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 .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to a method for potentiating the therapeutic efficacy of PD-1 and/or PD-L1 inhibition in a subject comprising administering a conjugate of a cytotoxic agent and an antibody capable of binding to human AXL and corresponding to claims 1-4, 8-10, 15, 20, 21, 30, 31, 33-36, 38, 39, 44, 46, 47, 49, 51-53, 55, 61, 80, 81, and 84, in the reply filed 10/03/2025 is acknowledged.
Applicant has further elected examination of the following species: elects (a) an antibody which binds to L121-Q129 of human AXL, has the VHCDR1-3 sequences of SEQ ID NOs: 36-38, and VLCDR1-3 sequences of SEQ ID NO: 39, the sequence GAS, and SEQ ID NO: 40, and the VH and VL sequences of SEQ ID NOs: 1 and 2, respectively, (b) microtubule-binding agents, (c) pembrolizumab, and (d) skin cancer.
Claim Status
Claims 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 46-47, 49, 51-53, 55, 61, 80-81, 84, 108, and 112 are pending. Claims 108 and 112 are withdrawn for being directed to a non-elected invention. Claims 46-47, 49, and 55 are withdrawn for being drawn to non-elected species.
Claims 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 are under examination.
Specification Objections
The specification is objected to for the following informality: In multiple locations, the specification incorrectly states “human Axl having the sequence set forth in SEQ ID NO: 1” (for example, Pg. 2, Line 20). SEQ ID NO:1 corresponds to VH of antibody clone 107 (Pg. 18, Table 1).
Appropriate correction at each location is required.
Claim Objections
Claims 10 and 21 are objected to for incorrectly stating “human AXL having the sequence set forth in SEQ ID NO: 1” where SEQ ID NO: 1 is not the human AXL sequence.
Claim 10 is objected to for referencing Example 3 of WO 2016/005593.
Claim Rejections - 35 USC § 112(b)
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 9, 10, 15, 36, 38, 44, 52, 80 and 81 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 9, 10, 36, 38, 44, 52, 80, and 81, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 15, the brackets at the end of each subsection, such as in “[107]” and “[148]”, renders the claim indefinite because it is unclear whether the limitations within the brackets are part of the claimed invention.
Claim Rejections - 35 USC § 112(a)
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, 8-10, 21, 31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claims are directed to anti-AXL antibody drug conjugates with claimed functions and phenotypes which include binding specific epitopes and use in the treatment of cancer. The claims as written either do not define the minimal required structure of the antibodies or allow for extensive modifications to the parent molecules and do not provide guidance as to how the components can be modified and still retain their respective functions.
The specification discloses IgG1-AXL-107-vcMMAE, with a defined VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a defined VL region comprising the CDR1, CDR2, andCDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, and provides evidence of anti-tumorigenic effects of the antibody drug conjugate (see for example, Fig. 1)
State of the relevant art
It is well established in the art that the formation of an intact antigen-binding site in an antibody or usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
The art thus underscores the importance of fully defined CDRs and evidence from the inventors that they were in possession of each claimed antibody embodiment.
Claim Analysis
In light of the state of the relevant art and the lack of guidance provided in the specification, the claims have the following written description issues:
Claim 1 teaches administration of antibody drug conjugate that binds human AXL with a function of inducing immunogenic cell death and/or tumor-associated inflammation. The claim requires a functional effect, but does not provide sequence structure required for the intended function.
Claims 4 and 8 teach the phenotype of the antibody drug conjugate, but do not provide sequence structure required for the intended function.
Claim 10 defines the antibody drug conjugate by binding epitope only.
Claim 21 is directed to VH and VL regions defined by percent identity of disclosed SEQ IDs. The claims do not preclude mutations within the CDR regions of the antibody.
Claim 35 states that the antibody of the method of enapotamab or a biosimilar thereof. The use of the term “biosimilar” constitutes claiming an agent defined only by function.
One of skill in the art would neither expect nor predict the appropriate functioning of the anti- anti-AXL antibody drug conjugates as broadly as is claimed. As the disclosure does not define the minimum structure of each component that would impart functionality to each of these claimed elements, the disclosure does not allow those of skill in the art to recognize other members of the claimed genus.
Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of structures as broadly claimed.
All dependent claims that do not define the structure of the anti-AXL antibody are also rejected for being dependent on claim 1 and not providing limitations that satisfy the written description requirement.
Claim Rejections - 35 USC § 102
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, and 61 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Breij (US2017/0157250A1, published 06/08/2017, effectively filed 07/11/2014).
The disclosure of Breij is directed to anti-AXL antibodies and immunoconjugates, compositions and methods of treatment of cancer with such anti-AXL antibodies, immunoconjugates of compositions (see Abstract). Breij discloses the AXL-antibody drug conjugate IgG1-AXL-107-vcMMAE (see for example, Fig. 7 and [0829] Anti-Tumor Activity of AXL-ADCs In Vivo).
Regarding claim 1, pertaining to a method of potentiating the therapeutic efficacy of programmed cell death-1 (PD-1) and/or programmed death-ligand 1 (PD-L1) inhibition in a subject, the method comprising administering to the subject an effective amount of a conjugate of a cytotoxic agent and an antibody capable of binding to human AXL, Breij discloses administration of IgG1-AXL-107-vcMMAE in a tumor model ([0829], Example 13). The preamble of the claim states the intended use of the AXL-ADC and does not require the administration of an inhibitor of PD-1 or PD-L1.
Regarding claim 4, wherein the antibody does not compete for AXL binding with the ligand Growth Arrest-Specific 6 (Gas6), Breij discloses IgG1-AXL-107 does not interfere with Gas6 binding (Fig. 12 and Table 11, [0824]. The characteristics of this claim are intrinsic to the antibody IgG1-AXL-107 of the disclosure.
Regarding claim 8, wherein the antibody is capable of being internalized when cell surface bound, Breij discloses the antibodies of the disclosure may be internalized into the cell upon binding to the target, AXL ([0451], Lines 1-3). Once internalized, the ADC may be delivered to lysosomes where the drug is released ([0453], Lines 1-4).
Regarding claim 9, wherein internalization is determined by the disclosed flow cytometry method, Greij discloses the identical method of detecting internalization of cell surface bound HuMab-AXL antibodies to MDA-MB-231 and Calu-1 cells in Example 16 (Pg. 65, [0844]-[0845]).
Regarding claim 10, wherein the antibody binds to an epitope which comprises or requires one or more amino acids corresponding to positions L121 to Q129 of human AXL having the sequence set forth in SEQ ID NO: 1,
Regarding claims 15, 20-21, and 30, wherein the antibody comprises at least one binding region comprising a variable heavy chain (VH) region and a variable light chain (VL) region a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively (claim 15 and 20) and wherein said at least one binding region comprises a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2 (claims 21 and 30), Breij claims 9, 11-13 disclose the VH and VL of the instant invention with identical sequence identifiers. Breij teaches the sequences correspond to anti-AXL clone 107 (Pg. 38, Table 1).
The sequence of the anti-AXL antibody clone 107 as disclosed in Breij Table 1 (Pgs. 38-40, relevant selections cropped) is shown below:
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859
1271
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Greyscale
Regarding claims 31, 33-36, and 38-39, Breij discloses IgG1-AXL-107-vcMMAE, identified in the instant specification as enapotamab vedotin (Specification Pg. 51, Lines 4-5). The ADC IgG1-AXL-107-vcMMAE anticipates the following limitations of the instant invention:
Claim 31, wherein said antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 – Breij claim 20
Claim 33, wherein the antibody is a full-length monoclonal antibody – Breij claim 22
Claim 34, wherein the antibody is human or humanized – Breij teaches the antibodies are HuMab ([0767], Lines 1-3)
Claim 35, wherein the antibody is enapotamab or a biosimilar thereof – instant Specification Pg. 51, Lines 4-5
Claim 36, wherein said cytotoxic agent is linked to said antibody with a cleavable linker – Breij claim 32
Claim 38, wherein said cytotoxic agent is a microtubule-targeting agent – Breij claim 34
Regarding claim 39, wherein said conjugate has bystander kill capacity – Breij claim 35
Regarding claim 44, wherein said conjugate has a Drug-to- Antibody Ratio (DAR) which is within the range of 1-8, Breij discloses a DAR of 1-20 ([0482]-[0485]).
