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 .
Response to Arguments
Applicant’s arguments, see page 5, filed on 10/20/25, with respect to the rejection(s) of claim(s) 1, 18, 35, 38, 39, 42, 50, 51, and 53 under 102 and 103 have been fully considered and are persuasive because of the amendment to claim 35 to recite “a human patient having being diagnosed with hepatitis B” and “a synergistically effective amount”. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 35.
In addition, the NSDP over several US Patents cited in the non-final rejection has been withdrawn because the claims of the patents do not appear to recite or make obvious the claimed method as amended. The disclosure of the patents discussed measuring additive or synergistic effect, but none of the disclosures of the patents appear to provide any working examples or teaching that any of the combination of agents in instant claim 35 were synergistic.
Election/Restrictions
Upon the amendment to claim 35 to require a synergistic effective amount of at least two agents from a)-f), species a) and f) are rejoined with the elected species and searched.
Items c) and e) in claim 35 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/11/25.
NOTE: Claims 36, 37, 40, 41, 44-49, 52, 54, and 55 were cancelled in the amendment filed on 10/20/25 and remain withdrawn without traverse to a non-elected species. In view of the new prior art rejection, several of the cancelled claims, including Claims 36 and 37, would have been rejoined with elected species but this is moot because the claims were cancelled.
Claims 1 and 18 were cancelled in a previously filed amendment and remain withdrawn to a non-elected invention.
Specification
The abstract filed on 10/20/25 has been entered.
The disclosure is objected to because of the following informalities: page 82 line 11 has the term ‘inhibitor’ twice.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35, 38, 39, 42, 43, and 50-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention does not provide written support for a synergistically effective amount of at least two agents selected from the group consisting of: a)-f) for treating a human patient having hepatitis B virus (HBV).
The amendment filed on 10/20/25 does not cite written support in the disclosure for the term. The specification including the working examples (pages 69-173) disclose synergistically effective amounts in murine model of hepatitis B using several combinations of specific agents embraced by the claimed method. Several examples contemplate studying the effect, but do not appear to disclose the results of the example.
There are 26 examples and a few examples and results will be discussed herein:
Examples 4-6 studied in vitro (HBV cell culture combination) combination with two drug combinations of a small molecule inhibitor of HBV encapsidation (compound 3), Entecavir (ETV), a reverse transcription inhibitor of HBV polymerase and siRNA-NP (a lipid nanoparticle formulation) and siRNA intended to facilitate potent knockdown of all viral mRNA transcripts and viral antigens for additive, synergistic, or antagonistic.
Examples 7-9 studied the effects of combination treatment with two-compound combinations on the process of HBV DNA replication, cccDNA formation, and cccDNA expression and stability. Compounds 3 and 4, two small molecule inhibitors of HBV encapsidation; entecavir (ETV) and lamivudine (3TC), two FDA-approved reverse transcriptase inhibitors of HBV polymerase; and SIRNA-NP, a lipid nanoparticle (LNP)-formulated siRNA inhibitor of viral mRNA and viral antigen expression were investigated. The studies were aimed at determining whether the combinations are additive, synergistic or antagonistic in vitro using an HBV cell culture model system.
Example 7 shows that compound 3 and entecavir combination resulted in synergistic inhibition or precore RNA expression.
Example 9 shows that compound 3 and siRNA-NP also resulted in synergistic inhibition of precure RNA expression.
Example 15 shows a two-drug combination of compound 24 (a small molecule inhibitor of HBV encapsidation) and TDF were found to be additive or synergistic.
Example 16 shows a two-drug combination of compound 23 (a small molecule inhibitor of HBV encapsidation) and TDF were found to be additive or synergistic.
The combination of IFNalpha2 and compound 25 in Example 18 and compound 25 and compound 3 in example 19 were found to be synergistic with no antagonism.
The combination of TAF and compound 3 in example 20 were found to be synergistic with no antagonism.
The combination of IFNalpha2 and compound 22 (a small molecule inhibitor of HBV encapsidation) in Example 21 were found to be synergistic or additive with no antagonism.
The combination of compound 22 and compound 25 (a small molecule inhibitor of HBV DNA, HBsAg and HBeAg) in Example 23 were found to be synergistic with no antagonism.
The combination of IFNalpha2 and compound 3 in example 24 were found to be synergistic with no antagonism.
