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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/18/2025 has been entered.
Election/Restrictions
Claims 1, 14, 16, 28-32, 34, 47-51, 53-60 are pending and examined here, along with the species of a first RNAi agent, SEQ ID NO: 126 and 252; a second RNAi agent, SEQ ID NO: 140 and 262 (the only remaining SEQ ID NOs in amended claims); NAG37(s) as targeting ligand, 5’ end for targeting conjugation, and chronic HBV infection.
Priority
The claim to benefit of Provisional Applications 62/802,614 and 62/853,659, filed on 02/07/2019 and 05/28/2019, respectively, via a CON of PCT/US2020/017264, filed on 02/07/2020, is recognized.
Information Disclosure Statement
The information disclosure statements submitted on 08/18/2025 was filed before the mailing date of this Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Objection of duplication for claim 58 is withdrawn, since amends it to depend on a different claim.
Objection of claim 1 is withdrawn regarding spaces.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 14, 16, 28-32, 34, 47-51, 53-59 is maintained, while the new claim 60 is rejected as noted below.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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 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 1, 14, 16, 28-32, 34, 47-51, 53-59, and 60 are rejected under 35 U.S.C. 103 as being obvious over Li et al. (WO2018027106A2, pub. 02/08/2018, in IDS, referred as Li) and Wooddell et al. (2017, Science Translational Research, 9, pg. 1-11, of Assignee, but outside the one year grace period).
The applied reference of Li has a common Assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding instant Cl. 1, 28, 49-51, 53-54, 59, Li discloses a method for treating Hepatitis B virus (HBV) infection and a disease associated with HBV infection in a subject, comprising administering RNA interference (RNAi) agents, wherein the first RNAi agent is AD04872 and the second RNAi agent is AD05070 (claims 35, 24). SEQ ID NO: 252 and its complementary sequence SEQ ID NO: 126 are provided by their sequences enumerated in a structural format on pg. 43-47 as a compound designated as AD05070; SEQ ID NO: 262 and its complementary sequence SEQ ID NO: 140 are provided by their sequences enumerated in a structural format on pg. 68-72 as a compound designated AD04872 (relevant to instant cl. 1). Further, SEQ ID NOs: 262 and 252, each have a NAG37 structure conjugated to an inverted abasic nucleotide at its 5 ‘end. A subject includes humans (pg. 84, line 7, relevant to instant cl. 1). Li discloses various dosage ranges for the RNAi agent ranging from 0.1 mg/kg to about 100 mg/kg of body weight/day and indicates that amount administered will depend on variables, such as overall health status, relative biological efficacy, formulation, route of administration, etc. . . (see generally pg. 141 for various dose ranges, lines 5-15). Further, in a mice study, RNAi agents were administered weekly (i.e. 7 day intervals). The results of treatment individually with AD04872 (Group 2) or with AD05070 (Groups 3, 4, and 5) are provided in Table 36 for a serum viral marker, HBsAg, showing a decrease in HBsAg levels (see below):
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Li does not disclose the treatment of humans in specific day intervals nor administration of a combined amount of 50-200 mg per dose at one month or 28-day intervals (cl. 1, 53); or administration of doses recited in claims 49-51 and 59 (combined dose of 50, 100, 200 mgs at a 2:1 ratio for 1st and 2nd RNAi agents); or of duration of at least 18 wk. or up to 6 m. (cl. 54, 28).
Wooddell discloses a clinical trial of a RNAi-based treatment of chronically infected HBV patients and chimpanzees (title, abstract, pg. 1). The study discloses patients treated at various doses 1, 2, 3, 4 mg/kg, with one cohort receiving multiple doses 2-week apart (pg. 2). The RNAi therapeutic ARC-520 used for treatment of chronic HBV infection comprises liver-tropic cholesterol conjugated siRNAs siHBV-74 and siHBV-77 and each target a different region of the HBV virus mRNA (pg. 2, 2nd full paragraph). Thus, similarly, there were two RNAi agents in the ARC-520 compound. A chimpanzee study discloses administering in a 28-day interval for up to 225 days (see Fig. 2B-2F, “Dosing days are indicated by vertical dashed lines”, pg. 4) (relevant to cl. 1, 28, 49-51, 53, 54, 59). The study showed that continuous administration of the ARC-520 treatment over 225 days resulted in a steady decline of HBV DNA in serum (Fig. 2B). Study also includes a treatment of up to 169 days (see Fig. 2F, relevant to instant cl. 28).