Regarding claim 61, wherein immunogenic cell death and/or tumor- associated inflammation is characterized by a) increased release of ATP from cells of said tumor, b) secretion of high-mobility group box 1 (HMGB1) from cells of said tumor, and/or c) cell surface expression of Calreticulin on cells of said tumor, these properties are inherent to the anti-AXL ADC IgG1-AXL-107-vcMMAE, as evidenced by the instant specification (for example, Fig. 8).
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 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Breij (US2017/0157250A1, published 06/08/2017, effectively filed 07/11/2014) as applied to claims 1, 4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, and 61 above, and further in view of Van Berkel (US2019/0218291A1, published 07/18/2019, effectively filed 04/20/2017).
The disclosure of Breij discloses administration of the anti-AXL antibody drug conjugate IgG1-AXL-107-vcMMAE.
Regarding claims 80 and 81, wherein the cancer according to the method of claim 3 is a solid tumor (claim 80) and wherein the cancer is skin cancer (claim 81), Breij discloses use of the anti-AXL ADC for the treatment of skin cancer (Breij claims 55 and 56).
The disclosure of Breij does not teach (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, and (3) the subject has received prior treatment with a PD-1 pathway inhibitor.
These deficiencies are taught by Van Berkel.
The disclosure of Van Berkel is directed to clinically advantageous combination therapies in which an anti-AXL ADC is administered in combination with at least one secondary agent. ([0014], Lines 1-6).
Regarding claims 2-3, 51-53, wherein the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1 (claims 2 and 3), wherein the inhibitor an inhibitor of the interaction between PD-1 and its ligand (claim 51), wherein the inhibitor is an antibody (claim 52), and wherein the inhibitor is pembrolizumab (claim 53), Van Berkel teaches the AXL ADC is co-administered with the PD-1 antagonist antibody pembrolizumab (Pg. 150, claims 28 and 29).
Regarding claim 84, wherein the subject has received prior treatment with a PD-1 pathway inhibitor, Van Berkel specifically teaches the alleviation of resistance to PD-1 inhibitors with the use of PD-1 inhibitors in combination with the ADC ([0325], Lines 6-11) and teaches that study groups include a subset of patients previously treated with a secondary agent to explore whether combination therapy might overcome resistance to secondary agent therapy ([1082], Lines 1-4).
It would have been obvious to one having ordinary skill in the art to modify the method of Breij with the teachings of Van Berkel wherein (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, and (3) the subject has received prior treatment with a PD-1 pathway inhibitor. One would have been motivated to do so because Van Berkel teaches co-administration of anti-AXL antibody drug conjugate with anti-PD1 antagonist antibody such as pembrolizumab to overcome resistance to the PD-1 inhibition therapy. There would be an expectation of success in treating with a combination therapy of anti-AXL ADC and pembrolizumab because both treatments have been administered individually to subjects and combination therapy for the treatment of cancer is standard in the field.
Double Patenting
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.
U.S. Patent No. 10,201,607
Claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10,201,607. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent discloses the anti-AXL ADC of the instant invention formulated for pharmaceutical use.
Regarding instant claim 1, pertaining to the conjugate of cytotoxic agent and an antibody capable of binding human AXL of the instant invention, ‘607 discloses the identical anti-AXL ADC comprising the same VH and VL (‘607 claims 1 and 2), cleavable linker, and MMAE conjugate (‘607 claims 9 and 10). ‘607 claim 26 discloses a pharmaceutical composition which anticipates administration of the ADC to the subject.
Regarding instant claims 8, 9, 10, 20, 21, 30, 31, 33, 35, 36, 38, 39, 44, and 61, pertaining to the structure and characteristics of the anti-AXL ADC of the instant invention, the structure and characteristics are anticipated by the anti-AXL ADC of ‘607 claims 1-28.
Claims 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10,201,607 as applied to claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 above and further in view of Van Berkel (US2019/0218291A1, published 07/18/2019, effectively filed 04/20/2017).
‘607 discloses administration of the anti-AXL antibody drug conjugate of the instant invention.
‘607 does not teach (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor.
These deficiencies are taught by Van Berkel.
