DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I claims 1-15 and 21-22 in the reply filed on 04/21/2026 is acknowledged.
Applicant elected following species:
(i) the anti-PD-L1 antibody comprising HCDR1 of
SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, for the antibody, and
(ii) elected formula I or a pharmaceutically acceptable salt thereof for the toll-like receptor 7 agonist or pharmaceutically acceptable salt thereof.
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The elected species read on claims 1-15 and 21-22.
The Restriction/Election is made final.
Upon further search and consideration the claimed anti-PD-L1 additionally recited Markush listing of VH and VL CDRs 1-3 amino acid sequences (claim 1), and VH and VL sequences of PD-L1 antibody (claim 6) were examined for compact prosecution.
Status of Claims
3. Claims 1-15 and 18-22 filed on 09/22/2023 are pending.
4. Claims 18-20 are withdrawn from examination due to Restriction/Election.
5. Claims 1-15 and 21-22 are under examination.
Priority
6. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PRC China a Chinese Patent No. 202110333959.7, filed on March 29, 2021. This application is a 371 of PCT/CN2022/083661 filed on 03/29/2022.
Claim Rejections - 35 USC § 112
7. 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. This is a written description rejection.
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 1-15 and 21-22 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 instant claims 1-15 and 18-22 are directed to a composition and are interpreted to comprise a limitation on genus of an anti-PD-L1 antibody that binds to PD1-L1 receptor on a lymphocyte (instant specification page 2 lines 5-15). The full scope of the claims 1-15 and 18-22 is not clear because the instant claim 1 recited limitation wherein the anti- PD-L1 antibody comprises the following amino acid sequences: a heavy chain and light chain CDRs 1-3 region having at least 80% homology with an amino acid sequence set forth for the instant claimed antibody CDR 1-3 sequences. The instant claim 6 recited limitations, wherein a heavy chain and a light chain variable region having at least 80% homology with an amino acid sequence set forth for the instant claimed antibody sequences. Therefore, the inherently claimed 20% variability in the claimed antibody sequence (CDRs of antibody claim 1; VH and VL of antibody claim 6) can comprise deletion/insertion/substitution of amino acids which is neither defined, nor exemplified in the specification accordingly there is no standard for the degree of variability of amino acid sequence. The full scope of the claims 1-15 and 18-22 is not clear. The applicant in the instant specification has not provided examples of amino acid sequences with at least 80% homology (reads on 20% variability) to the instant claimed anti-PD-L1 antibody comprising CDRs 1-3 or VH and VL.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. The written description requirement for a claimed genus (anti-PD-L1 antibody) may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). See MPEP 2163 “Written Description Guidelines”.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Amgen Inc. vs Sanofi (2017-1480, Fed Cir, 2017) states that "an adequate written description must contain enough information about the actual makeup of the claim products - a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material," which may be present in "function "terminology "when the art has established a correlation between structure and function" (page 17,1st paragraph).
It has been well known in the art that minor structural differences even among structurally related compounds or compositions can result in substantially different biological or pharmacological activities. It is known in the art that the substitution of amino acids within the protein sequence may cause the loss of function of the protein. Thus, the large number of amino acid sequences (“80% homology” in CDRs 1-3 or VH and VL has inherently claimed 20% variability) encompassed by the current claims may or may not be effective in achieving the binding affinities for the PD-L1 receptor molecule. Specifically in relation to CDRs, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR 1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: ncbi.nlm.nih.gov/books/NBK27144/. See entire article). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al. Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982;79(6):1979-1983, see entire article, particularly the abstract and the middle of the left column of page 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Therefore, the ordinary skill in the art is not reasonably convinced that the applicant and inventors had possession of the claimed composition invention of claims 1-15 and 18-22 at the time the application was filed, since there is insufficient representative species and/or identifying characteristics to place applicant in possession of the generic scope of the claimed composition comprising anti-PD-L1 antibody with 80% homology (reads on 20% variability) to CDRs 1-3 sequence or 80% homology (reads on 20% variability) to VH and VL amino acid sequences.
Claim Interpretation
8. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: The instant claim 1 is directed to a pharmaceutical combination comprising a toll-like receptor 7 agonist or a pharmaceutically acceptable salt thereof and an anti-PD-L1 antibody, wherein the anti- PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 12.
Claim 6: The pharmaceutical combination according to claim 1, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 13 or SEQ ID NO: 14; and a light chain variable region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16.
The claimed composition comprises an anti-PD-L1 antibody comprising VH and VL CDRs 1-3 or VH and VL with 80% homology to the claimed antibody from the spec that are within the scope of the claims (see, instant specification pages 9-10). The genus of claimed anti-PD-L1 antibody comprising VH and VL CDRs 1-3 or VH and VL is interpreted to comprise at least 20% variability (modifications) for meeting the requirement for the full scope of the claim.