MPEP 2144.05(II) provides that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, both Li and Wooddell indicate testing various dose ranges to identify optimal range is considered a part of routine experimentation known in the art and, further, one purpose of a clinical trial is to identify workable and/or optimal dose range (relevant to instant cl. 1, 28, 49-51, 53-54, 59).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the doses and time intervals between doses of the RNAi agents of Li in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. Because here Wooddell discloses a positive results of a clinical trial/trial where different doses and time-interval of RNAi agents targeting HBV were tested on primates, including humans, with chronic HBV infection, and Li uses similar RNAi agents to treat HBV infection, one of ordinary skill in the art would have been motivated to modify the doses and time intervals of RNAi agents of Li to test various doses and time intervals as provided by Wooddell and would successfully result in identifying an optimal dose range to treat a human subject with chronic HBV infection. Thus, the claims 1, 28, 49-51, 53-54, 59 are obvious.
Regarding instant claim 14, Li discloses the ratio of AD04872 to AD05070 administered to a subject in need thereof is about 2: 1 (pg. 39, line 12-13); group 4 above shows a substantial decrease at a 2:1 ratio.
Regarding instant claims 16, 55-57, Li discloses the pharmaceutical composition administered via subcutaneous injection (pg. 83, line 29-30, relevant to instant cl. 16); discloses pharmaceutical composition is a sterile injectable solution (pg. 139, line 13, relevant to instant cl. 55), discloses a sterile powder for the extemporaneous preparation of sterile injectable solutions (pg. 139, line 14, relevant to instant cl. 56); discloses packaging in a pre-filled syringe or a vial (pg. 141, line 25, relevant to instant cl. 57).
Regarding instant claims 29-32, 34, 58, Li discloses combining additional therapeutics, such as entecavir (pg. 83, line 9-13), and notes “Entecavir administration was expected to reduce serum HBV DNA in chronically infected human patients” (pg. 185, line 19).
Instant claim 32 recites the results of administration of the composition of claim 1 and is inherent property of the structure of composition of claim 1. Thus if prior art discloses the same composition, it will also have the inherent property/characteristics. Here Li discloses the composition of claim 1, thus its inherent property would be to reduce the level of HBsAg, HBeAg or serum HBV DNA by at least 40% in a human subject.
Li does not specifically disclose a treatment to a human subject.
Wooddell discloses a clinical trial of chronic hepatitis B human patients receiving entecavir long-term (pg. 2, relevant to instant cl. 29-31, 34, 58). Further one chimpanzee “4x0139” was given both entecavir and tenofovir to further reduce viral load in this chimpanzee with a highly replicative HBV (pg. 9).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have combined the RNAi agent combating HBV of Li in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the treatment of RNAi agent targeting HBV mRNA to reduce HBV levels of Li with treatment of entecavir and/or tenofovir to reduce HBV viral load of Wooddell and would successfully result in reduction of serum HBV DNA in chronically infected human patients. Thus, claims are 29-32, 34, 58 are obvious.
Regarding instant claims 47 and 48, Li discloses the sequence structural formula of AD04872 (pg. 68-72) and AD05070 (pg. 43-47) in sodium salt forms.
Regarding instant cl. 60, Li discloses the free acid forms of AD05070 (pg. 53-57, along with structure) and AD04872 (pg. 78-82).
Thus, claims 1, 14, 16, 28-32, 34, 47-51, 53-59, 60 are rejected under 103.
Response to Arguments
Applicant's arguments filed 08/18/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks insist, similar to the argument in prior action, that a skilled artisan “would not have arrived at the dosing regimen recited in claim 1” based on the references of record (pg. 30) and the use of MPEP 2144.05(II), cited by the Examiner, is “misplaced” and cannot be used to establish a prima facie case since the dosing regimen of claim 1 cannot be obtained through optimization (pg. 19, 30) and base this insistence on noting detailed differences between Li and Wooddell, indicating that Action mis-understood Wooddell, and citing exhibits and several cases (PTAB, CFAC) discussing dosing and, suggest unexpected results, as noted below.