Several of the examples show that there is a variation amongst species of combination of agents used in the examples that did not result in a synergistic effect or resulted in an additive or synergistic depending on the dose. For example, ETV and siRNA; compound 3 and TDF; and compound 5 and siRNA-NP resulted in an additive effect when treating hepatitis in mice.
The specification and prior art cited in the previous office action display that the agents selected from a)-f) are well known to one of skill in the art and can be used to treat hepatitis B in a subject, including humans.
WO 2004050613 discloses 3TC, AT-61 acted synergistically to inhibit HBV infection in HEPAD38 cells.
WO 0145712 disclose the in vitro combination of AT-61 and lamivudine is described as being synergistically effective.
WO2014032176 (AU2013308045) discloses PBHBV-001 and PBHBV-2-15 as lead candidate compounds for blocking the release of HBsAg from the HBV producing cell line HepG2.2.15 (Figures 1A and 1B). Agents that remove HBsAg form the blood and a second agent which stimulates immune function results in a novel synergistic action between these two agents which has an improved effect on enabling the recovery of immunological control of HBV infection (paragraphs 97-104).
While the prior art teaches synergistic effect using these agents in a cell line, they do not appear to disclose what amount is considered synergistically effective at treating hepatitis B in a human subject. In addition, with respect to these specific examples taught in the prior art or in the working examples of the as-filed specification, it is not described if one of skill in the art could determine the amounts for these specific combinations for use in human patients through routine experimentation.
Furthermore, there are millions of possible combinations of a)-f) and a limited number of examples in the prior art or specification for several combinations of the agents showing a synergistic effect for treating hepatitis B in a murine model of HBV or HBV infected cell lines.
King et al. (Antimicrobial agents and chemotherapy Vol. 42, pages 3179-3186, 1998) teach that an additive or synergistic effect for treating Human hepatitis B was observed depending on the amount of AT-61 and 3TC.
The specification does not provide written description for the genus of synergistically effective amounts, since the results for these combinations vary and there is no known core structure of an inhibitor(s) or known function of a species of inhibitors for observing the desired synergistic amount. For example, there is no guidance that using at least one capsid inhibitor in claim 39 and/or at least one sAg secretion inhibitor in claim 43 with any other agent embraced by the claimed method would result in a synergistic effect in treating human with hepatitis B. The skilled artisan would have to further experiment with possible amounts of inhibitors embraced by the claimed invention to determine if they would have a synergistic effect in treating hepatitis B in a human patient. The claims are trying to pre-empt the future before it has arrived. See MPEP 2163, Ariad Pharmaceuticals, Inc. v. Eli Lilly and Company, 598 F. 3d 1336 (Fed. Cir. 2010).
In view of the very large number of possible combinations and variations amongst species of combination of agents, the written description requirement for the claimed genus is not satisfied through sufficient description of a representative number of species. The limited number of combinations and variation of biological activities (additive and/or synergistic) of these combinations do not adequately described and considered to be representative of the entire genus of combinations embraced by the claimed invention. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of a synergistically effect amount of at least two agents selected from a)-f) for treating hepatitis B in human in the pending claims as of the effective filing date.
Claims 35, 38, 39, 42, 43, and 50-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a human diagnosed with hepatitis B using the following combinations of agents: compound 3 and entecavir; compound 3 and siRNA-NP; compound 24 and TDF; compound 23 and TDF; IFNalpha2 and compound 25; compound 25 and compound 3; TAF and compound 3; IFNalpha2 and compound 22; compound 22 and compound 25; IFNalpha2 and compound 3; AT-61 and 3TC (also known as lamivudine); lamivudine and adefovir; and HBsAg removal from blood using PBHBV-001 or PBHBV-2-15 and interferon-based therapy, does not reasonably provide enablement for using at least two agents selected from a)-f) in a synergistic amount to treat hepatitis B in a human patient. NOTE: the scope of enablement does not indicate that these combination have written support in the specification of the instant disclosure for using a synergistically effective amount of at least two agents selected from the group consisting of a)-f) to treat hepatis B in a human patient diagnosed with hepatitis B. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized in In re Wands, 858 F.2d 731, 8USPQ2d 1400 (Fed. Cir. 1988). They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claimed invention embraces a synergistically effective amount of at least two agents selected from the group consisting of: a)-f) for treating a human patient having hepatitis B.
