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 .
DETAILED ACTION
Election Response
The Election filed 9/12/2025 in response to the Office Action of 8/4/2025 is acknowledged. Applicant elected with traverse Group III, claims 10-17, and the species: antibody 2E5, which include heavy chain SEQ ID NO: 30 and light chain SEQ ID NO: 31, and CDR sequences: 38-39-41 and 42-47-49.
Applicants argue that all four asserted groups share a single inventive concept and share the special technical feature of a pharmaceutical combination comprising Compound F and a specific antibody comprising claimed CDR amino acid sequence, which provide synergistic effects in the treatment of tumor.
The arguments have been considered but are not persuasive because the technical feature is the combination of Compound F (or lenvatinib) and antibody M or antibody N. As noted in the restriction, this technical feature does not constitute a special technical feature in view of the prior art: Kimura et al (Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma mode; Cancer Sci. 2018 Dec;109(12):3993-4002), Zheng et al (1) (WO2017020291 A1; Published 2/9/2017), and Zheng et al (2) WO2018053709 A1; Published 3/29/2018).
Kimura teaches the use of lenvatinib for the treatment of cancer and teaches the use of lenvatinib in combination with anti-PD-1 antibodies. Kimura teaches that this combination of lenvatinib with an anti-PD-1 antibody resulted in increased tumor regression and higher response rate versus treatment with either agent alone. Kimura teaches that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination with an immune checkpoint inhibitor. [Abstract] Kimura does not teach the sequences of “antibody M” or “antibody N” as claimed. Zheng (1) teaches the sequences of “antibody M”, that is a heavy chain CDR amino acid sequence SEQ ID NO: 1, which matches 100% to the instantly claimed SEQ ID NO: 1. (see sequence alignments below) Zheng teaches that this antibody is an anti-PD-L1 antibody, and further teaches that this antibody may be combined with other therapeutic agents, such as chemotherapy. [00164-00165; pgs 44-45] Zheng (2) teaches the sequences of “antibody N”, that is an antibody comprising a CDR amino acid sequence SEQ ID NO: 13, which matches 100% to the instantly claimed SEQ ID NO: 41. (see sequence alignments below) Thus, it would have been obvious to substitute the antibodies of Zheng (1) and (2) in the method of Kimura, with a reasonable expectation of success.
Thus, “special technical feature” does not define a contribution over the prior art. For these reasons, the restriction requirement is deemed to be proper and is therefore made FINAL.
Claims 1-19 are pending. Claims 1-9 and 18-19 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 10-17 are currently under prosecution.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: PHARMACEUTICAL COMBINATION COMPRISING LENVATINIB AND AN ANTI-PD-1 ANTIBODY
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 10 and 11-17 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. This is a WRITTEN DESCRIPTION rejection.
The claims are directed to a pharmaceutical combination comprising a substance A and a substance C, wherein the substance A is Compound F, and substance C is an antibody N comprising a CDR amino acid sequence selected from the group consisting of SEQ ID Nos: 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51, or an antigen binding fragment thereof. This written description is directed to substance C, as the claims provide a partial sequence of antibody N.
Claim 11 recites: (a) a heavy chain variable region comprising a HCDR1 amino acid sequence of SEQ ID NO: 38, (b) a light chain variable region comprising a LCDR1 amino acid sequence selected from the group consisting of SEQ ID Nos: 42, 43, 44, 45 and 46. Claim 12 recites limitations in (a)-(i) – “a heavy chain variable region comprising a HCDR1 amino acid sequence...” Claim 13 recites the limitations “a heavy chain variable region comprising an amino acid sequence…” and “a light chain variable heavy region comprising an amino acid sequence…” Claims 11 and 12 refer to the CDRs comprising an amino acid set forth in their respective sequences, which includes full-length CDRs as well as fragments. Claim 13 reads on any amino acid sequence found in the indicated sequence, including fragments.
The instant specification defines antibody N by the following sequences:
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 40, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 42, 47, and 48, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 41, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 42, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 41, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 43, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 41, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 44, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 40, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 45, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 40, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 44, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 41, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 45, 47, and 49, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 41, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 45, 47, and 50, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 40, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 46, 47, and 51, respectively
A heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID Nos: 38, 39, 40, respectively; a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID Nos: 46, 47, and 48, respectively
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 29 and SEQ ID NO: 31, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 31, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 32, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 33, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 29 and SEQ ID NO: 34, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 29 and SEQ ID NO: 33, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 34, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 35, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 29 and SEQ ID NO: 36, respectively.