The Remarks urge the following:
dose optimization is not “routine optimization” (pg. 19);
Wooddell does not cure Li’s deficiencies due to substantial differences because:
Li and Wooddell are “directed to different pharmaceutical composition with different RNAi active agents that target different mRNA sequences” and Wooddell “received a treatment regimen that was entirely different from the presently claimed method” and non-human model is not adequate to predict “treatment responses in humans” (pg. 20);
Wooddell’s ARC-520 is a cholesterol-conjugated RNAi comprising equimolar of siHBV-74 and siHBV-77 with a delivery excipient containing hepatocyte-targeted GalNAc-conjugated peptide and both target the X ORF of HBV genome; while instant siRNA product comprises a GalNAc structure and has a different siRNA sequences targeting a different region of the HBV genome, each targeting a X ORF and S ORF (pg. 21);
there are differences between the dosing of human subjects of instant claimed invention and chimpanzee of Wooddell (pg. 21-22) and thus suggests it is an “incorrect equivocation;” Wooddell human given only a single dose of ARC-520 composition and would have looked at only human dosing and not chimpanzee dosing frequency (pg. 22);
citing Exhibit E, the Remarks suggest that “dosing is one of the primary reasons why experimental drugs fail in phase 2 clinical trials” (pg. 23);
pointing to Wooddell’s “human clinical trial described in Wooddell was not successful” (pg. 24);
citing a PTAB Marom case, addressing unpredictability of dose optimization, the Remarks insist that there is no reasonable expectation of success. The PTAB in Marom reversed an Examiner’s rejection, which noted that it is well known in the medical art that the goal of clinical trial was to optimize a dose for safety and efficacy, so routine optimization could have been used based on the cited references (pg. 25); the Board dismissed the Examiner’s obviousness finding because there was no reasonable expectation of success (pg. 25). In this action, the Remarks suggest that the Examiner relies on doses for a different combination of RNAi agents (pg. 25) and is contrary to In re O’Farrell, which explicitly cautioned against finding a claimed invention obvious when it was merely “obvious to try” (pg. 26);
that the presumption set forth in MPEP 2144.05(II) should not be applied to the claimed invention (pg. 26) and suggests that the Action “has not demonstrated” that determining recited dose is “routine experimentation” (pg. 26);
Citing Federal Circuits that have addressed “overlapping-range cases” and directs for application of “the normal full obviousness analysis, rather than a truncated version based on the invoked presumption” (pg. 21 of case), the Remarks argue that presumption is not sufficient or is improper (pg. 27-28);
that the application provides unexpected results (pg. 29-30).
The argument is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, the Remarks provide a detailed analysis of Wooddell being insufficient to cure shortcomings of Li but, respectfully, do not provide sufficient basis for why Li would not apply. Under the requirement for 103 rejection, the Li reference would be sufficient along with the presumption of obviousness provided under MPEP 2144.05 (both MPEP 2144.05(I), overlapping, approaching, and similar ranges; and 2144.05(II)). Li reference claims both (1) the exact first RNAi agent and second RNAi agent (cl. 16, 24) as instant application and (2) the effective amount of the first RNAi agent is between about 0.5 mg/kg and about 5 mg/kg, and same for second RNAi agent (cl. 46; if the weight of individual, e.g., is 70 kg, the total dose ranges from 35 mg to 350 mg, respectively; instant claimed dose range is 50-200 mg, or). The instant dose ranges of 50-200 mg per dose (along with dependent claims 65mg-1st/35mg-2nd, or 133mg-1st/67mg-2nd) are within the dose ranges of Li. One study provides (Ex. 18) dose at day 1 and day 29, also within the range of administering at one month interval. Thus, this is sufficient for a 103 rejection of claim 1 along with presumption of obviousness provided under MPEP 2144.05. Further, Li provides sufficient exemplary rationale supporting the rejection. Li also notes that administration can be human subject, and a skilled artisan would reasonably expect success based on extensive non-human examples provided. Thus, Li’s disclosure along with presumption of obviousness under MPEP 2144.05 meets the reasonable standard for a 103 rejection, i.e., a reasonable expectation of success by a skilled artisan.
Thus, for the reason noted above, the Examiner cannot disregard or ignore the MPEP and is required to follow the guidance of and apply the MPEP as required. However, the action also adds a secondary reference of Wooddell to fully support the obviousness and other clinical trial references (not cited in this action but in prior action).