The disclosure of Van Berkel is directed to clinically advantageous combination therapies in which an anti-AXL ADC is administered in combination with at least one secondary agent. ([0014], Lines 1-6).
Regarding claims 2-3, 51-53, wherein the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1 (claims 2 and 3), wherein the inhibitor an inhibitor of the interaction between PD-1 and its ligand (claim 51), wherein the inhibitor is an antibody (claim 52), and wherein the inhibitor is pembrolizumab (claim 53), Van Berkel teaches the AXL ADC is co-administered with the PD-1 antagonist antibody pembrolizumab (Pg. 150, claims 28 and 29).
Regarding claims 80 and 81, wherein the cancer according to the method of claim 3 is a solid tumor (claim 80) and wherein the cancer is skin cancer (claim 81), Van Berkel discloses treatment of skin cancers which express PD-L1 ([0319], Lines 1-5).
Regarding claim 84, wherein the subject has received prior treatment with a PD-1 pathway inhibitor, Van Berkel specifically teaches the alleviation of resistance to PD-1 inhibitors with the use of PD-1 inhibitors in combination with the ADC ([0325], Lines 6-11) and teaches that study groups include a subset of patients previously treated with a secondary agent to explore whether combination therapy might overcome resistance to secondary agent therapy ([1082], Lines 1-4).
It would have been obvious to one having ordinary skill in the art to modify ‘607 with the teachings of Van Berkel wherein (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, and (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor. One would have been motivated to do so because Van Berkel teaches co-administration of anti-AXL antibody drug conjugate with anti-PD1 antagonist antibody such as pembrolizumab to overcome resistance to the PD-1 inhibition therapy. There would be an expectation of success in treating with a combination therapy of anti-AXL ADC and pembrolizumab because both treatments have been administered individually to subjects and combination therapy for the treatment of cancer is standard in the field.
U.S. Patent No. 10, 500,276
Claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 10,500,276. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent discloses the anti-AXL ADC of the instant invention formulated for pharmaceutical use.
Regarding instant claim 1, pertaining to the conjugate of cytotoxic agent and an antibody capable of binding human AXL of the instant invention, ‘276 discloses the identical anti-AXL ADC comprising the same VH and VL (‘276 claims 1 and 2), cleavable linker, and MMAE conjugate (‘276 claim 3). ‘276 claim 31 discloses a pharmaceutical composition which anticipates administration of the ADC to the subject.
Regarding instant claims 8, 9, 10, 20, 21, 30, 31, 33, 35, 36, 38, 39, 44, and 61, pertaining to the structure and characteristics of the anti-AXL ADC of the instant invention, the structure and characteristics are anticipated by the anti-AXL ADC of ‘276 claims 1-35.
Claims 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 10,500,276 as applied to claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 above and further in view of Van Berkel (US2019/0218291A1, published 07/18/2019, effectively filed 04/20/2017).
‘276 discloses administration of the anti-AXL antibody drug conjugate of the instant invention.
‘276 does not teach (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor.
These deficiencies are taught by Van Berkel.
The disclosure of Van Berkel is directed to clinically advantageous combination therapies in which an anti-AXL ADC is administered in combination with at least one secondary agent. ([0014], Lines 1-6).
Regarding claims 2-3, 51-53, wherein the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1 (claims 2 and 3), wherein the inhibitor an inhibitor of the interaction between PD-1 and its ligand (claim 51), wherein the inhibitor is an antibody (claim 52), and wherein the inhibitor is pembrolizumab (claim 53), Van Berkel teaches the AXL ADC is co-administered with the PD-1 antagonist antibody pembrolizumab (Pg. 150, claims 28 and 29).
Regarding claims 80 and 81, wherein the cancer according to the method of claim 3 is a solid tumor (claim 80) and wherein the cancer is skin cancer (claim 81), Van Berkel discloses treatment of skin cancers which express PD-L1 ([0319], Lines 1-5).
Regarding claim 84, wherein the subject has received prior treatment with a PD-1 pathway inhibitor, Van Berkel specifically teaches the alleviation of resistance to PD-1 inhibitors with the use of PD-1 inhibitors in combination with the ADC ([0325], Lines 6-11) and teaches that study groups include a subset of patients previously treated with a secondary agent to explore whether combination therapy might overcome resistance to secondary agent therapy ([1082], Lines 1-4).
