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 .
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international application PCT/US2022/029022, filed on May 12th, 2022, which claims domestic priority under 35 U.S.C. 119(e) to U.S. provisional application no. 623/188,339, filed on May 13, 2021.
Election/Restrictions
Applicant’s election without traverse of the following species:
Species A, directed to the PD-1/PD-L1 inhibitor, and wherein the PD- 1/PD-L1 inhibitor is nivolumab. The claims readable on the elected species include 1, 4, 6, 23, 28, 31-35, 37-43, 45, 46, 48, 50, and 52
Species B, wherein the virologic response of the subject assessed from termination of treatment is wherein the subject has a hepatitis B viral load of less than about 20 international units per milliliter (IU/mL) following completion of treatment. The claims readable on the elected species include 1, 4, 6, 23, 28, 31-43, 45, 46, 48, 50, 52, and 56,
in the reply filed on 15th Jun, 2026 is acknowledged.
Accordingly, claims 7-8 and 58, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Election was made without traverse in the reply filed on 15th Jun, 2026.
Status of Claims
Claims 1, 4, 6, 23, 28, 31-43, 45-46, 48, 50, 52, 56 and 59 are under consideration.
Information Disclosure Statement
The IDS submitted on 3/18/2024:
lists the Name of Patentee or Applicant of cited Document of WO 2020/036862 A1, see pg. 11, as The Government of the United States of America. It should be: ALNYLAM PHARMACEUTICALS, INC. Examiner refers to this reference as Jadhav (WO 2020/036862 A1).
Lists the reference of Lee et al., Int. J. Mol. Sci. 2021, 22, 213, with its on line publication date of 2020.
Other references on the same IDS lists the Name of Patentee or Applicant of various cited Documents as The Government of the United States of America. Examiner requests that Applicant check all references for the correct citations.
Accordingly, this IDS has not been considered to its fullest extent.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed 10/15/2024 has been considered.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites SEQ ID NO.:1 and SEQ ID NO.:2. The correct representation of SEQ ID NO is a colon following SEQ ID NO without an intervening period; i.e., as shown below:
SEQ ID NO:
Appropriate correction is required.
Specification
The abstract of the disclosure is objected to because:
The abstract is less than 50 words in length, and reads like a title. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Claim Rejections - 35 USC § 112
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 36 and 56 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.
Regarding claims 36 and 56, claims 36 and 56 are indefinite in the recitation of “less than about”. The phrase “less than” typically indicates a value less than a maximum point; however, the phrase “less than” is controverted by the term “about,” which implies that values above and below the indicated amount are permitted. The specification in [0009] term defines the term "about" to include the indicated amount + 1% to + 10%.Therefore, the juxtaposition of these two terms, less than and about, makes it unclear what min / maximum values are encompassed by the claim.
In Amgen, Inc. v. Chugai Pharmaceutical co., 927 F.2d 1200 (CAFC 1991), the CAFC stated, “[t]he district court held claims 4 and 6 of the patent invalid because their specific activity of “at least about 160,000” was indefinite.” After review, the CAFC states “[w]e therefore affirm the district court' s determination on this issue.” Thus, the CAFC found the phrase “at least about” indefinite where the metes and bounds of the term were not defined in the specification. The phrase “less than about” is therefore also deemed indefinite.
See MPEP 2173.05(b) III.
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 1, 4, 6, 23, 28, 31-43, 45-46, 48, 50, 52, 56 and 59 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 hepatitis B viral infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a dsRNA specific for the target, and a PD-1/PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, does not reasonably provide enablement for preventing HBV (claim 1). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
As evident in the statement of rejection, this rejection is limited to the elected species claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
Scope of the Invention
The claims are directed to a method for treating /preventing an HBV infection a subject, comprising administering to the subject: a) a dsRNAi agent represented by sense: SEQ ID NO: 2 and antisense: SEQ ID NO: 1 that inhibits expression of HBV; b) a TLR8 stimulator/agonist which is represented by Formula I (selgantolimod); and c) a PD-1 inhibitor which is nivolumab (REGN2810/ cemiplimab); and further administering d) a nucleoside analog represented by Formula II (Tenofovir alafenamide (TAF)) thereby treating/preventing HBV infection in the subject.