Heavy chain variable region and a light chain variable region comprising amino acid sequences SEQ ID NO: 30 and SEQ ID NO: 37, respectively.
Thus, the instant specification fails to disclose any other representative variants comprising only one CDR and maintain antibody binding function.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
It is also well known in the art that that changes in amino acid structures, particularly in CDR regions, can have impacts on antigen binding that are unpredictable. Rabia et al (Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochemical engineering journal, 137, 365–374, 2018) and Vajdos et al (Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. Journal of molecular biology, 320(2), 415–428, 2022) teaches that changes to CDRs are unpredictable in terms of affinity, specificity, and solubility, (see Rabia whole documents), and teaches that even minute changes to the CDR region can impact binding affinities. (see Figure 2, effects of CDR mutations on binding affinity), respectively. Rudikoff et al (Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83) teaches that single amino acid substitutions alter antigen-binding specificity. [Abstract] Lastly, Herold et al (Sci Rep. 2017 Sep 25;7(1):12276) teaches and demonstrates that single and double mutations in exemplary antibodies, and found that single point mutations in the VH CDR region can completely abolish antigen binding. [see pg 8]
To provide adequate written description and evidence of possession of the claimed antibodies, the instant specification can structurally describe representative variants of the antibodies, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In the instant case, the specification does not disclose any variants of the antibodies that function as claimed. The instant specification does not disclose any other representative variants having less than the full CDR sequences. Applicants have not established any reasonable structure-function correlation with regards to the sequences of the antibody that can be altered and still maintain function. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the antibody variants, and lack of reasonable structure-function correlation with regards to the unknown variant sequences that can be altered and still maintain antibody binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the vast genus of sequence antibodies, that is required to practice the claimed inventions.
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.
Claim(s) 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Kimura et al (Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma mode; Cancer Sci. 2018 Dec;109(12):3993-4002; of record), in view of Zheng et al (2) WO2018053709 A1; Published 3/29/2018; of record).
It is noted that Compound F is lenvatinib as noted in the instant specification, [0004, 0106 – published application]
It is noted that antibody N is an anti-PD-1 antibody, 2E5. [0108 of published application]
Kimura et al teaches that lenvatinib (Compound F) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Kimura teaches that preclinical studies have demonstrated that lenvatinib has potent antiangiogenic activity through inhibition both the VEGF and FGF signaling pathways and show antitumor activity consistently across diverse solid tumor models. Kimura teaches that agents targeting immune checkpoint signaling have shown promising results in patients with several malignancies. Kimura teaches that immune checkpoint inhibitors, such as anti-PD-1 antibody, may be combined with other targeted therapies to increase the benefits obtained from immune checkpoint blockade therapy. [pg 3994]
Applicant argues that Compound F and the specific antibody demonstrate synergistic effects in the treatment of tumor. With regards to Kimura teaches and demonstrates the combination of lenvatinib and an anti-PD-1 antibody, as the combination of an immune checkpoint inhibitor with an angiogenesis inhibitor is an attractive way to improve immunotherapy outcome because many angiogenic molecules, such as VEGFs have immunosuppressive functions. [pg 4000] Kimura teaches that while anti-PD-1 antibody treatment alone provided partial treatment, the combination of lenvatinib and anti-PD-1 antibody significantly reduced the tumor volume compared with each treatment alone, and even regressed the tumors to nonpalpable sizes in some cases. Kimura also explicitly teaches that the combination of lenvatinib with an immune checkpoint inhibitor, may exert a synergistic anti-tumor activity. Thus, the combination of lenvatinib and anti-PD-1 antibodies [pg 3998 (3.3), 4000-4001] Thus, the expectation of lenvatinib and immune checkpoint inhibitors having synergistic results is known and expected based on the disclosure of the prior art. [See MPEP 716.02]
However, Kimura does not teach the exact sequence of the anti-PD-1 antibody, or that substance A and substance C are in a “kit” as stated in claim 17.
Zheng teaches antibody N (2E5) which comprises the instantly claimed sequences. [see sequence alignments below, pg 6]
A heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 2, which matches 100% to the instantly claimed SEQ ID NO: 30
BFE07376
ID BFE07376 standard; protein; 115 AA.
XX
AC BFE07376;
XX
DT 17-MAY-2018 (first entry)
XX
DE Anti-PD-1 antibody heavy chain variable region SEQ ID 2.
XX
KW PD-1 protein; Programmed cell death ligand 1; antibody production;
KW antibody therapy; cancer; cytostatic; expression;
KW heavy chain variable region; humanized antibody; immune disorder;
KW immune modulation; immunoconjugate; immunomodulator; programmed death-1;
KW prophylactic to disease; therapeutic; transgenic animal;
KW tumor suppressor; vector.