It would have been obvious to one having ordinary skill in the art to modify ‘276 with the teachings of Van Berkel wherein (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, and (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor. One would have been motivated to do so because Van Berkel teaches co-administration of anti-AXL antibody drug conjugate with anti-PD1 antagonist antibody such as pembrolizumab to overcome resistance to the PD-1 inhibition therapy. There would be an expectation of success in treating with a combination therapy of anti-AXL ADC and pembrolizumab because both treatments have been administered individually to subjects and combination therapy for the treatment of cancer is standard in the field.
U.S. Patent No. 10,765,743
Claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46 of U.S. Patent No. 10,765,743. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent discloses the anti-AXL ADC of the instant invention formulated for pharmaceutical use.
Regarding instant claim 1, pertaining to a method of treating cancer comprising administering the conjugate of cytotoxic agent and an antibody capable of binding human AXL of the instant invention, ‘743 discloses administration of the identical anti-AXL ADC comprising the same VH and VL (‘743 claims 1 and 2), cleavable linker, and MMAE conjugate (‘743 claims 13-15).
Regarding instant claims 8, 9, 10, 20, 21, 30, 31, 33, 35, 36, 38, 39, 44, and 61, pertaining to the structure and characteristics of the anti-AXL ADC of the instant invention, the structure and characteristics are anticipated by the anti-AXL ADC of ‘743 claims 1-46.
Claims 1-4, 8-10, 15, 20-21, 30-31, 33-36, 38-39, 44, 51-53, 61, 80-81, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of U.S. Patent No. 10,765,743 as applied to claims 1, 4, 8-10, 15, 20-21, 30, 31, 33-36, 38-39, 44, and 61 above and further in view of Van Berkel (US2019/0218291A1, published 07/18/2019, effectively filed 04/20/2017).
‘743 discloses administration of the anti-AXL antibody drug conjugate of the instant invention.
‘743 does not teach (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor.
These deficiencies are taught by Van Berkel.
The disclosure of Van Berkel is directed to clinically advantageous combination therapies in which an anti-AXL ADC is administered in combination with at least one secondary agent. ([0014], Lines 1-6).
Regarding claims 2-3, 51-53, wherein the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1 (claims 2 and 3), wherein the inhibitor an inhibitor of the interaction between PD-1 and its ligand (claim 51), wherein the inhibitor is an antibody (claim 52), and wherein the inhibitor is pembrolizumab (claim 53), Van Berkel teaches the AXL ADC is co-administered with the PD-1 antagonist antibody pembrolizumab (Pg. 150, claims 28 and 29).
Regarding claims 80 and 81, wherein the cancer according to the method of claim 3 is a solid tumor (claim 80) and wherein the cancer is skin cancer (claim 81), Van Berkel discloses treatment of skin cancers which express PD-L1 ([0319], Lines 1-5).
Regarding claim 84, wherein the subject has received prior treatment with a PD-1 pathway inhibitor, Van Berkel specifically teaches the alleviation of resistance to PD-1 inhibitors with the use of PD-1 inhibitors in combination with the ADC ([0325], Lines 6-11) and teaches that study groups include a subset of patients previously treated with a secondary agent to explore whether combination therapy might overcome resistance to secondary agent therapy ([1082], Lines 1-4).
It would have been obvious to one having ordinary skill in the art to modify ‘743 with the teachings of Van Berkel wherein (1) the conjugate is used in combination with an inhibitor of PD-1 and/or PD-L1, (2) the inhibitor is pembrolizumab, and (3) the cancer treated is skin cancer, and (4) the subject has received prior treatment with a PD-1 pathway inhibitor. One would have been motivated to do so because Van Berkel teaches co-administration of anti-AXL antibody drug conjugate with anti-PD1 antagonist antibody such as pembrolizumab to overcome resistance to the PD-1 inhibition therapy. There would be an expectation of success in treating with a combination therapy of anti-AXL ADC and pembrolizumab because both treatments have been administered individually to subjects and combination therapy for the treatment of cancer is standard in the field.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671