Breadth of the Claims
Instant claims encompass:
“treating and preventing”
This encompasses administration of a therapeutically effective amount to a subject to elicit both treatment of an existing HBV disease or prevention of HBV disease, i.e., prophylaxis. Prophylaxis can be understood as preventing an HBV infection from turning into a chronic HBV infection or preventing the onset of HBV infection ([0010-0011]).
The broadest reasonable interpretation of the claimed method is a combination of known agents to treat or prevent HBV disease which is accomplished in one of two ways:
1. by combining three known agents and following a particular regimen (claims 1, 4, 6, 23, 28, 31, 45-46, 48, 50, 56 and 58-59).
2. by combining four known agents and following a particular regimen (claims 32-43, and 52).
The end-goal is to achieve:
3. prevention or treatment of HBV disease in a subject, characterized by:
a. (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU/mL); (ii) negative for the hepatitis B e-antigen (HBeAg); and (iii) a hepatitis B surface antigen (HbsAg) concentration of less than about 100 international units per milliliter (IU/mL), (claim 36 (depends on claim 32));
b. (i) wherein the subject has a hepatitis B viral load of less than about 20 international units per milliliter (IU/mL) following completion of treatment,
(ii) wherein the subject is negative for the hepatitis B e-antigen (HbeAg) following completion of treatment, (claims 56 and 59 (depend on claim 1));
wherein
“a subject”
This encompasses all possible mammalian subjects [0014].
“administering”
This encompasses all ways of administering which includes but is not necessarily limited to:
All routes of administration including topical, injection, inhalation, and others [0014].
"therapeutically effective amount" is an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease [0016].
No "therapeutically effective amount" to include an amount that is effective to “prevent” is provided.
Thus, the breath of claims is vast.
Direction or Guidance Presented
The focus here will be on elements for which written description is provided.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of preventing a disease such that the clinical symptoms of the disease do not develop [0011].
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Method of treating or preventing
There is no disclosure on how prevention is achieved. Only dosing regimens are described. For e.g., [0238]-[0243] discusses the regimen for Formula I; [0244] discusses the regimen for nivolumab [0245]; discusses the regimen for Formula II; [0259] discusses the regimen for the duplex antisense oligo.
Method of assessing end-goal
There is no disclosure on how to assess if prevention is achieved.
In [0221] the spec discloses: In some embodiments, administration of the compound of Formula II is terminated if after 36 weeks the subject is characterized by: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU/mL); (ii) negative for the hepatitis B e-antigen (HBeAg); and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU/mL). In some embodiments, administration of the compound of Formula II is terminated if after 36 weeks the subject is characterized by: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU/mL); (ii) negative for the hepatitis B e-antigen (HBeAg); and (iii) negative for the hepatitis B surface antigen (HBsAg). These are valid assessable end-points for treatment. However, one of skill cannot imagine how these may also be contemplated as assessable end-goals for “protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop” as disclosed in [0011] of the specification. This is further discussed in the state of the art.
The practice of a method without the need for substantial undue experimentation and additional inventive contribution requires the disclosure of an effective method of assessing whether the end-goal is achieved and this information is not provided by the instant specification.
Undue Experimentation and Unpredictability of the Art
Because of the known unpredictability of the art, as confirmed by the State of the Art below, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that a composition comprising the three or four agents as laid out in the beginning can be useful in the preventative treatment of HBV as inferred by the claims and contemplated by the specification. Without further guidance, one of skill in the art would have to practice a substantial amount of experimentation, an amount considered undue and not routine, to practice the instantly claimed invention. This is considered undue because there is no assurance of success, even a reasonable modicum thereof.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. The Wands factors were laid out in the beginning. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970).
State of the Art
Known Prevention Methods
As per World Health Organization, (Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis b infection (text extract): executive summary. Infect Dis Immun 2024;4(3):103–105), there are guidelines for prevention of HBV but these are limited to preventing mother-to-child transmission of hepatitis B and use of antiviral prophylaxis (see chapter 7). The antiviral recommended for prophylaxis in this case is tenofovir disoproxil fumarate, TDF (a derivative of tenofovir, similar to Formula I (tenofovir alafenamide fumarate, TAF) recited in instant). As evidenced by Hill, there is no efficacy difference between TAF and TDF (at least title).