Claim Rejections - 35 USC § 103
9. 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.
10. Claims 1-15 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al 2014 (PLoS pathogens, 10(1), e1003856), and further in view of Zha et al 2019 (US10435470B2, 10/08/2019), Zhaozhong et al 2016 (CN105367576A, 03/02/2016), Irving et al 2012 (US8217149B2, 07/10/2012), and Colonno et al 2001 (US20010033864A1, 10/25/2001).
Claim 1: Liu et al 2014 discloses that a TLR7 agonist and a PD-L1 antibody are combined for therapy, so as to activate different targets of the immune system and have synergistic effects on control of chronic hepatitis B virus infection. Further disclosed is combined therapy with entecavir (ETV) (See, abstract, page 6, figure 4 and page 11, left column, paragraph 3).
Liu et al 2014 do not disclose the elected/claimed anti-PDL-1 antibody VH CDR 1-3 (SEQ ID NOs: 1-3) and VL CDR 1-3 (SEQ ID NOs: 7-9) with 80 % homology to the CDR amino acid sequences.
Zha et al 2019 (US10435470B2) disclosed humanized anti-PD-L1 antibodies for treatment of Hepatitis B virus (See, abstract, col 33 lines 44-67), claims 1-30).
Zha et al 2019 disclosed SEQ ID NO 10 that has 100% identity with instant claim 1 anti-PD-L1 antibody VH CDRs 1-3 SEQ ID NO: 1-3.
Query Match 84.7%; Score 136.4; Length 116;
Best Local Similarity 38.7%;
Matches 29; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 TYGVH--------------VIWRGVTTDYNAAFMS------------------------- 21
||||| ||||||||||||||||
Db 31 TYGVHWVRQSPGKGLEWLGVIWRGVTTDYNAAFMSRLTITKDNSKSQVFFKMNSLQANDT 90
Qy 22 -------LGFYAMDY 29
||||||||
Db 91 AIYYCARLGFYAMDY 105
Zha et al 2019 disclosed SEQ ID NO 12 that has 100% identity with instant claim 1 anti-PD-L1 antibody VL CDRs 1-3 SEQ ID NO: 7-9.
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391
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Claim 2: Liu et al 2014 do not disclose TLR-7 agonist compound formula I.
Zhaozhong et al 2016 is directed to pyrrolopyrimidine compounds as TLR7 agonists, and particularly relates to compounds of the formula (I) or pharmaceutically acceptable salts thereof, a preparing method of the compounds, pharmaceutical compositions containing the compounds or the salts, and uses of the compounds or the salts for preparation of antivirus medicines. The formula (I) is shown in the specification (See, abstract, claims 1-14). Zhaozhong et al 2016 (See, CN105367576A Chinese version of published application page 4 col 2, structure formula number 2) teaches the toll-like receptor 7 agonist or the pharmaceutically acceptable salt thereof is selected from a compound of formula I.
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113
329
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In addition, Zhaozhong et al 2016 (See, CN105367576A Chinese version, pages 4-7) teaches multiple toll-like receptor 7 structures that are reasonably expected to have similar effect.
Claims 3-5: Zhaozhong et al 2016 teaches the pharmaceutical composition pyrrolopyrimidine compounds as TLR7 agonists, and particularly relates to compounds of the formula (I). A therapeutically effective amount of a compound of formula I is from about 0.0001 to 20 mg/Kg body weight/day, for example from 0.001 to 10 mg/Kg body weight/day. Administration may be intermittent, for example, wherein a patient receives a daily dose of a compound of formula I over a period of several days, followed by a period of several days or more in which the patient does not receive a daily dose of a compound of formula I (See, Zhaozhong et al 2016 CN105367576A English Translation, Disclosure of Invention). In the instant claim 3 claimed range for TLR agonist is a single dose 0.01 mg – 10 mg or a pharmaceutically acceptable salt of the TLR agonist in a single dose of 0.2 mg or 0.5 mg. According to MPEP 2144.05, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
The optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Claim 6: Zha et al 2019 (US10435470B) teaches added limitation of instant claim 6, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 13 or SEQ ID NO: 14 and a light chain variable region having at least 80% homology with an amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16.
The instant SEQ ID NO: 13 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 42.
Query Match 100.0%; Score 620; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYN 60
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Db 1 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYN 60
Qy 61 AAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSS 116
The instant SEQ ID NO: 14 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 46.
Query Match 100.0%; Score 607; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKGLEWVASISSGGSTYYP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKGLEWVASISSGGSTYYP 60
Qy 61 DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVTVSS 116
The instant SEQ ID NO: 15 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 44.
Query Match 100.0%; Score 563; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPD 60
Qy 61 RFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIK 107
The instant SEQ ID NO: 16 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 48.