Now to the Wooddell reference, the Remarks provide a detailed analysis of differences between Wooddell and Li reference, and therefore Wooddell is not sufficient to support a 103 rejection, as noted above. To be clear the Wooddell reference provides support that it is routine in the field of discovery of anti-viral therapy to administer different doses and test various time points to a subject. Here, Wooddell reference provides exemplary support of different doses/time-intervals, thus the action did not attempt to “incorrectly equivocate” the composition, even if the composition are different. Similar to instant invention, Wooddell tests two different siRNAs targeting two different regions of the HBV gene in humans chronically infected with HBV (i.e. instant cl. 1), and both siRNAs of Wooddell are in a delivery excipient with Gal-NAc moieties for delivery to the liver (i.e. similar to GalNAc moieties (NAG37) conjugated to the siRNAs), along with testing different time points and doses in humans (relevant to claims reciting doses/time intervals); thus Wooddell is an analogous art to instant claimed invention and applied as a secondary reference under the flexible approach to obviousness, provided by the Supreme Court in Graham, despite the noted differences.
Further, all evidence relevant to the question of obviousness must be considered, including treatment of non-human animal subjects. Wooddell, which shares co-inventors with instant application, suggesting a molecular genetics study of HBV in chimpanzee to understand the ARC-520 differential response that can be applied “potentially by extension in HBeAg-positive and HBeAg-negative humans” (pg. 4), explicitly indicates that the conclusion of studies in chimpanzees can apply to humans due to the similarity in physiological response to the siRNA treatment(s). Thus, a skilled artisan would seek the guidance of Wooddell in determining the timing of the doses and the dose.
Further, the issue raised in Wooddell is not of dosing or time intervals of the dosing. In fact Wooddell provides: “[t]he lack of robust HBsAg knockdown was unlikely due to inherent RNAi inefficiency or lack of ARC-520 efficacy in the CHB patients, as evidenced by measuring knockdown of other viral parameters” (pg. 2). The issue is rather to a different, non-relevant to dosing, matter: it is the source of HBV antigens: whether they are from an integrated HBV into the host genome or non- integrated HBV, i.e. an episomal covalently closed circular DNA (cccDNA) virus state (which is not relevant to the instant dosing issue). If the Remarks, on pg. 24, quoted the Wooddell language completely, it would point out the issue: “The differential response to RNAi therapeutic ARC-520 reflected in the lower magnitude of HBsAg knockdown in HBeAg-negative or NUC-experienced HBeAg-positive CHB patients in comparison to NUC-naïve HBeAg-positive CHB patients could not have been predicted based on current models, which assume that cccDNA is the only significant source of HBV transcripts (emphasis added of the language removed in the quote). Further discussion of Wooddell is discussed below, in unexpected results.
Regarding the PTAB Marom case (the correct Proceeding # is provided: Ex Parte Marom NO. 2024-001947 (pg. 25)), the distinguishing facts are that Marom claimed a single dose and a specific weight ratio of about 1:11.5 (see pg. 10 of Proceeding), while the instant claims recite a broad range of 50-200 mg of combination of first and second RNAi agents. Further, the Board provided that the secondary reference taught only a single, higher dose and no teaching why it would be cut in half (pg. 10). Here, Wooddell provides the time ranges for the dosing and different ranges of doses recited in the claims. Thus, here the primary and secondary references both make the dependent claims obvious too, since the dependent claims recite specific 1st and 2nd RNA doses; the primary and secondary references of the Action disclose the routine optimization of time intervals of doses/range of doses by exemplary evidence, which the primary reference in PTAB Marom case did not.
Regarding the CAFC Janssen case, the Court provides that “In these circumstances, we hold that the proper course at present is to apply the normal full obviousness analysis, rather than a truncated based on the invoked presumption” (pg. 21 of Janssen). Both in the prior Action and in this Action, a full obviousness analysis is provided and explanation of why it applies. The Remarks point to the non-binding statements/observations of the case, while the response here provides the holding of the Court and notes that the holding is followed in the action.
Regarding Exhibit E, noting “dosing is one of the primary reasons why clinical trials fail,” the Table only provides that either too high or too low dosing as the rationale (see Table I, pg. 686, of Exh. E). The Examiner would agree with that observation, since “too low or too high” are presumably extreme outliers and here the claimed dose ranges are not outliers relative to the ranges referred within the prior art of record.