The state of the art teaches that there were limited examples of a combination of agents embraced by the claimed invention to have synergistic effect in treating hepatitis B in a subject.
Lomonosova et al. (Antimicrobial Agents and Chemotherapy Vol. 61, pages 1-12, 2017) teach that, at the time of filing, no such combination therapy was established for human hepatitis B virus (HBV) (page 1). Lomonosova studied combination of RNase H inhibitors with HAP12 (a core protein allosteric modulator) had additive antiviral effects (page 1). Two specific RNase H inhibitors (compound 1 and 46, Figure 1) were synergistic with lamivudine against HBV DNA synthesis (page 1).
WO 2004050613 discloses 3TC and AT-61 acted synergistically to inhibit HBV infection in HEPAD38 cells.
King et al. (Antimicrobial agents and chemotherapy Vol. 42, pages 3179-3186, 1998) teach that an additive or synergistic effect for treating Human hepatitis B infected cell lines was observed depending on the amount of AT-61 and 3TC.
WO 0145712 disclose the in vitro combination of AT-61 and lamivudine is described as being synergistically effective.
WO2014032176 (AU2013308045) discloses PBHBV-001 and PBHBV-2-15 as lead candidate compounds for blocking the release of HBsAg from the HBV producing cell line HepG2.2.15 (Figures 1A and 1B). Agents that remove HBsAg form the blood and a second agent which stimulates immune function results in a novel synergistic action between these two agents which has an improved effect on enabling the recovery of immunological control of HBV infection (paragraphs 97-104).
While the prior art teaches synergistic and/or additive effect using these specific agents in cell lines infected with HBV, they do not appear to disclose what amount is considered synergistically effective at treating hepatitis B in a human subject. In addition, when a synergistic result using a combination of agents to treat HBV is obtained it appears to be unexpected or a surprising discover (for example see pages 49-51 of WO 2014032176). Thus, it appears that using a combination of antiHBV agents in a synergistically effective amount to treat a human patient with HBV is considered unpredictable.
The specification including the working examples (pages 69-173) disclose synergistically effective amounts in murine model of hepatitis B using several combinations of specific agents embraced by the claimed method. Several examples contemplate studying the effect, but do not appear to disclose the results of the example.
There are 26 examples and a few examples and results will be discussed herein:
Examples 4-6 studied in vitro (HBV cell culture combination) combination with two drug combinations of a small molecule inhibitor of HBV encapsidation (compound 3), Entecavir (ETV), a reverse transcription inhibitor of HBV polymerase and siRNA-NP (a lipid nanoparticle formulation) and siRNA intended to facilitate potent knockdown of all viral mRNA transcripts and viral antigens for additive, synergistic, or antagonistic.
Examples 7-9 studied the effects of combination treatment with two-compound combinations on the process of HBV DNA replication, cccDNA formation, and cccDNA expression and stability. Compounds 3 and 4, two small molecule inhibitors of HBV encapsidation; entecavir (ETV) and lamivudine (3TC), two FDA-approved reverse transcriptase inhibitors of HBV polymerase; and siRNA-NP, a lipid nanoparticle (LNP)-formulated siRNA inhibitor of viral mRNA and viral antigen expression were investigated. The studies were aimed at determining whether the combinations are additive, synergistic or antagonistic in vitro using an HBV cell culture model system.
Example 7 shows that compound 3 and entecavir combination resulted in synergistic inhibition or precore RNA expression.
Example 9 shows that compound 3 and siRNA-NP also resulted in synergistic inhibition of precure RNA expression.
Example 15 shows a two-drug combination of compound 24 (a small molecule inhibitor of HBV encapsidation) and TDF were found to be additive or synergistic.
Example 16 shows a two-drug combination of compound 23 (a small molecule inhibitor of HBV encapsidation) and TDF were found to be additive or synergistic.
The combination of IFNalpha2 and compound 25 in Example 18 and compound 25 and compound 3 in example 19 were found to be synergistic with no antagonism.
The combination of TAF and compound 3 in example 20 were found to be synergistic with no antagonism.
The combination of IFNalpha2 and compound 22 (a small molecule inhibitor of HBV encapsidation) in Example 21 were found to be synergistic or additive with no antagonism.