Query Match 100.0%; Score 584; Length 111;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLES 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLES 60
Qy 61 GVPARFSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVPARFSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIK 111
Claim 7: Zha et al 2019 (US10435470B) teaches added limitation of instant claim 7, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO: 17; and a light chain amino acid sequence set forth in SEQ ID NO: 18.
The instant SEQ ID NO: 17 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 70.
Query Match 100.0%; Score 2385; Length 446;
Best Local Similarity 100.0%;
Matches 446; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYN 60
Qy 61 AAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSSASTK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSSASTK 120
Qy 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180
Qy 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 240
Qy 241 LFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 300
Qy 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 360
Qy 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 420
Qy 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
||||||||||||||||||||||||||
Db 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
The instant SEQ ID NO: 18 is taught by Zha et al 2019 (US10435470B) SEQ ID NO: 74.
Query Match 100.0%; Score 1116; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPD 60
Qy 61 RFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Claims 8-10: Zha et al 2019 (US10435470B) teaches anti-PD-L1 antibody is in the form of a pharmaceutical composition (See, col 18 para 2, claim 26).
Zha et al 2019 do not teach the optional limitation on quantity in mg of single dose or multiple doses of anti-PD-L1 antibody per week.
Irving et al 2012 (US8217149B2, 07/10/2012) is directed to treatment of Hepatitis B virus inflection using combination therapy and disclosed the anti-PD-L1 antibodies of the invention may be combined with conventional treatments for hepatitis B infections for therapeutic advantage (See, col 88, line 44-67, entire prior art). Pharmaceutical dosage of anti-PD-L1 antibody is disclosed (See, col 97-98) as 1-10 mg/kg/body weight/day depending on route of administration (See, col 97, lines 30-49). Thus, based on Irving et al 2012 teachings the dose of anti-PD-L1 antibody for an average human body weight of 62 kg the dose would be fall in the claimed ranges in mg in claim 8. For example, a 60 kg human would need a dose of 600 mg at 10 mg/kg/body, and 240 mg at 4 mg/kg/body. The treatment with anti-PD-L1 antibody for multiple times in a week is taught as exemplified for LCMV virus infection (See, Example 7).
Claim 11: Zhaozhong et al 2016 teaches the pharmaceutical composition pyrrolopyrimidine compounds as TLR7 agonists, and particularly relates to compounds of the formula (I). A therapeutically effective amount of a compound of formula I is from about 0.0001 to 20 mg/Kg body weight/day, for example from 0.001 to 10 mg/Kg body weight/day.
Irving et al 2012 (US8217149B2, 07/10/2012) is directed to treatment of Hepatitis B virus inflection using combination therapy and disclosed the anti-PD-L1 antibodies and teaches pharmaceutical dosage of anti-PD-L1 antibody is disclosed (See, col 97-98) as 1-10 mg/kg/body weight/day depending on route of administration (See, col 97, lines 30-49).
The combined teachings of Zhaozhong et al 2016 and Irving et al 2012 on doses of TLR7 agonists, and particularly relates to compounds of the formula (I) and anti-PD-L1 antibody results in the claimed ratio of the pharmaceutical combination of TLR7 agonist as 1: anti-PD-L1 antibody (10-200) or, the average daily dose ratio of the toll-like receptor 7 agonist or the pharmaceutically acceptable salt thereof to the anti-PD-L1 antibody is selected from the group consisting of 1:(100-120), 1:(102-118), 1:(104- 116), and 1:(108-116). For example, 1 mg TLR7 agonist to anti-PD-L1 antibody 10 mg results in 1:10 ratio.
According to MPEP 2144.05, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
"[W]here 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”, See, MPEP 2144.05(II).
Claims 12-15: The combined teachings of Liu et al 2014, Zha et al 2019, Zhaozhong et al 2016, and Irving et al 2012 teaches the pharmaceutical combination according claim 1, and comprising entecavir, however, does not teach dose and a weight ratio of the toll-like receptor 7 agonist to the anti-PD-L1 antibody to the entecavir from about 0.01 mg to about 5 mg of entecavir.
Colonno et al 2001 is in the art and teaches pharmaceutical composition comprising entecavir administered on a daily basis contains from about 0.01 mg to about 5 mg of entecavir to treat hepatitis B virus infection (see, abstract, claims 40-41, claim 1, entire document).