Regarding unexpected results, the Remarks, citing Ex. 19-21, note that “unexpected results are more than a difference in a ‘degree’ compared to the prior art, but are so meaningfully different that the results are different in ‘kind’ compared to the prior art,” because “it demonstrates efficacy across patient populations [HBeAg-positive chronic HBV infection, HBeAg-negative chronic HBV infection] that were resistant to treatment with ARC-520 [of Wooddell]” (pg. 29, 30). This is unpersuasive because, first, the siRNA targets HBV virus regardless of the patient type. Second, the patient type is also not claimed (the unexpected results have to be in commensurate in scope with claimed invention). Third, as pointed out by the Remarks, ARC-520 only targets the X ORF, while Li’s products, like instant claimed subject matter, targets both S ORF and the X ORF of HBV (pg. 23). This was the “surprising finding” of Wooddell, which suggested, based on their results in Fig. 4-6:
Our finding that integrated HBV DNA can serve as a source of HBsAg has implications for design of next-generation antivirals to treat CHB. For example, that HBsAg appears to be produced from integrated HBV DNA rather than solely from cccDNA implies that eliminating cccDNA will likely not eliminate HBsAg. Immune control that prevents reinfection and allows clearance of the virus remains the desired endpoint. Loss of HBsAg is the more relevant biomarker of immune control. This is likely the case whether the HBsAg is produced from cccDNA or from integrated HBVDNA. (Underline added to emphasize the suggestion that siRNAs should target HBsAg, i.e. the S antigen/ORF, and here the ADO4872 (SEQ ID NO: 140/262) targets the S ORF.)
Thus, S ORF (i.e. the HBsAg) of HBV also needs to be targeted. Fig. 6 of Wooddell, see below, clearly points out the results of siHBV-75 treatment (which as noted in Exhibit D, Fig. 3, targets the S ORF).
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Wooddell notes that “[w]e tested the hypothesis that the reason for less efficient ARC-520–mediated HBsAg reduction in HBeAg-negative chimpanzees was due to loss of ARC-520 siRNA target sites in the mRNA encoding their HBsAg” and the results demonstrated that the HBsAg was reduced after each of the three successive siHBV-75 doses in 88A010 and 95A010, respectively (Fig. 6), and these reductions demonstrated that HBsAg could be just as effectively reduced by RNAi in the HBeAg-negative chimpanzees as in the HBeAg-positive chimpanzees (pg. 7). Thus, the results across patient-types are expected, as demonstrated by Wooddell.
Thus, the rejection is maintained.
Double Patenting
The rejection of claims 1, 14, 16, 28-32, 34, 47-51, 53-55, 57, 58 and 59, 60 is maintained.
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.
US10780108
Claims 1, 14, 16, 28-32, 34, 47-51, 53-55, 57-59, 60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 14, 15, 18, 21, 23, 24, 25, 36, 38, 39 of U.S. Patent No. US10780108 (issued 09/22/2020, in IDS) to Arrowhead (referred as Arrowhead) in view of Wooddell et al. (2017, Science Translational Research, 9, pg. 1-11, also of Assignee, but outside the one year grace period).
Regarding instant claim 1, 28, 34, 49-51, 53-54, 59:
Arrowhead teaches in claim 1: A composition comprising an RNAi agent for inhibiting expression of a Hepatitis B Virus (HBV) gene, wherein the RNAi agent comprises: an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:100, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:171, SEQ ID NO:179, and SEQ ID NO:180, and a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:229, SEQ ID NO:252, SEQ ID NO:253, SEQ ID NO:273, SEQ ID NO:302, and SEQ ID NO:319; claim 12 teaches comprising a pharmaceutically acceptable excipient; and claim 21 teaches a method for inhibiting expression of a Hepatitis B Virus (HBV) gene in a subject that has an HBV infection, the method comprising administering to the subject an effective amount of the composition of claim 1 to inhibit an HBV gene, claim 23 teaches the method of claim 21, wherein the composition comprises a first RNAi agent and a second RNAi agent, wherein the first RNAi agent and the second RNAi agent are each independently conjugated to a targeting ligand that includes N-acetyl-galactosamine, and the first RNAi agent has the duplex structure of AD04872 (SEQ ID NO:126 and SEQ ID NO:252) and the second RNAi agent has the duplex structure of AD05070 (SEQ ID NO:140 and SEQ ID NO:262); and claim 24 teaches the method of claim 23, wherein administering the composition further treats a disease, disorder, or condition associated with the HBV infection in the subject.
Arrowhead claims do not claim the treatment of humans in specific day intervals nor administration of a combined amount of about 50-200 mg per dose at one month or 28-day intervals (cl. 1, 53); or administration of doses recited in claims 49-51 (combined dose of 50, 100, and 200 at a 2: 1 ratio for 1st and 2nd RNAi agents); or specific duration (cl. 28, 54).
