every 3 months until 1 year after stopping Peg-IFN therapy. Yeh concludes that Peg-IFN re-treatment is effective for a proportion of HBeAg-positive treatment-experienced patients; it has limited efficacy for HBeAg-negative treatment-experienced patients. Peg-IFN might facilitate HBsAg loss in HBeAg-negative treatment-experienced patients. See Abstract.
Accordingly, teachings of Yeh indicate that Peg-IFN α can be used in the treatment of chronic HBV infection at a dosage value of 180 μg weekly for more than 20 weeks.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Sepp-Lorenzino, Maiser and Yeh to arrive at the invention as claimed. One would have been motivated to do so to introduce the (Agn) into the modified siRNA AD-66810 of Sepp-Lorenzino to modify the function of the siRNA agent. As to the claimed position the (Agn) in the antisense strand of siRNA AD-66810, one of skill in the art would have found it obvious to arrive at it through routine experimental optimization. As to the additional limitations about dose, administration schedule and route, one of skill in the art would have found them obvious to arrive at them based the teachings of the cited prior art references as well as on experimental or clinical needs or through routine experimental optimization, unless there is evidence that the claimed conditions are critical.
Regarding claims 48-49 and 52-53, one of skill in the art would have found it obvious to apply the treatment methods suggested by Sepp-Lorenzino and Maiser to any HBV-associated diseases, including conditions with positive or negative HBeAg as well as HBV-associated HDV infection, as long as the methods are effective.
Response to Applicant’s Arguments
Applicant’s arguments filed on Mar. 6, 2026 have been fully considered and addressed as follows.
To the 103 rejections, Applicant argues that the cited references, taken alone or in combination, fail to teach or suggest the claimed subject matter, and that the method recited in present claim 1, as amended, yield superior and unexpected results. Applicant argues that the references describe several different dose amounts and administration schedules but do not provide a specific motivation to choose and combine the amounts and frequencies and length of administration recited in the claims, or teach that the features of present claim 1 would lead to superior results.
Applicant refers to a post-filing publication, Yuen et al., arguing that improved results were observed in cohorts receiving the siRNA specified in claim 1 at 200 mg every 4 weeks and PEG-IFNa at 180 ug weekly, for at least 20 weeks. Applicant argues that HBsAg loss was observed in cohorts receiving the siRNA and PEG-IFNa for at least 20 weeks, at 200 mg every 4 weeks and 180 ug weekly, respectively (cohorts 3, 4, and 5), and that HBsAg loss was more pronounced in these cohorts that in cohorts receiving this combination treatment for a shorter period of time (cohorts 2 and 6) or receiving siRNA monotherapy (cohort 1), referring to Table 4 of Yuen. Applicant argues that Yeh in particular indicated that they found no relationship between duration of therapy and treatment response (Yeh at page 10), so the recited number of doses administered and treatment duration time would not be predicted or expected based on Yeh. Applicant argues that Yuen also provides evidence that the method recited in claim 1 is associated with HBsAg seroconversion, and likely long-term control of HBV levels, referring to results in Table 3 and Figure 2B. Applicant argues that Yeh describes lower success in treating HBeAg-negative patient with PEG-IFNa monotherapy, even at longer durations than the minimum duration in present claim 1, and that therefore, Yeh teaches that efficiency in HBeAg-negative subjects is more unpredictable and challenging to achieve. Applicant argues that, in contrast, Yuen found that among HBeAg-negative patients receiving siRNA and PEG-IFNα for up to 48 weeks, HBsAg seroclearance was achieved in 17% (cohort 4) and 15% (cohort 5) within the treatment period (see Yuen at Table 4), and that the Yuen data demonstrate that the claimed method can achieve clinically meaningful results in this patient subpopulation, further underscoring the unexpectedness of these results.
Applicant’s arguments are not persuasive.
Regarding Applicant’s argument that the cited references do not provide a specific motivation to choose and combine the amounts and frequencies and length of administration recited in the claims, both Jadhad and Sepp-Lorenzino teach ranges of siRNA amounts that can be used encompassing the amount recited in the present claims (i.e. a fixed amount of 200 mg/dose). Additionally, Jadhad teaches various siRNA administration schedules, such as Q2Wx6 and QMx3, to be used in mouse model studies, indicating that the administration regimens of 6 doses (Q2Wx6) or 4-week intervals (QMx3) have been used. One of skill in the art would have found it obvious to optimize the dose amount and administration schedule for a specific study through routine experimentation. It is not required that the cited references must teach or suggest combination of prior arts as long as there is a rationale to support a conclusion of obviousness. See MPEP 2143.
As to applicant’s arguments about unexpected results, as an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established.
Here, Applicant presents arguments that siRNA and PEG-IFNa combination therapy produces better results than an siRNA monotherapy, and that longer therapy duration or more doses produce better results than shorter duration or less doses. Both Jadhad and Sepp-Lorenzino teach that siRNA therapy can be combined with other therapies, including a PEG-IFNa therapy (see discussion in the rejection body above), suggesting that such a combination therapy is expected to improve the siRNA monotherapy. Additionally, Jadhad teaches administration regimens of Q2Wx6 and QMx3, indicating that a six-dose regimen and a one dose per 4-week interval are practiced and evaluated. One of skill in the art would have reasonably expected that increase in doses on the basis of the QMx3 disclosed in Jadhad to QMx6, as claimed, would improve the effect on HBsAg reduction (seroconversion). Indeed, a decrease in the therapeutic effect caused by increasing the number of doses, when the HBsAg level can still be reduced, would be unexpected, not the other way around.
Conclusion
No claims are allowed.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671