However, the WHO guidelines do not have any recommendations for administering to the subject … thereby preventing the disease in the subject.
This begs the question, why? Is it not possible to achieve complete elimination of HBV in a subject by administering a known agent that will target and degrade HBV?
Martinez discuss cutting-edge technologies that could lead to non-cytolytic direct cccDNA targeting and cure of infected hepatocytes (Martinez et al., Journal of Hepatology 2021 vol. 75 j 706–717). Martinez define a complete HBV cure as undetectable serum HBsAg and serum and intracellular HBV DNA, including covalently closed circular DNA [cccDNA] clearance and a functional cure as undetectable serum HBV DNA and serum HBsAg, with or without seroconversion, accompanied or not by cccDNA silencing. Martinez discuss that complete HBV cure is hampered by the lack of therapies that can directly affect the viral minichromosome (in the form of covalently closed circular DNA [cccDNA]). Martinez discuss that a few copies of cccDNA left might be sufficient to reinitiate a full-blown HBV infection (pg. 706, first para on R). In §.Perspectives, Martinez discuss that treatments that could non-cytopathically eradicate cccDNA have not yet reached clinical development, owing to their lack of specificity, inadequate and ineffective delivery approaches and to our incomplete understanding of off-target effects (pg. 713, first para on L).
Therefore, the examiner maintains that absent demonstration from applicant demonstrating prevention of HBV disease, one would not be able to ascertain if indeed said prevention occurs. Therefore, claim 1 is rejected for lack of scope of enablement.
Dependent Claims
Claims 4, 6, 23, 28, 31-43, 45-46, 48, 50, 52, 56 and 59 do not provide any guidance on “method of preventing” and are therefore rejected for the same reasons as recited above for claim 1.
Conclusion
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Accordingly, claims 1, 4, 6, 23, 28, 31-43, 45-46, 48, 50, 52, 56 and 59 are rejected for lack of scope of enablement. Claims are enabled only for treating HBV infection comprising administering a particular regimen of known agents.
Examiner Suggestion: Amend the claims by deleting references to “preventing”.
Claim Rejections - 35 USC § 103
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.
Claim 1 is directed to a method for treating /preventing an HBV infection a subject, comprising administering to the subject: a) a dsRNAi agent represented by sense: SEQ ID NO: 2 and antisense: SEQ ID NO: 1 that inhibits expression of HBV; b) a TLR8 stimulator which is represented by Formula I, and c) a PD-1 inhibitor which is nivolumab, thereby treating/preventing HBV infection in the subject.
The rejections below are limited to the limitation “treating”.
Claim(s) 1, 4, 6, and 23, is/are rejected under 35 U.S.C. 103 as being unpatentable over Sepp (US 11,324,820 B2, effectively filed on Apr 18 2018 as PCT /US2018/028116) in view of Mackman (Mackman et al., J. Med. Chem. 2020, 63, 10188−10203) and Jadhav (WO 2020/036862 A1).
Regarding claims 1, 4, and 23, Sepp teaches: a method for treating HBV infection a subject, comprising administering to the subject: a) a dsRNAi agent b) a TLR8 stimulator and c) a PD-1 inhibitor, thereby treating HBV infection in the subject (summary of invention; claim 1; In certain embodiments, the methods further comprise administration of an immune stimulator to the subject, col 7, 3rd para). Sepp’s dsRNA is called, AD-66810, which has the target site of GTGTGCACTTCGCTTCACA (SEQ ID NO: 39) which is nucleotides 1579-1597 of NC 003977.1 (SEQ ID NO: 1).
Sepp’s target site is complementary to instant SEQ ID NO: 1
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 90.5%; Score 19; Length 19;
Best Local Similarity 84.2%;
Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGUGAAGCGAAGUGCACAC 19
:|:|||||||||:||||||
Db 19 TGTGAAGCGAAGTGCACAC 1
Sepp’s modified sense and antisense sequences that target this site are shown below, duplexed as AD-66810:
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The methods further comprise administration of an immune stimulator to the subject selected from the group :Toll-like receptor 3, 7, 8 or 9 (TLR3, TLR7, TLR8, TLR9) agonist, a PD-1 inhibitor, Nivolumab (col 7, 3rd para).