The combination of compound 22 and compound 25 (a small molecule inhibitor of HBV DNA, HBsAg and HBeAg) in Example 23 were found to be synergistic with no antagonism.
The combination of IFNalpha2 and compound 3 in example 24 were found to be synergistic with no antagonism.
Several of the examples show that there is a variation amongst species of combination of agents used in the examples that did not result in a synergistic effect or resulted in an additive or synergistic depending on the dose. For example, ETV and siRNA; compound 3 and TDF; and compound 5 and siRNA-NP resulted in an additive effect when treating hepatitis in mice.
There are millions of possible combinations of a)-f) and a limited number of examples in the prior art or specification for several combinations of the agents showing a synergistic effect for treating hepatitis B. Since the results for these combinations vary and there is no known core structure of an inhibitor(s) or known function of a species of inhibitors for observing the desired synergistic amount.
In view of the following factors including prior art of record, teaching in the specification, and the unpredictability of using two agents embraced by the claimed invention in an amount to observe a synergistic effect for treating a human having hepatitis B, one of skill in the art could not reasonably extrapolate from the limited examples in the prior art and/or in the specification to practicing the full scope of the claimed method(s) without an undue amount of experimentation.
With respect to these specific examples taught in the prior art or in the working examples of the as-filed specification, the art of record does not teach that it would not have been unpredictable to determine the amounts for these specific combinations for use in human patients through routine experimentation.
The skilled artisan would have to perform an undue amount of experimentation with other possible amounts of inhibitors embraced by the claimed invention to determine if they would have a synergistic effect in treating hepatitis B in a human patient.
Thus, the instant claims 35, 38, 39, 42, 43, and 50-51 are not fully enabled.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 35, 38, 39, 42-43, and 50-51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “a synergistically effective amount” in claim 35 is a relative term which renders the claim indefinite. The term “a synergistically effective amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define the metes and bounds of the limitation ‘treating a human patient having been diagnosed with hepatitis B…a synergistically effective amount’. Pages 69-173 disclose that depending on which agents are the at least two agents the amount can vary and the examples are not in humans having HBV. Since there is no definition of the limitation in the specification, a person of skill in the art would not know if they were infringing on the claimed invention when using any combination of agents embraced by the instant claims.
Dependent claims are also rejected because they depend on claim 35.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 35 and 50-51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou (WO 2011082331).
NOTE: the specification does not appear to define any amount of an agent that is considered a synergistically effective amount to treat hepatitis B in a human.
Zhou teaches compositions and methods for treating hepatitis B virus infection. More particularly, the invention relates to treating hepatitis B virus infection and related conditions in humans using unique and synergistic combinations of lamivudine and adefovir that maximize favorable therapeutic outcomes while minimizing or preventing viral resistance, which commonly occurs from using lamivudine or adefovir alone, and reducing the side effects of adefovir. See pages 1-7 and 32-38. The agents are administered orally (page 2). Zhou teaches amount for observing a synergistic effect to HBV in a human and thus the amount of the agents would reads on the limitation ‘synergistically effective amount’.
Claims 35, 42-43 and 50-51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Reflicor Inc. (WO2014032176 also published as AU2013308045).
‘176 teaches combination treatment of hepatitis B in human patients comprising removing hepatitis B surface antigen from the blood and a second agent that stimulates immune function for treating hepatitis B infection, interferon alpha-2b (pages 41-70). ‘176 further discloses PBHBV-001 and PBHBV-2-15 as lead candidate compounds for blocking the release of HBsAg from the HBV producing cell line HepG2.2.15 (Figures 1A and 1B). Agents that remove HBsAg from the blood and a second agent which stimulates immune function results in a novel synergistic action between these two agents which has an improved effect on enabling the recovery of immunological control of HBV infection (paragraphs 97-104). Thus, the method taught by ‘176 reads on administering PBHBV-001 or PBHBV-2-15 and immunostimulators (interferon alpha-2b) to a human subject having hepatitis B. NOTE: the specification does not appear to define any amount of an agent that is considered a synergistically effective amount to treat hepatitis B in a human. ‘176 teaches an amount for observing a synergistic response of the combination of agents to HBV in a human and thus the amount of the agents used in the working examples of ‘176 would read on the limitation ‘synergistically effective amount’. Pages 53-64 discloses that the agents are orally administered to the patient to treat HBV.
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.
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636