Wooddell discloses a clinical trial of a RNAi-based treatment of chronically infected HBV patients and chimpanzees (title, abstract, pg. 1, relevant to instant cl. 1, 34 and 58). The study discloses patients treated at various doses 1, 2, 3, 4 mg/kg, with one cohort receiving multiple doses 2 week apart (pg. 2). The RNAi therapeutic ARC-520 used for treatment of chronic HBV infection comprises liver-tropic cholesterol conjugated siRNAs siHBV-74 and siHBV-77 and each target a different region of the HBV virus mRNA (pg. 2, 2nd full paragraph). Thus, similarly, there were two RNAi agents in the ARC-520 compound. A chimpanzee study discloses administering in a 28-day interval for up to 225 days (see Fig. 2B-2F, “Dosing days are indicated by vertical dashed lines, pg. 4) (relevant to cl. 1, 28, 49-51, 53-54, 59). The study showed that continuous administration of the ARC-520 treatment over 225 days resulted in a steady decline of HBV DNA in serum (Fig. 2B). Study also includes a treatment of up to 169 days (see Fig. 2F, relevant to instant cl. 28).
MPEP 2144.05(II) provides that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, both Wooddell and Arrowhead indicate testing various dose ranges to identify optimal range and duration as a routine experimentation known in the art, and, further, one purpose of a clinical trial is to identify workable and/or optimal dose range (relevant to instant cl. 1, 28, 49-51, 53-54, 59).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the doses and time intervals between doses of the RNAi agents of Arrowhead in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the doses and time intervals of RNAi agents of Arrowhead to test various doses and time intervals to determine optimal or workable dosage ranges as taught by Wooddell and would successfully result in identifying an optimal dose range to treat a human subject with chronic HBV infection. Thus, claims 1, 28, 34, 49-51, 53-54, 59 are obvious.
Regarding instant claim 14, Arrowhead claim 18 teaches the composition of claim 17, wherein the ratio of the first RNAi agent duplex (AD04872) to the second RNAi agent duplex (AD05070) in the composition is about 2:1.
Regarding instant cl. 29-31, Arrowhead claim 36 teaches the method of claim 21, further comprising administering to the subject one or more additional therapeutics, and claim 38 teaches the method of claim 36, wherein the one or more additional therapeutics comprises lamivudine, tenofovir, tenofovir alafenamide, tenofovir disoproxil, or entecavir.
Arrowhead claims do not specifically disclose a treatment of entecavir or tenofovir to a human subject.
Wooddell discloses a clinical trial of chronic hepatitis B patients receiving entecavir long-term (pg. 2). Further one chimpanzee “4x0139” was given both entecavir and tenofovir to further reduce viral load in this chimpanzee with a highly replicative HBV (pg. 9).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have combined the treatment of RNAi agents combating HBV of Arrowhead in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the treatment of RNAi agent targeting HBV mRNA of Arrowhead with treatment of entecavir and/or tenofovir for chronic HBV infection of Wooddell and would successfully result in reduction of serum HBV DNA in chronically infected human patients. Thus claims 29-31 are obvious.
Regarding instant cl. 32, Arrowhead claim 25 teaches the effective amount of composition is sufficient to reduce the level of HBsAg, HBeAg, and/or serum HBV DNA, in a subject by at least about 40% relative to the subject's respective expression level prior to administration of the composition.
Regarding instant claims 55, 57, Arrowhead claims do not teach sterile injectable solution nor the pharmaceutical composition packaged in a pre-filled syringe or vial.
Wooddell discloses in Supplemental Material (pg. 4) of supplying the ARC-520 as two sterile 10-mL vials, which are mixed by the pharmacist and administered to a subject for treatment.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the pharmaceutical composition of RNAi agent of Arrowhead in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the pharmaceutical composition of RNAi agent of Arrowhead as a sterile injectable solution in vials taught by Wooddell and would expect a successful result in ease of administering the RNAi agent to a human patient for treatment. Thus, claims 55, 57 are obvious.
Regarding the Arrowhead claims 1, 12 limited only to compositions comprising the recited oligonucleotides, the instant method claims 16, 48, 60 are considered obvious over these claims in view of the findings of the court in Sun Pharmaceutical Industries, Ltd. v. Eli Lilly & Co., No. 10-1105 (Fed. Cir. July 28, 2010) in which the court indicated that obviousness-type double patenting encompasses any use for a compound where that use is disclosed in the specification of an earlier patent claiming the compound and is later claimed as a method of using that compound. Thus the invention as a whole was prima facie obvious.