XX
OS Homo sapiens.
OS Rattus sp.
OS Chimeric.
XX
CC PN WO2018053709-A1.
XX
CC PD 29-MAR-2018.
XX
CC PF 21-SEP-2016; 2016WO-CN099576.
XX
PR 21-SEP-2016; 2016WO-CN099576.
XX
CC PA (WUXI-) WUXI BIOLOGICS SHANGHAI CO LTD.
XX
CC PI Zheng Y, Li J, Gololobov G, Zhang X, Yang B, Tang Z, Li D;
CC PI Xu J, Wang Z;
XX
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 601 100.0 115 BFD41773 -- 22 Anti-PD-1 antibody heavy chain variable region, SEQ ID 2.
ALIGNMENT:
Query Match 100.0%; Score 601; Length 115;
Best Local Similarity 100.0%;
Matches 115; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGSSVKVSCKASGFTFTTYYISWVRQAPGQGLEYLGYINMGSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGSSVKVSCKASGFTFTTYYISWVRQAPGQGLEYLGYINMGSGGTNY 60
Qy 61 NEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAIIGYFDYWGQGTMVTVSS 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAIIGYFDYWGQGTMVTVSS 115
A light chain variable region comprising an amino acid sequence of SEQ ID NO: 3, which matches 100% to the instantly claimed SEQ ID NO: 31
BFE07377
ID BFE07377 standard; protein; 112 AA.
XX
AC BFE07377;
XX
DT 17-MAY-2018 (first entry)
XX
DE Anti-PD-1 antibody light chain variable region SEQ ID 3.
XX
KW PD-1 protein; Programmed cell death ligand 1; antibody production;
KW antibody therapy; cancer; cytostatic; expression; humanized antibody;
KW immune disorder; immune modulation; immunoconjugate; immunomodulator;
KW light chain variable region; programmed death-1; prophylactic to disease;
KW therapeutic; transgenic animal; tumor suppressor; vector.
XX
OS Homo sapiens.
OS Rattus sp.
OS Chimeric.
XX
CC PN WO2018053709-A1.
XX
CC PD 29-MAR-2018.
XX
CC PF 21-SEP-2016; 2016WO-CN099576.
XX
PR 21-SEP-2016; 2016WO-CN099576.
XX
CC PA (WUXI-) WUXI BIOLOGICS SHANGHAI CO LTD.
XX
CC PI Zheng Y, Li J, Gololobov G, Zhang X, Yang B, Tang Z, Li D;
CC PI Xu J, Wang Z;
XX
DR WPI; 2018-25690D/24.
XX
CC PT Antibody or antigen binding fragment use in preparation of medicament for
CC PT treatment orprophylaxis of immune disorder or cancer that is melanoma, is
CC PT binds to epitope of programmed cell death protein 1 comprises amino acids
CC PT sequences.
XX
CC PS Claim 8; SEQ ID NO 3; 84pp; English.
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 590 100.0 112 BFD41774 -- 21 Anti-PD-1 antibody light chain variable region, SEQ ID 3.
ALIGNMENT:
Query Match 100.0%; Score 590; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DVVMTQSPLSLPVTLGQPASISCRSSQSLLDSDGGTYLYWFQQRPGQSPRRLIYLVSTLG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DVVMTQSPLSLPVTLGQPASISCRSSQSLLDSDGGTYLYWFQQRPGQSPRRLIYLVSTLG 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQLTHWPYTFGQGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQLTHWPYTFGQGTKLEIK 112
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the instantly claimed antibody and lenvatinib. One would have been motivated to, and have a reasonable expectation of success because: (1) Kimura teaches the combination of lenvatinib and an anti-PD-1 antibody and demonstrates that the combination allows for significant anti-tumor effects compared to each treatment alone, and (2) Zheng teaches the known “antibody n” and the instantly claimed sequences. One of skill in the art could have substituted one known anti-PD-1 antibody another, and the results of synergistic and additive effects would have been predictable.
It is noted that claim 17 requires a kit comprising a first container comprising substance B and a second container comprising substance C as defined by claim 10. This limitation would have been obvious to those of ordinary skill in the art because: (1) Kimura teaches the combination of lenvatinib and an anti-PD-1 antibody, and (2) Zheng teaches the known instantly claimed “antibody N”. Given the recognized need to utilize a kit, and given the known methods of utilizing kits, one of skill in the art would recognize that storing an antibody and a drug in separate containers, are routine.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600