The teachings of Zhaozhong et al 2016 on (i) doses of TLR7 agonists, and particularly relates to compounds of the formula (I) about 0.0001 to 20 mg/Kg body weight, for example from 0.001 to 10 mg/Kg body weight and Irving et al 2012 on anti-PD-L1 antibody dose 1-10 mg/kg body weight as recited supra and the teachings of Colonno et al 2001 on entecavir dose from about 0.01 mg to about 5 mg/day reasonably teaches the instant claim 15 limitation wherein a weight ratio of the toll-like receptor 7 agonist or the pharmaceutically acceptable salt thereof to the anti-PD-L1 antibody to the entecavir or the pharmaceutically acceptable salt or solvate thereof is 1:(10-200):(1-10); or, the average daily dose ratio of the toll-like receptor 7 agonist or the pharmaceutically acceptable salt thereof to the anti- PD-L1 antibody to entecavir or the pharmaceutical salt or solvate thereof in the pharmaceutical combination is selected from the group consisting of 1:(10-200):(1-10), 1:(100-120):(1.2-4.0), 1:(102-118):(1.6-3.8), 1:(104-116):(1.8-3.8),and 1:(108-116):(2.0-3.6).
According to MPEP 2144.05, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
"[W]here 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”, See, MPEP 2144.05(II).
The optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Claims 21-22: The combined teachings of Liu et al 2014, Zha et al 2019, Zhaozhong et al 2016, Irving et al 2012, and Colonno et al 2001 teaches pharmaceutical combination according to claim 1 comprising TLR agonist, anti-PD-L1 antibody and entecavir and combination of dose ranges. However, does not explicitly teach the exact claim limitations of instant claims 21-22. Based on the prior art teachings, it would have been obvious to one of the ordinary skills in the art to reasonably arrive at the pharmaceutical composition combination claimed in instant claims 21-22.
According to MPEP 2144.05, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
"[W]here 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”, See, MPEP 2144.05(II).
The optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Liu et al 2014 with additional teachings on anti-PD-L1 antibody VH and VL CDR sequences disclosed by Zha et al 2019, and the toll-like receptor 7 agonist or the pharmaceutically acceptable salt thereof is selected from a compound of formula I of Zhaozhong et al 2016, Irving et al 2012 on dose of anti-PD-L1 antibody and Colonno et al 2001 on dose of entecavir to arrive at the inventions of claims 1-15 and 21-22. One of ordinary skills in the art would have been motivated to combine the prior art teachings to develop efficacious pharmaceutical composition and optimize doses and administration schedule comprising combination of TLR agonist, anti-PD-L1 antibody and entecavir for treatment of Hepatitis B virus infection for efficacy and commercial success. One of the ordinary skills would have been apprised of a reasonable expectation of success to arrive at the invention of claims 1-15 and 21-22 given the combined prior art teachings as applied and as recited supra. This is analogous to 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 invention of instant claims 1-15 and 21-22. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Double Patenting
12. 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.
Claims 1-15 and 18-22 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of Xu et al 2025 U.S. Patent No. US12336996B2 (06/24/2025) in view of Liu et al 2014 (PLoS pathogens, 10(1), e1003856), and further in view of Zha et al 2019 (US10435470B2, 10/08/2019), and Zhaozhong et al 2016 (CN105367576A, 03/02/2016).
Both the instant claims 1-15 and 18-22 and patented claims 1-19 of Xu et al 2025 U.S. Patent No. US12336996B2 are directed to drug combination comprising TLR agonist and entecavir for the treatment of hepatitis B virus infection.
The instant claims 1-15 and 18-22 comprise anti-PD-L1 antibody whereas the patented reference claims do not comprise combination comprising anti-PD-L1 antibody.
In view of the combined prior art teachings of Liu et al 2014, Zha et al 2019, and Zhaozhong et al 2016 it would have been obvious to one of the ordinary skills in the art to modify the patented reference claims to comprise anti-PD-L1 antibody in the pharmaceutical composition combination because both the instant application and patented reference application are directed to pharmaceutical composition and method for treatment of Hepatitis B virus. Zha et al 2019 (US10435470B2) provides motivation by disclosing a composition comprising anti-PD-L1 antibody for treatment of Hepatitis B virus infection, the anti-PD-L1 antibody and the additional therapeutic agent are administered in the same formulation ( and different viral and bacterial infections) because anti-PD-L1 antibody modulate regulatory T cell function (e.g. restore the capacity for IFNγ production to effector T cells in contact with regulatory T cells) (See, col 33 lines 44-66, col 34 lines 1-36, entire document). One of ordinary skills in the art would have been motivated to modify the patented reference claims by applying the combined prior art teachings as recited supra to develop efficacious pharmaceutical composition comprising combination of TLR agonist, anti-PD-L1 antibody and entecavir for treatment of Hepatitis B virus infection for efficacy and commercial success. One of the ordinary skills would have been apprised of a reasonable expectation of success given the applied prior arts in Hepatitis B virus treatment.
13. Relevant Prior Arts
Korolowizc et al 2019. Liver‐targeted toll‐like receptor 7 agonist combined with entecavir promotes a functional cure in the woodchuck model of hepatitis B virus. Hepatology Communications, 3(10), 1296-1310.
Balsitis et al 2018. Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection. PLoS One. 2018 Feb 14;13(2):e0190058.
Conclusion
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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