Regarding claim 16, Arrowhead teaches HBV RNAi agent(s) are administered to a subject in need thereof via subcutaneous injection (Col. 85, line 1-3).
Regarding instant cl. 47, 48, 60 Arrowhead teaches, in Col. 61 (bottom) to Col. 67, AD04872 linked to (NAG37)s as a sodium salt structure and teaches, in Col. 30, line 40 to Col. 34, line 25. AD05070 linked to (NAG37)s shown as a sodium salt structure. Further, a specification can be used for definitional purposes to define a term, e.g. here AD04872 and AD05070.
Claim 56 rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. No. US10780108 to Arrowhead (referred as Arrowhead) in view of Wooddell et al. (2017, Science Translational Research, 9, pg. 1-11, also of Assignee, but outside the one year grace period) for claims 1, 16, and further in view of Hiwale et al. (2008, Pharmaceutical Technology, 32).
Teachings of Arrowhead and Wooddell are noted above.
Arrowhead and Wooddell do not teach pharmaceutical composition is a sterile powder for a preparation of a sterile injectable solution.
Hiwale et al. disclose that certain drugs in aqueous environment are unstable, even when exposed for a short duration, thus requiring packaging, storage and shipping in a powder or lyophilized state to keep the product stable during its shelf life (par. 1, pg. 1). Hiwale et al. note reconstituting the PI drug by a sterile water diluent (par. 1, pg. 2). Further it is obvious for one of skill in the art for administering sterile substances to a human subject due to the concern for patient safety and preventing side effects due to administration of a contaminated product.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the pharmaceutical composition comprising RNAi agents of Arrowhead in view of Hiwale et al. and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the pharmaceutical composition comprising RNAi agents of Arrowhead as a lyophilized powder and then prior to use reconstitute with sterile water as taught by Hiwale et al. and would successfully result in keeping the product stable during its shelf-life. Thus, claim 56 is obvious.
US11517584B2
Claims 1, 14, 16, 28-32, 34, 47-51, 53-57, 58, 59, 60 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 16, 17, 18, 19, 20, 23, 24, 25-28, 32, 34, 35, 37, and 39 of U.S. Patent No. 11517584 to Arrowhead (issued 12/6/2022, in IDS, referred as Arrowhead ‘584) in view of Wooddell et al. (2017, Science Translational Research, 9, pg. 1-11, also of Assignee, but outside the one year grace period).
Regarding instant claims 1, 28, 34, 47-51, 53-54,58-59, 60, Arrowhead ‘584 claim 14 teaches a pharmaceutical composition comprising a first RNAi agent of SEQ ID NO: 126 and SEQ ID NO: 252 and a second RNAi agent comprising SEQ ID NO: 140 and SEQ ID NO: 262. Claim 18 teaches SEQ ID NO: 126 is instant SEQ ID NO: 126 (asGfsasAfaAfuUfgAfgAfgAfaGfuCfcasc) and SEQ ID NO: 252 is instant SEQ ID NO: 252 ((NAG37)s-(invAb)sguggacuuCfUfCfucaauuuucus(invAb)) and SEQ ID NO: 140 is instant SEQ ID NO: 140 (usAfscsCfaAfuUfuAfuGfcCfuAfcAfgcsg) and SEQ ID NO: 262 is instant SEQ ID NO: 262 ((NAG37)s(invAb)scgcuguagGfCfAfuaaauugguas(invAb)) and claims 19 and 20 teach both are in a sodium salt form regarding instant claims 47, 48, 60). Claim 32 of Arrowhead teaches method of treating HBV infection and/or HDV infection in a subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 14 (relevant to instant cl. 1).
Arrowhead ‘584 does not teach the treatment of humans in a specific day intervals nor administration of a combined amount of about 50-200 mg per dose at one month or 28-day intervals; or administration of doses recited in claims 49-51, 59 (combined dose of 50, 100, 200 and 300 mgs at a 2: 1 ratio for 1st and 2nd RNAi agents); or specific duration (cl. 28, 54).).