Thus, Sepp teaches a method for treating HBV infection a subject, comprising administering to the subject: a) a dsRNAi agent represented by modified sense and antisense sequences that inhibit expression of HBV; b) a TLR8 stimulator, and c) a PD-1 inhibitor which is nivolumab, thereby treating HBV infection in the subject.
Regarding claim 6, Sepp teaches Nivolumab is a PD-1 inhibitor (col 19, 1st para).
Sepp does not teach examples of TLR8 agonists or the exact modified SEQ ID NO: 1 as claimed.
Mackman teaches, selgantolimod is a TLR8 agonist (title) and has the structure of Formula I (Fig. 1).
Jadhav teaches double stranded RNA agents 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 (abstract). Jadhav tests various sequences that target HBV. Amongst these are: AD-66810 (the dsRNA duplex taught by Sepp, described as the parent compound) and several other sequences. AD-81890 comprises sequences that are exactly like instant SEQ ID NO: 1 and SEQ ID NO: 2; i.e., SEQ ID NO: and 16 SEQ ID NO: 10 respectively.
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Jadhav teach AD-81890 is comparable to AD-66810 (Example 3, pg. 79):
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention to combine agents known for use in treating HBV as taught by Sepp, Mackman, and Jadhav to derive synergistic/additive benefits and also to reduce the dosage amount of the active ingredients. The MPEP in 2144.06 I states:
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus claims 1, 4, 6, and 23 would have been obvious over the combined prior art teachings. There would have been a reasonable expectation of success in making this modification because all the agents being combined are known anti-HBV agents whose efficacy was already demonstrated at least individually, and in combination, the agents were expected to perform similarly.
Claim(s) 28, 31-43, 45-46, 48, 50, 52, 56 and 59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sepp (US 11,324,820 B2) in view of Mackman (Mackman et al., J. Med. Chem. 2020, 63, 10188−10203) and Jadhav (WO 2020/036862 A1) as applied to claim 1, 4, 6, and 23, above, and further in view of Lee (Lee et al., Int. J. Mol. Sci. 2021, 22, 213) as evidenced by 1. ClinicalTrials.gov (i. retrieved from the ClinicalTrials.gov webpage on the internet <https://clinicaltrials.gov/study/NCT03615066> 21 pgs., [retrieved on 23rd Jun 2026] and ii. <https://clinicaltrials.gov/study/NCT04412863> 15 pgs., [retrieved on 23rd Jun 2026]) and 2. Gane (Gane et al., Journal of Hepatology 2019 vol. 71, 900–907).
The method of treating HBV was rendered obvious by the combination of Sepp, Mackman, and Jadhav.
Regarding claims 32-33, and 38, Sepp further teaches the method further comprises administering the nucleot(s)ide analog, Tenofovir alafenamide (TAF) (col 6, 1st para). As evidenced by Product Monograph of PrVEMLIDY®, TAF is an approved drug for HBV treatment and has the structure as recited in claim 32 (pg. 18).
Neither Sepp nor Mackman nor Jadhav teach the dosing regimen of claims 28, 31, and 34-35, 37, 39-43, 45-46, 48, 50, 52, or the assessment methods of claims 36, 56, and 59.
Regarding claims 28 and 31, Lee teaches the TLR8 agonist, selgantolimod (instant Formula I) is in clinical trials (Table 1, pg. 4). As evidenced by ClinicalTrials.gov retrieved from the ClinicalTrials.gov webpage on the internet < https://clinicaltrials.gov/study/NCT03615066> 21 pgs. [retrieved on 23rd Jun 2026], this study was started on 8-28-2018 and the study completion was 4-12-2021, wherein selgantolimod was administered orally every 7 days for 24 doses in fasted state.
Lee teaches selgantolimod (1.5 mg or 3 mg once a day) is combined with NA therapy (pg. 8, 2nd to the last para).
