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 .
Remark
Preliminary amendment was filed on 12/18/2025. Claims 2-5, 10 and 14 were canceled. Claims 1, 11, 12 and 13 were amended. Claims 1, 6-9, 11-13 and 15-22 are pending.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
Claims 1, 6-9, 11-13, 15-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO2009/072767A2 to Moon et al. and Erik De. Clercq (Journal of Clinical Virology 30 (2004), 115-133).
The claimed subject matter is drawn to a pharmaceutical combined formulation for the prevention or treatment of chronic hepatitis B, which comprises the following components:
I). an antiviral agent for hepatitis B; wherein said antiviral agent for hepatitis B is an oral antiviral agent, wherein the oral antiviral agent is at least one selected from the group consisting of Entecavir, Tenofovirdisoproxil fumarate (TDF), Tenofoviralafenamide fumarate (TAF), Besifovirdipivoxil maleate, Lamivudine, Telbivudine, Clevudine and Adefovirdipivoxil
Ii). A vaccine composition including an antigen, wherein the antigen is an entire surface antigen (L-HBsAg) of HBV (Hepatitis B Virus),
Iii). a lipopeptide and a poly(I:C) adjuvant,
Iv). and lipopeptide is at least one selected from the group consisting of Pam3Cys- SKKKK (SEQ ID NO: 1), PHC-SKKKK (SEQ ID NO: 2), Ole2PamCys-SKKKK (SEQ ID NO:32,Pam2Cys-SKKKK (SEQ ID NO: 4),PamCys(Pam)-SKKKK (SEQ ID NO: 5), Ole2Cys- SKKKK(SEQ ID NO: 6), Myr2Cys-SKKKK (SEQ ID NO: 7), PamDhc-SKKKK (SEQ ID NO:8),PamCSKKKK(SEQ ID NO: 9), and Dhc-SKKKK (SEQ ID NO: 10). Wherein the ratio of the lipopeptide and poy I:C is 0.1 to 10 :1 in weight. .
Moon et al. present an invention related to an immunogenic composition with an adjuvant composition used for treatment or prevention of HBV infection, wherein the composition comprises a lipopeptide and poly I:C , in combination of HBV surface antigen (HBsAg). In particular, the lipopeptide molecule is also the chemically modified lipopeptide selected from the group consisting of Pam3Cys-SKKKK, Pam3Cys-SR8, FLS-I, PHC-SKKKK, Ole2PamCys-SKKKK, Pam2Cys-SKKKK, PamCys(Pam)-SKKKK, Ole2Cys-SKKKK, Myr2Cys-SKKKK, PamDhc-SKKKK, PamCSKKKK and Dhc-SKKKK. The poly I:C is about 50 - 2,000 bp in length. The surface antigen of the HBV includes entire of HBsAG with different transcriptional product i.e. HBsAg, S-HBsAg, M-HBsAg, pre S, or L-HBsAg is consisted of S-protein (small protein without pre S 1 and pre S2), M-protein (medium protein with pre S2 only), and L-protein (large protein with both preSl and preS2).( see pages 1-7, 9, 11-12) or individually differential transcriptase L, preS or S etc. (Claims 7 and 13).
While the HBV surface antigen used by Moon et al to prepare the vaccine formulations comprising many forms of HBV surface antigens, but it does especially including L-HBsAg (See Figs: 1-2., 6, 10) described through the content.
For example, Figure 1 is a graph showing the titer of S-protein antibody elicited by various vaccine formulations containing L-HBsAg composed of L-protein (S-protein-preS2-preSl), M-protein (S-protein-preS2), and S-protein in aluminum hydroxide (Alum), Pam3Cys-SKKKK alone, poly I:C alone, or both Pam3Cys-SKKKK and poy I:C as adjuvants. Fif.2 is a graph showing the titer of antibody against preS antigen induced by various vaccine formulations with L-HBsAg and Alum, Pam3Cys-SKKKK alone, poly I:C alone, or both Pam3Cys-SKKKK and Poly I:C as adjuvants. In this experiment pronounced effect of synergy between Pam3Cys-SKKKK and poly I:C can be seen. Figure 3 is a set of graphs showing the antibody isotypes induced by various different vaccine formulations with L-HBsAg in Alum, Pam3Cys-SKKKK alone, poly I:C alone, or both Pam3Cys-SKKKK and Poly I:C as adjuvants, a; Antibody titer of each isotype, b; IgG2a/IgGl, c; IgG2b/IgGl. Fig. 6 cites: Figure 6 is a graph showing the immunogenicity against HBsAg antigen (S-protein) from Hansenula polymorpha and preS from Saccharomyces cereviciae formulated in different adjuvants; Alum, Pam3Cys-SKKKK alone, poly LC alone, or both Pam3Cys-SKKKK. And Fig. 10 cites: Figure 10 is a graph showing the titer of antibody against preS antigen induced by various vaccine formulations with L-HBsAg and aluminum hydroxide (Alum).
Therefore, Moon ‘s vaccine composition comprises : L-HBsAg and Poly-I:C , and lipopeptide Pam3Cys-SKKKK.
Moon et al. do not teach using an anti-viral agent although they claimed the method for preventing and treating HBV infection as well. Moon et al. also teach that the composition comprises phosphate calcium or calcium salts as well as a surfactant as pharmaceutical acceptable carrier or dilutes and adjuvant.
Moon et al. also teach that the vaccine composition of the present invention can be administered parenterally by various routs such as subcutaneous injection, intravenous injection, intramuscular injection and intrathoracic injection. To prepare the vaccine composition as a formulation for parenteral administration, the vaccine composition is mixed with a stabilizer or a buffering agent to produce a solution or suspension, which is then formulated as a content of ampoules, syringes, or vials in single or multiple doses.
Moon et al. also teach that the ratio of lipopeptide to poly I:C seem to be 1:1 as Moon et al. teach that : Particularly, as shown in Table 4, 0.5 μg of L-HBsAg absorbed to aluminum hydroxide was formulated with 20 βg of each of the lipopeptides or poly LC (experimental group 1 -4). Also the same amount of antigen was formulated with the mixture of lipopeptide and poly LC (experimental group 5-7). See the last paragraph on page 11, paraphs 4-5 of page 14, last 3 paragraphs on page 15)., which implicitely teaches that the same amount of the lipopeptide and poly I:C are added when a vaccine is formulated.
However, Moon et al. do not explitely teach the dosages cited in claim 15, however adjustment of dosage is generally recognized as being within the level of the ordinary skill in the art, In re Rose, 105 USPQ 237 (CCPA 1995) because it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the workable ranges involves only routine skill in the art, In re Aller, 105, USPQ 233. Hence, the claimed invention as a whole is prima facie obvious absence unexpected results.
Erik De. Clercq teach the current armamentarium for the chemotherapy of viral infections for many virus infections including HBV consists of 37 licensed antiviral drugs. For the treatment of chronic hepatitis B virus (HBV) infections, lamivudine as well as adefovir or dipivoxil (Summery in the abstract).
Therefore, it would have been obvious for any person with an ordinarily skilled in the art to be motivated by the cited reference to combine the teachings from Moon et al. and Erik De. Clercq to obtain a good combination of immunological treatment and anti-HBV specific treatment together with a reasonable expectation of success.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/Primary Examiner, Art Unit 1671
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