Wooddell discloses a clinical trial of a RNAi-based treatment of chronically infected HBV patients and chimpanzees (title, abstract, pg. 1, relevant to instant cl. 34, 58). The study discloses patients treated at various doses 1, 2, 3, 4 mg/kg, with one cohort receiving multiple doses 2 week apart (pg. 2). The RNAi therapeutic ARC-520 used for treatment of chronic HBV infection comprises liver-tropic cholesterol conjugated siRNAs siHBV-74 and siHBV-77 and each target a different region of the HBV virus mRNA (pg. 2, 2nd full paragraph). Thus, similarly, there were two RNAi agents in the ARC-520 compound. A chimpanzee study discloses administering in a 28-day interval for up to 225 days (see Fig. 2B-2F, “Dosing days are indicated by vertical dashed lines, pg. 4) (relevant to cl. 1, 28, 49-51, 54, 59). The study showed that continuous administration of the ARC-520 treatment over 225 days resulted in a steady decline of HBV DNA in serum (Fig. 2B). Study also includes a treatment of up to 169 days (see Fig. 2F, relevant to instant cl. 28).
MPEP 2144.05(II) provides that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, both Wooddell and Arrowhead ‘584 indicate testing various dose ranges (claims 16, 23, 17, 24) to identify optimal range and duration as a routine experimentation known in the art, and, further, one purpose of a clinical trial is to identify optimal dose range (relevant to instant cl. 1, 28, 49-51, 53-54, 59).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the doses and time intervals between doses of the RNAi agents of Arrowhead ‘584 in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. Because here Wooddell discloses a positive results of a clinical trial/trial where different doses and time-interval of RNAi agents targeting HBV were tested on primates, including humans, with chronic HBV infection, and Arrowhead ‘584 uses similar RNAi agents to treat HBV infection, one of ordinary skill in the art would have been motivated to modify the doses and time intervals of RNAi agents of Arrowhead ‘584 to test various doses and time intervals as provided by Wooddell and would successfully result in identifying an optimal dose range to treat a human subject with chronic HBV infection. Thus, claims 1, 28, 34, 47-51, 53-54,58-59, 60 are obvious.
Regarding instant cl. 14, Arrowhead ‘584 claim 17 teaches the ratio of the first RNAi agent and the second RNAi agent in the composition is about 2:1.
Regarding instant cl. 16, Arrowhead ‘584 claim 34 teaches subcutaneous administration for a method of treating a HBV infection and/or a Hepatitis D virus (HDV) infection in a subject in need thereof, comprising administering to a subject an effective amount of the composition of claim 14. Subcutaneous means under the skin and infers injection since that is the only way to administer a drug subcutaneously.
Regarding instant cl. 29-31, Arrowhead ‘584 claims 37 and 39 teach administering additional therapeutics and additional therapeutic being one or more of tenofovir or entecavir.
Regarding instant cl. 32, instant claim 32 recites the results of administration of the composition of claim 1 and is inherent property of the structure of composition of instant claim 1. Thus if prior art discloses the same composition, it will also have the inherent property/characteristics. Here Arrowhead ‘584 teaches the composition of instant claim 1, thus its inherent property would be to reduce the level of HBsAg, HBeAg or serum HBV DNA by at least 40%.
Regarding instant cl. 34, Arrowhead ‘584 claim 35 recites HBV infection is a chronic HBV infection.
Regarding instant claims 55 and 57, Arrowhead ‘584 claims do not teach sterile injectable solution nor the pharmaceutical composition packaged in a pre-filled syringe or vial.
It should be noted that the limitation “is packaged in a pre-filled syringe or vial” of claim 57 is the intended use of the product and therefore is considered a preamble of the claim and does not further limit the structure of the pharmaceutical composition of aforementioned the sequences of the prior art.
Wooddell discloses in Supplemental Material of supplying the ARC-520 as two sterile 10-mL vials, which are mixed by the pharmacist and administered to a subject for treatment.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the pharmaceutical composition of RNAi agent of Arrowhead in view of Wooddell and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the pharmaceutical composition of RNAi agent of Arrowhead as a sterile injectable solution in vials taught by Wooddell and would successfully result in ease in administering the RNAi agent to a human patient for treatment. Thus, claims 55 and 57 are obvious.
Regarding instant claim 56, Arrowhead ‘584 claim 28 teaches lyophilizing. i.e. a powder, the salt form of SEQ ID NO: 126/252 and SEQ ID NO: 140/262. The limitation “for the preparation of a sterile injectable solution” is the intended use