Lee teaches VIR-2218 (RNA interference) is in clinical trials (Table 1, pg. 3). As evidenced by ClinicalTrials.gov retrieved from the ClinicalTrials.gov webpage on the internet <https://clinicaltrials.gov/study/NCT04412863> 15 pgs. [retrieved on 23rd Jun 2026], this study was started on 7-3-2020, wherein VIR-2218 was given by subcutaneous injection.
Lee teaches a phase I pilot study evaluated anti-PD-1 (nivolumab) treatment (At week 24, 14% (3/22) of the patients had > 0.5 log10 reduction in HbsAg levels [49], pg. 9, 2nd para). As evidenced by the cited reference [49], which is Gane, Nivolumab is administered as an intravenous (IV) infusion (§ Clinical Trial Design, pg. 901, 1st para on R).
Regarding claim 34-35, Lee teaches the TAF (instant Formula II) is in clinical trials wherein it is tested when combined with Selgantolimod (Formula I )(Table 1, pg. 4). As evidenced by ClinicalTrials.gov retrieved from the ClinicalTrials.gov webpage on the internet < https://clinicaltrials.gov/study/NCT03615066> 21 pgs. [retrieved on 23rd Jun 2026], this study was started on 8-28-2018 and the study completion was 4-12-2021, wherein Selgantolimod and TAF were administered orally, wherein TAF was administered orally daily for 24 weeks in fasted state, followed by TAF alone administered orally daily for another 24 weeks in fasted state; i.e., a total of 48 weeks as recited.
Regarding claims 36, 56, and 59, Lee teach clinical trials with combination treatments for HBV, wherein the treatment includes TAF, measure (i) hepatitis B viral load of less than about 20 international units per milliliter (IU/mL) and (ii) HBeAg-negative status, (In recent data (NCT03576066), 100% of HBeAg-negative CHB patients (n = 18) had virologically suppressed HBV DNA plus pgRNA levels <20 IU/mL after 48 weeks of treatment with vebicorvir 300 mg once daily in combination with oral entecavir, TDF or TAF, pg. 6, 2nd to the last para); and (iii) HBsAg concentration of less than about 100 IU/mL (After the 48-week treatment, HBsAg levels were ≤0.05 IU/mL in 60% (24/40) of the patients, pg. 7, 2nd to the last para).
Regarding claims 37, 39-43, 45-46, 48, and 50, Lee teach see §4. Future Perspectives, “We expect that combination of new drugs may have a higher chance of inducing functional cure of HBV infection.”. However, such combination and dosing needs to be optimized (optimized regimens must be validated, pg. 9, 2nd to the last para). Lee teach, “A significant decrease in HBsAg levels was achieved with an RNA interference-based triple-combination therapy (JNJ-3989, JNJ-6379, and NAs) after 12 weeks of treatment [52]. Various therapeutic combinations can be considered”. In concluding, Lee recommend, “A better chance of functional cure of HBV infection may come from a combination of new drugs that act via different mechanisms.”. They further contemplate, “Combinations that target the viral life cycle directly and induce host immunity are likely to be the most effective. Further studies are needed to demonstrate the safety and efficacy of these drugs.”.
It would have been obvious to have optimized the dosing regimen, and such optimizing is predicted to arrive at the claimed dosing and regimen schedule because Lee teaches that each of the individual treatments were already tested in Phase I/II trials, and some tested in combination with others, and the study results already demonstrated safety and efficacy profiles to allow for continued regimen optimizing. Lee teaches many other similar drugs tested in combination for HBV were received favorably. One of skill would have been motivated to optimize dosing and schedule because Lee suggest that it is necessary to do so in order to obtain a higher chance of inducing functional cure of HBV infection.
Further, MPEP 2144.05 II considers such optimizing to be a matter of design choice. Also see In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
Thus, in instant case, one skilled in the art could have optimized a combination of elements as claimed (combination of known drugs, each having a different mode of action, with optimized schedule and dose) by known methods with no change in their respective functions, with reasonable expectation of success and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See MPEP 2143 I.(A) and 2144 II.
Thus claims 28, 31-43, 45-46, 48, 50, 52, 56 and 59 would have been obvious over the combined prior art teachings.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
No claims are allowed.
Correspondence
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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